Dwi'n mynd i'n ffrifonio a chael gwrs ar y cyfle ym mwyaf, yma yw'r ystafell ar gyfer y cyfle yma o'r unrhyw hwn. Mae'r cyfle yn wych yn ychydig o'r ddau'r cyflog. Fy hwn yn ymgyrch o'i ddau'r cyflog yma i'r cyflog yma yn y dyfodol. Fy hwn yn ymgyrch ar gyfer y sydd weithio'r llaw o'r cyflog hefyd, ar gyfer y dyfodol ymgyrch ar gyfer y cyflog hefyd, yn ym 2009. Mae'r cyflog hefyd yn gwylliant. ac mae'r pandemi h1n1, mae'r gweithio a'r bwysig yn gweld i gael y fyrus o gweithio h1n1 a'r llwyddiol. Mae'r ddod yn ei ddefnyddio'r cyfrifysgol, a'r diameter o ddod yma, yn ystod y cwm ni'n gwybod, a'r ddod yn gwneud y dyfnod o'r cyfrifysgol. Mae'r ddod yn 6 ddweud 2009. Rydyn ni'n ddiddordeb o'r virus a'r ddod yn ymwneud o'r prifysgol. Rydyn ni'n dda'r bod 100 o'r cyfrifysgol rydym yn gwir cydwyd ar y gweld, nid o'n gwneud i gael y gallau y anteil ar gyfalau glasgo'r dyddiol. That's what happens when we have a pandemic emerging today and what we're going to think about is where does that virus come from and what we're going to do about it when the next one comes along. But of course it's quite an apt time for me to be talking to about it and the best thing to do is to think about that. around it when the next one comes along. But it is quite an apt time to be talking to us about flu because we've got our annual pandemic, our annual outbreak going on right now. We're right in the middle of flu season. There are hundreds and hundreds of people going to their GPs going to the hospitals with influenza at the moment, and we have an outbreak of seasonal flu every single year. About 10% of us contract o'r flu sefydlu ar y fyw, ac mae'r gael eich ysgrifennu o'r fif yn cael unrhyw gweithio o'r 15 miliwn. Felly, mae'r gael eich ddweud o'r fif yn cael unrhyw gweithio o'r llwyddoedd, mae'n gweld eich ysgrifennu, mae'n ddod i wneud y pandemig, ond mae'n gweithio gweithio'r newid ysgrifennu sy'n bwysig, ond wef wedi cael ei wneud, ac mae'n gweithio'n gweithio'r newid ysgrifennu sy'n bwysig 5 wedi bod yn cael ei symud yn llwy, sy'n ei gynnwysu yn cyfohodwyr a'r rwysau cerdwr â phwy, yn ôl eu lŷ, sy'n ei wneud ar gyfer teuluadau pergyllwydol yn susiol, ond byddai'n deaw nhw sy'n iawn i gyd. Rwy'n credu chi'n meddwl i'n meddwl yw'r cyffrediniaeth, ac yn y teuluad yn werthicio, yn gwneud ei oed, o bobl y byd yn cynnwysu, The pandemic we really know more about are the other ones that have happened in the last 100 and one years because those are the ones that wear good clinical medical records and some evidence of what the virus is available to us. As has already been mentioned in the very nice introduction, we know the most deadly pandemic that we have experienced in recent history at least as a human population is in 1918 with this pandemic called Spanish Flu. a son fyddwch yn 50 miliwn sydd wedi wneud yn oed, yn y ddesmytiau. Rwy'n fyddo'n ei gynnig eu bod ar hyn eich bod yn sicr oher� oherwydd'n mynd i mi whatynau. Ond fe yw'n ddweud yn i blygu ar y rai o hyd yn y rhael cyntaf hynny oherwydd y cadwyr yma.   So, for all of those reasons, because it's worrying, it's scary and because it costs a lot of money, various people, including the UK government, would very much like to know more about what to do about a panda leg. And this little illustration here shows you that indeed the UK government are worried about a panda leg. They have a thing called a national risk register for civil emergencies and they imagine all the different terrible things that could happen from a travel accident to a bad weather incident, volcanoes erupt in the UK and they plot those on this graph. So, along the x-axis here of this graph is how likely is this bad thing to happen and then up on the y-axis is how bad would it be if it happened. And you can see right up here scoring the highest on both caps is pandemic influenza. So, it's really something that everybody knows is going to happen again and we know that it will be of some concern and we need to be prepared for it. What we don't know is exactly when is the next pandemic going to come nor exactly how severe it will be because as you can see from the spectrum of the full pandemics I showed you can have pandemics which have quite a low case fatality rate which thankfully the most recent one was or you can have very different situations. But whichever one of those ideas we're going to need a strategy to deal with it because when the first appears the newspapers will have headlines which will worry everybody, the public will need to know that something is being done. So, what can we do and can we do anything once it's happened and can we do anything to make it less likely to happen in the first place? So, if you cast your mind back to how it must have been in 1918 it must have been incredibly scary because back then of course there was no treatment, there was no flu vaccine, there was no idea of what was actually causing this devastating disease and as has been mentioned what was particularly scary was as we've seen in pandemics it's the young adults, the 25, 20-year-olds and 45-year-olds who seem to unusually come down with flu whereas normally in a flu season as we're such experiencing now we see the very young baby business in two years old, the very old people of the 70s and above, the people in the middle are normally not suffering from flu. In the pandemics we see the opposite and here's a lovely stained glass window from a small church in a Leicestershire