Flu Do You Think You Are?

25 September 2018
Presented by Chris Smith, Georgia Mills.

In 1918, Spanish flu wiped out more people than World War 1. Now, a century on, we're asking why this pandemic packed such a punch, where flu came from in the first place, and how flu vaccines are made. Plus, fossilised fats from the world's first animals, a look at the IgNobel prizes, genes linked to hypertension, and the computer game that gets kids into engineering...

In this episode

Fossil of Dinckinsonia

00:56 - Fossil fats reveals the world's oldest animals

The mysterious fossils called Dickinsonia may have been revealed to be our early ancestors...

Fossil fats reveals the world's oldest animals
with Jochen Brocks, Australian National University

The Earth’s about 4 and a half billion years old. And we’ve got evidence that life started here pretty rapidly - it was up and running within 500 million years. But then, things stayed very small and very simple for the next few billion years - it was just microbes. Then something special happened because, about 600 million years ago, large, complex multicellular life as we know it suddenly appears in the fossil record.  But the question is: are these fossils the remains of animals, plants or some other bizarre evolutionary offshoot? No one could tell from their appearance alone. But now scientists in Australia have nailed it by achieving the incredible feat of extracting from one of these ancient fossil species called Dickinsonia the fats and cholesterols that would have been in the tissue when it was alive. So is it an animal, a vegetable, or a mineral. Chris Smith heard from Jochen Brocks...

Jochen - Dickinsonia is an oval shaped creature that was lying flat on the seafloor in relatively shallow water. It looks a little bit like a big coffee bean with lots of ribs and the smallest we analyse about 1 centimetre; the biggests 6 centimetres, but there were some true giants that came up to 1 metre 40. It is a 558 million year old creature, and the fat tells us it was the earliest animals in the record.

Chris - And they’re important, of course, because if these are big animals then they are some of the earliest big animals and effectively they’re what gave rise to the life that turned into us?

Jochen - I think those fossils are the most important fossils in the entire geological record. If you have a time machine and you go back to 580 million years ago - go scuba diving - you would need a microscope to see anything at all. Life was microscopic. And about 570 million years ago, those Ediacaran creatures appeared and they became enormous quite quickly - up to 2 metres. That’s when life became big and that’s why it’s important to know what these creatures actually were.

Chris - How did you actually decide to pursue this in terms of looking at the fats and how did you get at the fats? It’s extraordinary to think there are fats there which are more than half a billion years old.

Jochen - The idea for this project, in fact, comes from a PhD student Ilya Bobrovsky. He contacted me from Russia; he’s a Russian student, in 2013 and said “well, Jochen, I’ve found these Ediacaran fossils and they are almost mummified. They are preserved organically. I want to extract fat molecules from them and that should tell me if this creatures were or were not our earliest animals”. And I thought it was the most stupid idea I’ve ever heard. I thought it was totally crazy. But he was a very very smart student so I thought well, he should try it for himself. So I hired him as a PhD student; he extracted these things and it simply worked. It was completely stunning.

Chris - How do you get the fats out of the fossils?

Jochen - You can’t try this at home. It’s a) very dangerous and b) difficult. What Ilya does is first he drips hydrofluoric and hydrochloric acid on them so that the organic matter is lifted up from the rock underneath and then we analyse the molecules using chemical techniques.

Chris - And those fats have definitely come from the fossil? They’re the vestige of the fossil when it was in life?

Jochen - That’s right. So you could think ah, I know, if we actually touch these fossils with our fingers we would introduce cholesterol, which is the hallmark of animals. And immediately “oh look, we found an animal” but actually it’s our own fingerprints. But we went into extraordinary lengths to exclude continents and look at exactly where these molecules came from.

Modern cholesterol from us humans is a modern living molecule, but what we found is actually a fossil molecule that has changed its structure. Where we can estimate approximately how old it is and the structure of the molecule fitted perfectly the age and the maturity of the rock we found it in.

Chris - So you’re saying because we can see this slightly different form of cholesterol that is the signature of complex animal life and it’s in the context of this fossil, we think it’s come from the fossil? But could there not be, for instance, microorganisms living on the fossil that themselves made this funny form of cholesterol or other organisms that have come along since and lived around the fossil and they put the cholesterol there and you’re saying well, it’s from the fossil but it’s not it’s from something else?

Jochen - Alright. That’s a very very good question. What we found is a little bit more. We can imagine a slab of rock in the middle of this beautiful fossil. Surrounding the fossil is a fossilised microbial mats because Dickinsonia was living on the seafloor, living on these microbial mats that are full of sand, bacteria and algae, and these mats were also fossilised around the Dickinsonia.

So what we did is we analysed the molecules in Dickinsonia, but also the molecules from the mats surrounding Dickinsonia, then we compared the two. There was a huge difference. Dickinsonia was full of fossil cholesterol, which is typical for animals. And the surround was typical of a different type of molecule which is produced by green algae.

Chris - Now you have got this, you can say at this moment in time we’ve got what looks like this animal. It’s not a plant, it’s not a fungus, it’s not some of these other possibilities. How does that change our view of what was going on almost 600 million years ago and, ultimately, how that line led to us?