village where this lady here was at the age of 29 getting married in the autumn of 1918 and two weeks later she is on her deathbed. So, that really brings home the personal stories of the sort of young lives lost. So, what is this all about? How can that happen? How can a young or previously healthy person get infected with something and then just die so quickly? What is the causative agent? So, the causative agent is a virus, the influenza virus and I really like this particular picture of flu virus because it's transparent and it's colorless and in one of the sort of medium interviews that I was persuaded to do, one of the clever journalists did ask me what color is a virus and I had to think for a long time because I didn't know and I think my conclusion is that viruses don't have color because viruses are so small that they are smaller than the wave length of light which has color therefore I think this is a very good representation of what a virus is like, it's sort of a super transparent thing which is so small and has no color. So, this virus here of course you're looking at a representation of what it is when we measure it by imaging the virus in the electron microscope because we can't see it in any other way you can see this virus is about 100 nanometers across and what that means is that if I have a one centimeter fingernail I can get 100,000 viruses end to end across my fingernail so these things are tiny and all they are is a bag of genetic material they're not really alive because this virus sitting here on its own sitting on a bench floating around the air will not do anything it is the absolute parasite the only way that this thing can work is if it gets inside your cells and when it does that it takes over your cells and it commands them to do its work for it it commands them to make hundreds or thousands of copies of itself each one identical to the first virus that got in. So, the virus we can think of as sort of a bag and you can see from this representation that the bag is studded with lots of little psyche protrusions and there are little sort of wobbly shapes on the end of those protrusions so there's about 400 of these spikes on the virus and the outside of the virus is this sort of copies after copies of this same shape repeated all over the place that outside is what your body your immune system can see when this virus is trying to infect you and the only way that you won't get infected by that virus is if you've already seen something like it before and made an antibody that can coat each one of those hundreds of spikes and stop them from latching on to your cells and entering the cells and that's how vaccines work and that's how protection works if you get infected with one type of flu virus once in your life you'll never get that one again but unfortunately there are lots of different types out there so you can keep on getting flu several times throughout your life inside that bag which is carrying the genetic material you can see this sort of coil here that's that's the genetic material that's what tells the virus what it's going to be and the whole purpose in the life if it even is the life of the virus is just to make more copies of that and to move around from one cell to another one person to another just commanding cells to make more copies of itself so this picture here is a force covered image to make it a little bit more beautiful this is a cell a human cell that has been infected about six hours previously with one of those influenza viruses and all of these sort of worm-like protrusions now are the virus pushing its way back out through the membrane of the cell and the end of these you can see little sort of bubbles on the end those will pinch off and make new copies of virus so this cell you can see is is making probably about a thousand viruses each one of them but I'm pushing out from its membrane and here's another picture looking down on the surface of a cell and this cell here colourful is coloured in blue each one of these little spheres is a new virus which has been made from a single virus entering that cell a few hours ago taking over the cell's machinery and commanding it to make thousands of copies of the virus and you can see that these are all rolling down almost like a wave ready to leave that cell and come on and affect all the neighbouring cells or perhaps to float out into the air and affect the next person so the virus has evolved over many years to do this extremely well and it's no wonder that we have quite a fight on our hands to to combat that sort of simple but very very effective biology in fact these viruses are not really viruses of humans at all the viruses are all parasites all viruses are parasites they all rely on a host to replicate them and the host for influenza are birds wild birds like ducks and geese and in those wild birds you can find many many different influenza viruses all of them looking subtly different in the shape of the spikes on the outside and that means these are antigenically distinct what i mean by that is that these bird viruses are completely different than any human viruses that we might ever have met in our lives before and therefore if one of those bird viruses crosses into a person it can very readily infect that person because that person won't have ever been immunised or infected with that virus they have no previous experience of that virus and that's the origin of