Jochen - It really changes the story of how we perceive our earliest animal ancestors when and how they evolved. Now that we know that Dickinsonia actually was an animal, and probably many of those Ediacarans were animals, we know that there was already an enormous animal ecosystem between 570 and 540 million years ago. But they were very peaceful animals. They were mostly vegetarians. None of these fossils have bite marks or predation marks.

And then about 540 million years ago those creatures died out and modern type animals appeared. It’s actually quite possible that the modern type animals drove those Ediacarans to extinction by simply eating them.

Cannibal potatoes

07:18 - IgNobel Prize: Calorific cannibals

This year's Ignobel winner discusses his work about human cannibalism...

IgNobel Prize: Calorific cannibals
with James Cole, University of Brighton

The Nobel prizes show off the best of human scientific achievement, but have you heard of the IgNobel prizes? Adam Murphy spoke to one of this year’s winners to learn about honouring the lighter side of science…

Adam - Every year the Nobel Prize is awarded to the most humanity advancing breakthroughs - the pinnacle of achievement. But they’re not what’s really important - the IgNobel Prizes are awarded to science that makes you laugh, before it makes you think.

Prizes this year were taken home for “analyzing the potential of saliva as a cleaning fluid”, and for “the effectiveness of employees using voodoo dolls against their bosses”. But what else wins that kind of prize. I got to speak to one of this year’s winners, James Cole of the University of Brighton about the work that earned him such a prestigious honour…

James - I was looking at trying to estimate the calorific value of the human body but in the context of looking a paleolithic sites and human evolution.

Adam - That is to say did ancient humans eat people? Is that nutritionally useful or does it cost you an arm and a leg?

James - We know from the archeological records that human cannibalism seems to be at least a persistent behaviour through our evolutionary journey, and one of the oldest sites that we have goes back almost a million years. Now we have a relatively small fossil record, and even within that small fossil record we still see signs on bones like cut marks, long bone breakage, even teeth marks that demonstrate that this cannibalism behaviour was present.

What is unclear though is exactly why this behaviour was done. If you compare the calories that you get from a human body, which is what my study was trying to work out, to animals we know were successfully hunted by our ancestors like the neanderthals. So this is things like horse, or bison, or mammoth even. It would seem that we actually aren’t terribly calorie rich in comparison to those big animals. The amount of calories you would get from a human being seems to fall kind of where you would expect for an animal of our size, but we are just much smaller than a horse or a cow or obviously a mammoth.

Adam - How did you work out the calorific content of a human being?

James - Yes, so no humans were harmed during the course of the study. But effectively what I did is I looked at some studies that were done in the 40s and the 50s that looked at the chemical composition of the human body. And they broke down various body parts into its various chemical components, and part of that were protein and fat values. If you have protein and fat values along with body weight, you can work out calories.

Adam - With your IgNobel Prize, how did that come about? How did you find out you had won that?

James - It was really quite a wonderful process really. In April I got a very mysterious email - friends in Boston are interested in talking to you, and this is what Mark Abrams really does who’s the IgNobel person in charge. They send out offers of invitation to accept the award in case anybody decides it’s not something that they would quite like. And thankfully, as he says in his welcome speeches and things, pretty much everybody always accepts, but there is always a chance to turn it down.

Personally, I was extremely honoured and very pleased to have been offered the award because the IgNobels stand for scientific studies that, I think in their catchphrase, make you laugh and then make you think. And whilst I wasn’t necessarily out to make people laugh with my study I was definitely out to make them think.

So I was really pleased that I had been recognised on that. Cannibalism is always going to be a controversial subject and a subject of interest, and slightly left field, so it was great that that was recognised in that way.

Adam - And this work is no exception, there’s some real ‘meat’ to this story too…

James - The more that we can understand our ancestors and even our own species in deep time, the more that we can really understand who we are today and how we got here. And that understanding can only lead to a better future and, hopefully, a more inclusive one that takes into account the full complexity and range of who we are.

Adam - But are the IgNobels just a silly joke or is there value to them?

James - The IgNobels, I mean they have a huge audience. I think from last year’s ceremony almost a hundred thousand people watched that live stream. So the IgNobels have this huge reach and that can only be good for science because science is not just about standing in a lab coat looking down a microscope thinking really deeply about something. Science is inquisitive; it can be fun and the IgNobels really capture the essence of that in the fun and quirky way that they present them. It’s science that makes you laugh and then think!

Blood pressure check

12:30 - Over 500 genes linked with high blood pressure

The results of a study that reports are dubbing “one of the biggest breakthroughs yet in blood pressure genetics” have just been released.

Over 500 genes linked with high blood pressure
with Mark Caulfield, Queen Mary University of London

The results of a study that reports are dubbing “one of the biggest breakthroughs yet in blood pressure genetics” have just been released. Scientists at Queen Mary University of London have looked at the genetic signatures of more than a million people and married their genes with their lifestyle factors and their blood pressures. The result is the identification of hundreds of new genes linked to high blood pressure which should highlight new ways to predict who’s at risk, reveal new drug treatments and even flag up some simple home remedies that are surprisingly effective. Chris Smith spoke to Mark Caulfield, who led the study…

Mark - We studied over one million people, most of whom are of white European ancestry. The main component of the study was The United Kingdom Biobank, which is the jewel in Britain’s crown in terms of understanding the genetic basis of disease - that’s half a million people. Then we combined it with other studies from across the world and that allowed us to reach the number of one million. And it is the size of the study and the precision of the analysis that’s allowed us to find these loci for blood pressure.

Chris - And when you look at these genetic regions that seem to be important for blood pressure, what emerges and why does this matter? How does this affect our ability to diagnose, manage, and better manage high blood pressure?

Mark - Actually measuring the blood pressure this way would not be efficient. But what this does do, is it gives us new biological insights into why some people’s blood pressure is higher than others. The other correlations we found in the project were with certain treatments so, for example, we found evidence that a fairly new diabetic treatment, which is very effective at lowering blood sugar that has also been shown to reduce adverse heart disease and stroke. The target for that drug is a gene for blood pressure. Could we take that medicine and use it more often in people with high blood pressure and diabetes so effectively treating two things at once? So this is about understanding how we can get new insights into the biology that will allow us to develop new therapies or approaches that will improve the care of people across the world with this burgeoning epidemic of high blood pressure.

Chris - But will it actually achieve that lofty goal though, Mark? Because I put it to you, we’ve known about some of the genes that lead to obesity and overweight for a long time but we’ve got record numbers of people on Earth with problems related to carrying too much weight. So at what point are we going to see this magic sort of translation of the genetic information that you’re flushing out with amazing studies like this one into a pill that I can take that means I’m not going to have the same heart attack and stroke risk?

Mark - I can give you some examples. In our own work at my institution we’ve been working on a pathway that we discovered a few years ago and that involves a chemical in our body call nitric oxide. When you drink beetroot juice, just 250 mls of beetroot juice, which contains very rich concentrations of a chemical called nitrate which is converted in our bodies to this nitric oxide and opens up blood vessels and lowers blood pressure.

We’ve shown now in convincing studies in people with high blood pressure that this can be taken as effectively, a form of lifestyle treatment. So you can go into supermarkets as a result of this research and buy that for yourself. Why this is popular with patients is that patients do like the idea of a lifestyle modification as opposed to just a pure chemical tablet.

The other areas where this has been particularly helpful is observations made in high cholesterol which can run in families have allowed us to invent an injection that you can give once every couple of weeks, or once a month, and it profoundly lowers cholesterol. So it’s not simply about discovering new things that don’t translate into the clinic.

Chris - So if I take the average person in the population with high blood pressure, what fraction of people can I explain their high blood pressure, on the basis of the genes that your study, and the ones we already knew about, tell us?

Mark - An important feature of this study, which makes this an incredibly good question, we estimate from this study that we’ve explained 27 percent, now, with all of the known findings, and the new ones we report here of the influences on blood pressure.

Chris - That said though, Mark, that still leaves two thirds of the field open, doesn’t it, unaccounted for? Where is that two thirds to three quarters of the cause of blood pressure then if you can only account with a huge study like this for 27 percent of it?

Mark - I think probably the best way to describe this is, there may be many routes for people’s blood pressure to be elevated. That means that the studies being done to date, mostly we’ve measured the common molecular signatures and not the rare ones. Now with whole genome sequencing and other technologies we’re able to read the entire genetic code of a human and therefore we get the entire blueprint for life, and then we can measure the rare variations that could be contributing significantly. So I believe we will gain access within the next few years to the remaining missing heritability for blood pressure.

Screenshot from WIRED

17:43 - Wired: Getting kids switched on to electricity

Can a videogame help teach people about electricity?

Wired: Getting kids switched on to electricity
with Diarmid Campbell and Richard Prager, University of Cambridge

Engineers at Cambridge University have launched a professional computer game to enable players to learn how electricity works. It’s called WIRED, and software engineer Diarmid Campbell and engineer and technologist Richard Prager are the creators. Chris Smith asked them how the game works...

Diarmid - It’s a video game and you control a character who has to get to the top of a building, and she goes into various rooms. And when you go into a room you’ll find that there’ll be mechanical doors and platforms that can rise up, and fuel cells and switches, but initially, nothing moves because nothing’s wired up. So what the player has to do is first wire up all the components in the room and then they can run through it pulling the switches, jumping on the platforms and get out of the room.

Chris - And the story is basically get through each room to escape from this building?

Diarmid - Well okay, yes. So that’s the puzzles. There’s a story that runs through it because the player encounters these sort of old cine projector screens at various points where there’s this slightly eccentric professor who explains about some of the electrical concepts.

Chris - So not like real life then? And that imparts some of the learning as well so you’re doing some of the teaching through there?

Diarmid - That imparts some of the learning, absolutely. But you also then get to find out who that professor is; what his relationship is to the player character and the story evolves through that. I’d like to think of it as perhaps a cross between the old sort of Roald Dahl's Tales of the Unexpected perhaps mixed with an Open University style lecture.

Chris - Well Richard, you’re the very non-eccentric professor who’s part of the project. What was your motivation for actually doing this in the first place? Why did you turn the Department of Engineering effectively into a software house? Why have you gone down this route?

Richard - Well, we had this opportunity through an educational project funded by The Underwood Trust to do something a bit outlandish and to try and go in an educational direction that hadn’t been done before, even if it was rather high risk. And we thought wouldn’t it be amazing if we could create a normal video game, which was attractive as a video game, but had inside it the idea of the fun of engineering problem solving in a genuine natural way so that we would lure teenagers into solving engineering problems without them realising.

Chris - So it’s science by surversion if you like?