the pandemics when bird viruses cross into humans we can get pandemics now we don't have a lot of close contact with ducks in our usual life but of course we do have contact with other animals found animals for example chickens or pigs and so we think that the route by which these bird viruses find their way into humans is probably through passing their virus on to farmed animals particularly chickens and we often see a scenario for example where a poultry farm with with open fields and water can attract migratory waterfowl for example to stop by and use to share the water and then that water may be then passing the virus on to chickens what i should say is that in these wild birds the ducks and the geese the virus isn't a virus of the respiratory system at all it's actually an enteric virus it infects their guts and it's shed out into the water and these migratory water birds go around in huge numbers and pass the virus to each other through the water in the chickens the virus can infect the birds throughout the whole body and sometimes you will have heard that people become infected by acquiring bird flu viruses through exposure to chickens so this has particularly been in the news in the last couple of decades and particularly seen in areas of Asia where there is a very sort of particularly this time of year actually a sort of preference to obtain live meat so they have live poultry markets very often in china hong kong and other parts of Asia like yet now where people prefer to have very fresh meat so they will go to the live poultry market purchase their birds live take them home slaughter and prepare them themselves but then become exposed if those birds are infected with a bird flu that exposes a person to a huge dose of virus perhaps is then plucking the feathers you can imagine a sort of aerosolisation that somebody might breathe in that virus and that has led to very severe cases of bird flu viruses with names like h5n1 or h7n9 have been in the news and featured in in things like time magazine where people are really worried that if these bird flu viruses continue to infect people this will spark the next pandemic what i want to make clear is that these viruses as they stand have only infected around about a thousand people that is not a pandemic those are individual cases of a person becoming exposed to a bird virus but that person can get very sick i can die but doesn't pass their virus onto the next person and the only way the next pandemic will happen is when that happens so what is it that a human seasonal flu does that a bird virus a bird flu does not do it's the difference between the transmission the transmission route so for human flu the only way that the virus can go from one person to another is through the air in airborne droplets so as that virus is replicating in the respiratory tract of the infected person it comes out into the secretions that are fluids that line the lungs and those virus particles can find their way into these small droplets so all of us right now are breathing out small droplets into the room tiny tiny tiny particles and if you were infected with a virus in your respiratory tract some of those particles would contain viruses those particles remain suspended as aerosols in the air for minutes or even hours after you even leave the room and someone else might then breathe those in and introduce the virus into close proximity with the cells of their own body by which the virus finds a route to enter an effect so this airborne transmission is what seasonal influenza viruses and all viruses influenza viruses a human manages to do but luckily for us the avian influenza viruses are not good at doing that however the problem is that they can change so it's a pretty tough life for a virus actually to be an airborne transmissible virus what you have to do is you have to float around in the air as a virus in these tiny particles you then have to be inhaled by a person and then you have to reach these cells this this layer here these represent the cells of your respiratory tract your nose and your throat and they are covered with this layer of mucus and what influenza viruses that can transmit through the air can do is that they can chop their way through the mucus and reach those cells below but avian influenza viruses because they've never had to deal with human respiratory because they they don't know how to do that unless they undergo some mutations some change so if the avian viruses can transform themselves by mutating the way they work into ones that can float in the air and chop through human mucus and infect the human airway cells then what can happen is that this individual not only acquires the bird flu from the chicken but also breathes out new viruses to more people and those people breathe out more viruses to others and so on and so on and get a chain of transmission and an explosive outbreak which is called the pandemic so we now understand a lot about which of the avian viruses which are out there in nature have the potential to undergo these kinds of mutations and transform themselves through farmed animals into airborne transmissible viruses and we know that all of the viruses that cause the pandemics of the 20th and 21st century must have reached us via this route and we can define the mutations that undergo and we can look out for them so we can look in the farms of Vietnam and China and Africa and America where