Richard - Yeah, exactly.

Chris - But it is actually good as a game in its own right isn’t it, Diarmid? Is that your motivation because I’ve played it and it’s pretty addictive.

Diarmid - Yes. A lot of educational games tend to be delivered through the classroom so they only ever end up having to be more fun than the lesson they’re replacing. And the whole idea with WIRED was saying let’s show that engineering is genuinely fun so let’s deliver it through gaming websites instead of the classroom so that people can choose to play it, so it needs to be at least as fun as other games that people choose to play. All the way through from the beginning it’s been designed with fun as being its primary driving force.

Chris - Well, I asked a young person to have a go of it? Would you like to hear? I’ve recorded having a go…

Diarmid - Yeah, I would.

Amelia - Hello. My name’s Amelia and I’m 12, and I’ve just been playing this really fun game called WIRED. You have to wire up circuits which make doors and platforms move so you can get around a school. I learned what a short circuit is. That you have to wire up machines correctly, you have to have a power supply to the machine and also you can’t have too many machines connected to a power supply, and the more machines you have connected to a power supply the machines will go slower.

This is a good game because I’m learning something and it’s definitely fun to do when you’re bored in the holidays.

Chris - Quite an endorsement that. Why did you go down the electricity route though, Richard? Why choose that subject?

Richard - I think it came from interviewing students for admission over many many years where I was surprised by how many people didn’t really understand the concepts behind voltage and current. Perhaps because you have to get both of them at the same time. You have to get voltage in order to get current. You have to get current in order to get voltage. And I thought this is maybe something that if we could get people to feel it, to experience it, to actually interact with it rather than just see it as a load of equations on paper it might help.

Chris - Diarmid, how have people received this? Obviously my n of 1 study there seemed to receive an enthusiastic appraisal, but what about the wider community? What sort of feedback are you getting? And also, one criticism leveled at projects like this is it’s one thing to do some public outreach and engagement, but it’s another to actually change people’s mindsets. Have you got sort of evidence that this is doing what Richard’s saying it aspires to do, which is to educate people more about the science of electricity?

Diarmid - The game has only been out for a few weeks, so all we’ve got so far is I guess feedback on the gaming websites where it’s been up and we’ve had lots of really positive messages up there. People just saying it’s very fun and I’ve learnt a lot. And I guess what’s gratifying is that because it’s up on a gaming website people are comparing it to other games and saying it’s a good game, it’s fun. But it’s not divorced from the education, they’re saying it’s fun that I learnt stuff as well. So the informal feedback has been very positive but I think it’s too early to say yet. We haven’t done formal studies about its educational effectiveness.

Five women battling spanish flu

24:13 - The worst flu pandemic in history

The Spanish Flu pandemic of 1918 was one of the deadliest disease outbreaks in human history

The worst flu pandemic in history
with Sean Lang, Anglia Ruskin University

The Spanish Flu pandemic of 1918 was one of the deadliest disease outbreaks in human history; in recognition of its Centenary and as the northern hemisphere heads into this year’s new flu season, we’re putting the influenza virus under the microscope. The 1918 pandemic coincided with the end of World War 1, which is thought to have catalysed the pace with which the disease took hold. To guide us through what happened that year Georgia Mills was joined by Anglia Ruskin University historian Sean Lang. But why was it called Spanish flu?

Sean - It’s terribly unfair because it didn’t start in Spain at all; in fact, Spain was no more affected than anywhere else. But because the war was on when it started, for example, among American troops and when it’s underway in Germany of course, they didn’t want the other side to know of a weakness so they didn’t report it. Spain was neutral in the war so there was no particular reason to hold back, and so the first major reports came out of Spain and everyone assumed it started there, which it didn’t.

Georgia - So they were being honest and got all of the blame?

Sean - Absolutely! They did try to blame it on the Portuguese incidentally, but that didn’t stick.

Georgia - How many people did it affect? How far around the world did it spread?

Sean - It spread absolutely all round the world; every continent. There were major outbreaks, for example, in Western Samoa where the population was absolutely decimated. Alaska, North America, all across Europe. Asia were very very badly affected.

In terms of the number of people who died, there’s a lot of argument about the figures because it’s not easy to get accurate death figures because not everyone kept them. Nevertheless, we reckon it’s about 50 million upwards. The highest estimates were about 100 million - probably 50 to 70 million something like that. Now to put that into context the total number of deaths in the First World War is about 17 million. And, of course, these 50 plus million who die all within the space of a year. In other words, it’s very concentrated compared with the First World War which, of course, is spread over 1914 to 1918. So it’s absolutely devastating and there’s no part of the world really which is immune.

Georgia - So people have just sort of made it through one of the biggest wars in the history of the world and then this hits us?

Sean - Absolutely, yes! You’ve got a lot of the soldiers coming home at the end of the war in November 1918 or thereafter. And so you get people who’ve come home, as you say who survived the war and expecting now to enjoy peace, and of course their families are expecting to have them home after the war, and then the death comes, so it’s absolutely tragic. Of course you do have plenty of people who catch it and survive but, of course, they’re debilitated as well. So it is an absolutely global tragedy - no question.

Georgia - And it’s been mentioned, as pandemics go, is the sort of big hitter, was this linked with the war?

Sean - Yes and no. Clearly there are areas like, for example, the Midwest of America or indeed China where you can’t really blame the effect of war. For example, you haven’t got population weakened by naval blockade or you haven’t got the direct influence of the war. On the other hand, where you do have that, where you have the population in Germany, for example, which is very badly hit and you’ve got a population which is very very badly weakened because of the naval blockade which cut off food supplies, then it clearly seems to have lowered people’s natural resistance to it. So yes, it’s linked with the war but it doesn’t seem to have been caused by the war.

Georgia - Who was affected the worst by the flu?

Sean - Ah, now this caught people out because the medical authorities tend to assume that the obvious candidates would be children or old people. So quite often, for example in Cambridge you have schools shut down or children excluded from places of public entertainment. But actually, and this really caught them out, it was young people apparently in the prime of health who were the most vulnerable, so young men, young, women in their 20s. So it really did catch them out and of course, it meant that the measures they were taking weren't very effective because they were aimed at the wrong people. So yeah, I’m afraid it’s sort of healthy young men and women in their 20s.

Georgia - Uh oh.

Sean - I don’t want to worry you.

Georgia - I’m a little bit worried. Was there any treatment or medicine around at the time?

Sean - Well, because they didn’t really know what was causing it there’s no sort of one effective measure that is taken. There was a sort of vaccination that was used, or at least it was a preparation, and it does seem to have had some success against the cases that were linked with pneumonia, but it didn’t actually affect against the flu. But they tried everything: in Cambridge there was a wonderful thing - I can’t remember the doctor’s name, but his ‘pink pills.’ Take pink pills and you’ll be fine.

A lot of the advice was simply go to bed; quarantine or keep away from other people; keep away from crowded areas; keep the windows open, and my favourite one which I discovered advertised was Bovril. And Bovril actually advertised itself as rendering you influenza proof.

Georgia - How did they get that idea? do we know? Was it just...

Sean - Very good marketing? I suppose it’s the idea that because people tend to think of flu as being like a bad cold. Very often people have got a bad cold and they say they’ve got the flu, which they haven’t. But they got that sort of link in people’s minds. So the idea is that you go to bed with a nice hot drink - it’ll see you through, so I think that’s what’s really going on there.

Flu virus

30:00 - What is Flu?

How does the flu virus make us ill?

What is Flu?
with Wendy Barclay, Imperial College London

What actually is the flu and where did it come from? Chris Smith spoke to Wendy Barclay who is a virologist at Imperial College London…

Wendy - Flu is a disease caused by a virus - the influenza virus. That virus gets into our bodies when we breathe in droplets from somebody else who’s been infected by the virus. And then those droplets containing the virus go down into our nose and throat and then into our deeper lungs perhaps, and like all viruses it’s an absolute parasite so it actually has to get inside our cells. And once the virus is inside our cells it takes over the cells, reproduces itself, kills the cell and then thousands of new viruses, copies of the original come out and spread.

Chris - And how does it actually make us ill? Why do we feel so ghastly when we’ve got it?

Wendy - I think there are two ways. Some of the first symptoms are sore throat. That could well be just because the virus, in replicating in those first few cells in your throat, have killed that important protective barrier which normally protects from incoming dust particles etc. And if you haven’t got those working then all those dust particles which are in the air can really hurt as they land on the nerves below.

But the other reason that you feel so really bad with flu is that your own immune system recognises that these cells have been invaded by a virus and responds by releasing chemical messengers. And they also, at the same time as telling the cells where to come, induce fever and aches and pains, lethargy, feeling hot, because your blood is now full of all these chemicals which have been released from the infected cells and are trying to signal to other immune cells to come and help.

Chris - Now, where did flu come from in the first place?

Wendy - All flu viruses are not human at all, they are bird viruses. There are lots and lots of different types of flu, which means that antibodies against one wouldn’t protect you against another. And they’re all out there, at least 16 of them, sitting in the wild birds  of the world - ducks and geese and also seabirds that migrate through very large distances, but also live in huge colonies. A fantastic place for a virus to hang out because there’s always new hosts for it to infect. It actually is a virus that infects the intestines of those birds and it comes out into the water, the birds all land on the lakes, and the water and the lakes is full of flu viruses that the birds can drink and take up and get re-infected.

Chris - So how did it get from being a bird virus to being a human virus, and when did that happen do you think?

Wendy - We know from historical records that pandemics, probably of flu virus, happened thousands of years ago, probably when humans started living in larger numbers in cities.

How does a virus transform from being a bird flu into a human flu is a matter of intense research, because it will help us ultimately predict the chances of pandemics happening, and it’s certainly not a single step. There are at least three changes and probably more that a bird virus would need to make to be a successful human virus. And it’s a bit like rolling a dice, if you want to get three sixes all at once, that’s not the most likely and therefore we don’t get pandemics all that often, but out there in nature that dice is being rolled all the time.

Chris - Is it fair to summarise then and say we’ve got this flu virus. It started off in birds; at some point it jumped into humans and we ended up with human forms of flu, which we keep on handing on to each other, year on year, but there remains this enormous reservoir of bird viruses that periodically can do that jump again, and when they do that jump again then we get a new kind of flu in humans?

Wendy - Yeah, that’s absolutely it. Certainly what we know is that in 1918 a virus came across that had recent ancestry in birds, became a human virus, and then stayed in humans for the next three or four decades.

Chris - Do we know what factors probably encouraged that jump in 1918 to make that virus seed into humans and produce that devastating pandemic?

Wendy - We don’t know for sure whether or not the circumstances that were present in 1918 were the perfect storm, if you like, for that virus, to make that jump. Certainly there are theories that when so many young men were moved into these huge army camps and lived in very close quarters, the chances of a virus accumulating the right numbers of mutations and then spreading onwards to others were increased. So there is some theory that that special circumstance would have allowed the virus to emerge in that way.

Chris - A number of people have looked at a cross section of the population who succumbed to the 1918 flu and it looked a bit unusual because in most winters you get lots of young people and lots of elderly vulnerable people who will succumb to flu, but with this we saw lots of previously hale and hearty young people dying of this. Why would there be that difference?

Wendy - Yeah, it’s a really excellent question. I think there are two main theories. The first is the cytokine storm theory. So that says that much of the symptoms of flu in a human is down to the person’s own immune system, as we’ve discussed, of sending out those chemical signals and responding to the viral infection. And in 1918 flu infections, those responses may well have been inappropriately big. If that’s the case, the people who are the healthiest and would make the biggest immune response are the people who would get very sick. So 25 to 45 year olds with their healthy immune system, kind of overreacted and consequently ended up that the lungs were full of inflammatory cells.

The other theory relies very much on this idea which is quite popular at the moment, of the flu that you experience in your very early life kind of sets the scene for the rest of your life and affects the way you respond to subsequent flus. So if we historically trace back to when previous pandemics were recorded in the world. Certainly in 1889 we think there was a previous flu pandemic and that may have somehow set the scene for people to respond differently to the next pandemic virus that came along.

Box of tissues

38:22 - How are flu vaccines made?

And when were the first flu vaccines available in history?

How are flu vaccines made?
with Othmar Engelhardt, National Institute for Biological Standards and Control

One powerful way we can defend ourselves against infections is through the use of vaccines; these educate your immune system so it can recognise an infection in future. They contain inactive components made from viruses, or bacteria, which stimulate the production of immune molecules called antibodies. This means that, if the infection is encountered for real later, these stick to the incoming disease agents and smother them, blocking the infection. But how are flu vaccines made? Izzie Clarke visited Othmar Engelhardt at the National Institute for Biological Standards and Control; they’re responsible for checking the quality and safety of UK medicines and treatments. Afterwards, it was back to historian Sean Lang who then explored other pandemics in the past 100 years. 

Othmar - Flu is a very special case because flu viruses change constantly. So if you’ve given a vaccine in a particular year you induce an immune response, you induce antibodies against the viruses of that year. But the virus evolves, changes and tries actually to escape the immune response in the population so one or two years later the virus will look different. It will have, if you want, a different coat with slightly different maybe patterns on its coat and, therefore, the antibodies are not so good at recognising it any more and you need to induce new antibodies and that’s why you give a new vaccine every year to keep up with the changes in the virus.

Izzie - And that’s the pesky thing about the flu virus. You can get vaccinated against flu but it can change and evolve or, as Othmar explains, disguise itself. And so our immune system doesn’t always react and attack it, which is why vaccines are so important. But how do we make them? It was off to the lab...

Othmar - We are in a room where we have incubators and fridges to keep chicken eggs.

Izzie - Chicken eggs; what have they got to do with the flu?

Othmar - Some viruses, and influenza virus in particular, grow very well in embryonated chicken eggs, and it’s technology for influenza that was developed in the 40s.

Izzie - Can we see any of these eggs?

Othmar - You can. We have an incubator here with uninfected eggs.

Izzie - Oh, wow! Oh, it’s quite warm in there as well actually.

Othmar - It is very warm. The eggs like to be warm. They are slightly different from eggs that you buy in your supermarket. We shine a strong light through the egg and then you can see the interior.

Izzie - The box that you’re using to shine this light literally just looks a bit like an old cinema projector. I feel like we’re going to get the slides out or something.

Othmar - Yes, it is a very simple equipment and you put the egg in front of it and, all of a sudden, you see the interior.

Izzie - Oh my goodness. That’s amazing!

Othmar - You can see the embryo, you can see blood vessels.

Izzie - The egg basically lights up to a sort of orangey red colour, and we can see all of these small blood vessels going through it.

Othmar - Yeah.

Izzie - Okay. So how do we take an egg and then actually get a flu vaccine by the end of it?

Othmar - Okay. You need a flu virus to start with. So you take viruses from patients which you analyse year round and you pick the ones that are most appropriate to be in the vaccine, and then we use a syringe to inject the virus. These viruses often don’t grow well in eggs so you need to change them, you need to manipulate them so that they grow better. And there are a few labs in the world, and one of them is our lab that does this process to change the viruses so that they can grow well in eggs.

Izzie - Okay. So we inject this virus into an egg and then what happens?

Othmar - Okay. The virus has grown in the egg so you have live virus in the main fluid in the egg. You can harvest this fluid from the egg, which is not yet suitable for a vaccine so you need to do further processing steps. You want to get rid of some of the egg components but you also want to concentrate the virus so that you have a higher amount of inactivated virus there to induce an immune response. And in many cases there’s further purification involved to enrich the components that you actually want in the vaccine. The coats of the virus that induce the relevant antibodies.

Izzie - How much of this vaccine could you get say from one egg?

Othmar - Not very much. Probably one or two doses depending on the yield.

Izzie - Oh wow! So we're going to need a lot of eggs to vaccinate the whole of the UK?

Othmar - Yes, millions.

Izzie - This is the most reliable way but what are some of the weaknesses to this method?

Othmar - One is dependence on eggs. If the chicken flocks were wiped out by a chicken disease there wouldn’t be a substrate to make vaccines so that would be a problem.

Izzie - And using eggs, is this the only way we can produce vaccines?

Othmar - No it isn’t. There are other methods. In recent years manufacturers started to use cell or tissue culture to make vaccines so they’re using cells, infect them with virus, harvest the virus again, and then the process is very similar to the egg based process.

Izzie - And it was off to a lab to explore this alternative method - cell culture…

Othmar led me to a corner of the room that had three incubators. They actually look like high tech mini fridges but they’d be the worst fridges ever considering they’re kept at 37 degrees celsius. And then he pulled out a rather surprising plastic container…

Othmar - In there are the plastic flasks with the cells inside.

Izzie - I wasn’t expecting it to look a bit like a clear hip flask. So we’ve got this plastic container with this orangey-looking liquid through it. What is actually in here?

Othmar - On one of the larger surfaces of this flask, the cells are attached to the surface, and then we have a liquid, a medium, which keeps the cells happy - gives them nutrients. We can take off the liquid on top, wash the cells, and then take virus in a small volume, put it on, add some more medium, and the virus will infect the cells in the flask and we put them back into the incubator. And two or three days later the viruses will have destroyed the cells and will be found in the liquid where we can harvest the liquid and then do with the virus what we need to do.

Izzie - Now that seems a more straightforward method than say all of the eggs?

Othmar - It is a more modern way and some other vaccines are made in cell culture, other than influenza virus. I’m sure this will be a method that increases in use, whether it will be the main method we’ll have to see.

Izzie - So whether our vaccines are using fertilized egg or whether it’s cell culture, who exactly needs these vaccines? Should we all be getting them?

Othmar - Many people need the influenza vaccine. Different countries have different vaccine recommendations. In the UK, it is recommended that the elderly get the influenza vaccine every year. It’s also recommended that ‘at risk’ groups of younger age so certain conditions; heart conditions, lung conditions, diabetes get the vaccine every year to protect them from influenza where in these people it can create a more serious disease, and also children. There is now a programme in the UK of vaccination for children that is expanding and lots of children are getting the vaccine.

Chris - That was amazing stuff. That was Othmar Engelhardt and he was speaking with Izzie Clarke

Georgia - Sean, are pandemics like this something we have to deal with often? Can you tell us about some of the other big pandemics that have hit since 1918?

Sean - Well luckily not too often. We haven’t had anything quite on the scale of the Spanish flu outbreak but, of course, there have been major outbreaks. In the Second World War, in the conditions of the war, you have things like the outbreak of typhus in camps and that sort of thing.

But more recently, the biggest one of course was AIDS in the 1980s, or starting in the 1980s. And then, of course, we’ve had the bird flu outbreak and more recently, I suppose, Ebola. So the age of the pandemic not only hasn’t passed but the judgement is that it’s highly likely, not say inevitable, they’ll be another major flu outbreak for which I hope from the sound of what we’ve been hearing we’re better prepared than we were in 1918, but you can never be complacent.

Georgia - Right, yeah. That’s quite scary because you think these are things from the past, but a lot of the pandemics you just mentioned are in very recent years?

Sean - Oh absolutely, yeah. Yes, it’s not just going back into long ago. And, of course, it is always changing and there are different variants of flu. And we tend to put a lot of faith of course that we just think science will solve it but the diseases or viruses respond to it and so new strains come in. And above all, I would say you’ve got to have international cooperation and the more that becomes under strain the harder it will be.

Vaccine injection

46:55 - Fighting back against flu

Why do we have a different flu vaccine every year?

Fighting back against flu
with Derek Smith, Cambridge University

Every year, human strains of the flu circulate around the world. And as they go they subtly change their appearance. This means we need to update the vaccines we make so the immune system can still recognise them. So how do scientists know when and what to put into these vaccines? Chris Smith spoke with Derek Smith who advises the World Health Organisation on this topic; he’s based in the Zoology Department at the University of Cambridge...

Derek - It’s really remarkable global effort orchestrated by the World Health Organisation to do this. There are thousands of people around the world, in GP offices and in hospitals who see people who come in with respiratory diseases that look like they could be flu, take a throat swab and that swab is sent to the National Influenza Centre in that country.

The strains then are analysed to see if they really are flu. And if they are, they’re sent to one of five international WHO collaborating centres; Tokyo, one in Melbourne Australia, Beijing China, Atlanta in the US, and in the UK in London at the Crick Institute. There the strains are analysed in great detail in terms of how they differ from other viruses and how our immune systems will see them different.

Chris - When you say you’re analysing them, what are you looking for? How do you tell one strain of flu apart from another?

Derek - This is the key question. First of all it is laboratory work to test whether or not strains of flu that are already in the vaccine will be protective against the new strains of flu that may be emerging across the world.

Chris - I see. So I send you let’s say a sample of flu that I got from Joe Bloggs and you’re asking does the vaccine produce antibodies in someone I give it to that if they met that virus tomorrow it would stop it?

Derek - That’s exactly right. And as well as this happening locally in over 130 countries worldwide, these five international centres coordinate this and do all the laboratory work. And then collaborate with our laboratory here at the University of Cambridge where we also look at them with mathematical and computational methods to track the evolution of these viruses for the purpose of keeping that vaccine strain updated.

Chris - On a practical level, how do you actually do those experiments to know if the vaccine is going to defend me against that particular strain I got from Joe Bloggs last week? Is that somebody physically, with a test tube and some virus and some cells, growing these things and then proving yes, the immune response will stop Chris Smith from catching this virus?

Derek - That’s absolutely right. It’s 20 thousand viruses a year tested in exactly that way to see whether or not those strains can protect Chris Smith this year.

Chris - So it’s quite a lot of guesswork then because you’re getting samples that are doing the rounds now, but this is going to inform the vaccines you’re going to make into the future?

Derek - Yeah. This is absolutely the key thing. And in some ways it’s absolutely not guesswork because this is a very well oiled machine and comprehensive surveillance and very good analyses. But, the point that you raise, the virus has six to eight months to go do its own thing in that intervening time and may evolve such that the strain that’s in the vaccine is no longer a perfect match.

The four major types of flu that circulate there’s a strain of flu for each of those in the vaccine. And when there is one of these mismatches it’s typically just for one of those types of flu. That one component of the vaccine, that one fourth of the vaccine protecting against one fourth of the strains that are circulating doesn’t do as well as we’d all like it to do, and people are not as well protected against getting infected.

Even in those cases they are protected against the other three strains of flu - main strains that circulate. There are also typically protected against sever disease from that other strain. They may still get a cold, or something that feels like a cold; they’re less likely to die or end up in hospital.

Chris - Can you use say maths or other techniques to try and anticipate what the next move might be on the part of the virus, perhaps informed by what’s happened in the past, to make your guesswork odds a bit better?

Derek - Absolutely. And this is a research programme that we have been doing for something like 15 years now to see if we can understand what are the deep evolutionary processes that are going on. What are the constraints or are there constraints on how the virus might evolve?

And it turns out that there are constraints to the extent that we think that we can predict this. And there is a new generation of flu vaccines that are being produced where the strain that’s in the vaccine is not the best representative of the strain that’s circulating in February, but is actually an educated guess of what’s going to circulate the following year. These are vaccines that will enter clinical trials in about two years from now.

Chris - It’s a bit like when you’re driving down the motorway, you should always look at the car not directly in front but one in front of the car in front, because you see the brake lights go on on that one before the car in front of you is going to brake and so it give you advance warning. You’re sort of saying well if I look at what the virus is doing now and then I second guess where it’s going to be later I’ll get a much more accurate picture?

Derek - This is exactly what’s happening. And for me it’s a really beautiful integration of basic science, evolutionary biology, and fantastic surveillance because the other thing that we have when we drive down the motorway is we have the experience of doing this before. And because there is this great surveillance over so many years one can go back and do retrospective studies to imagine that it is 1989, and then see if we can predict what happens in 1990 in 1991/92 and know whether or not the methods are working or not.

Gum on Shoe

QotW: Why is blu tack sticky?

It’s time for Question of the week. Adam Murphy has been stuck on this question from Tom.

Adam - Blu tack is everywhere, probably in every home and office, holding up our posters and our notices. But figuring out what’s in this adhesive puts us in something of a sticky situation. To learn more, I spoke to Jennifer Gaughran, a researcher in Dublin City University.

Jennifer - We don’t know exactly what Blu-Tack is made of because it’s a trade secret, but we do know that it contains something called hydrocarbon polymers. Hydrocarbon polymers are included in most glues and hat turns Blu-Tack into an adhesive. Polymers which are molecules that form these long chains, do tend to be quite sticky because, from chemical point of view, they have a lot of hydrogen on their surface which likes to form very strong physical bonds with anything they touch.

Adam - So that’s part of it, but is that the whole sticky story?

Jennifer - It’s actually the squishy nature of the Blu-Tack that’s the real trick though. Blu-Tack is a putty-like substance that’s moveable and able to deform. Blu-Tack seeps into any little indents on the surface that it’s sticking to and this makes it even stickier.

Adam - That might be why there’s still blu tack on the walls from the posters that covered my childhood bedroom.

Jennifer - When you press hard enough, it forms a very smooth flat surface against your surface and pushes all the air out. This creates a vacuum, which is a very difficult thing to break. It’s like when you stack two wet glasses together. The water pushes all the air out and it very difficult to pull them apart again. You have to twist them apart or disrupt the water somehow.

Adam - Or just like a plunger!

Jennifer - This also explains why Blu-Tack doesn’t feel sticky at first in your hand but does get stickier the more you handle it. It’s because it’s starting to fill all those nooks and crannies, getting you into a sticky situation!

Adam - Thank you Jennifer. I’m sure everyone was glued to their speakers. Next week, we’ll be tackling this muddy question from Daniel.

Daniel - If I stand in the shallow end of a swimming pool, I don't feel the pressure of the water around my legs. But if I put my wellies on and stand in a deep puddle, I do feel the pressure of the water on my lower legs. Why is this?

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