the bird flu's are found and we can say are there any of those dangerous mutations appearing in those viruses because if there are that's the first sign to ring the alarm bell to suggest that perhaps there's a pandemic on the way from that source now the 1918 Spanish influenza was such a virus we believe that it was a virus which originated either in Kansas or part of North America or perhaps in the camps where the army soldiers were at the end of the First World War but it certainly was a virus whose very recent ancestors were bird viruses because you can look at the sequence and work out that these viruses were very recently in birds the reason we can actually look at the genetic identity of that virus is because about 20 years ago now it became possible to recover the the bits of the virus from parts or archived samples which had been stored down in 1918 so as I said earlier back in 1918 people didn't know what was causing this but they did have the foresight to store samples so for example soldiers who had been infected and died from the 1918 flu so an army soldier an army medic had preserved the lungs by by putting them on paraffin thick slides and stored them all in the archives of an army medical centre over in the united states and back in the 1990s a young army medic called Jeffrey Tavernberg had discovered this big box of these slides and thought I wonder whether or not I can use them to understand anything about this 1918 Spanish flu so he was able to piece together what the virus must have been and then using modern day techniques that we have in the lab he could recreate that virus that was quite a controversial experiment this was a virus which had killed 50 million people around the world or even more the virus wasn't with us anymore it was 100 years later but this guy wanted to know more about that virus understand it so he pieced it together and recreated it in the lab and then what that enabled him to do was to do a bunch of experiments to ask a question that had been posed by many people many times was this 1918 scenario so devastating because it was the end of the first world war and nobody had eaten well for a long time and everybody was tired and undernourished and any virus would have done this to a population there was nothing special about this or was this a really really nasty virus such that if it were to come again we should be worried about this sort of scenario and that's an important question to ask because we need to know in modern day whether or not such a virus could exist and could be highly transmissible through the air in such a way that it could kill 2% of everybody with two effects so he posed that question and he recreated the 1918 Spanish boom and he performed a series of experiments in various models including animals and what you could see was that this virus really was a monster virus it was a real perfect storm as far as a virus is concerned of kicking off this horrible horrible response in the the animals for example that were giving this virus they would be dead within 24 hours and this picture here is the lungs where you can see this blood filled lungs the hemorrhaging just in the way that's been described by the medics back in 1918 who were describing these young men coughing up blood and being overcome by Spanish flu virus so why does a virus do that our seasonal flu viruses don't do this my theory and what I'm going to try to convince you of is that these viruses which just have crossed from animals into humans have just learned to be good enough to infect a human and pass amongst us they're a bit like teenagers they don't know how to behave they're kind of learning their way but they haven't learned the rules yet and they come into a new host the human host they are parasites that have learned to exist in birds for thousands of years but this virus now is in a human host and it's bashing around replicating in an unregulated manner in all kinds of cells where it shouldn't be you find these viruses have found their way into immune cells and they're replicating inside immune cells which flu viruses don't normally do flu viruses just infect the lungs so when viruses are in the wrong place at the wrong time they kick off all of these silly and useless immunological responses the immunopathology is what kills you the person's own immune system has really been turned on itself and this aberrant and inappropriate thing that we call the cytokine storm is going on where there's so much response that the virus is not being restricted but the person's own immune system is actually shutting down their organs and causing multi-organ failure and the reason I think that's the case is several fold for example there are lots of other instances where we have animal viruses that cross into humans and we see very very devastating effects if you think about ebola virus we know ebola virus comes out from animals and gets into humans and those people have a very severe reaction and often diem quite similar scenarios like this hemorrhaging but also we know that once that pandemic virus emerged in 1918 it caused a lot of bother it killed 50 million or so people around the world but it didn't actually go away what happens with pandemics is that they stay with us and they come back year after year reinfecting humans as seasonal flu viruses but we know that in the 1920s and 30s and 40s we didn't see medical records of people dying from these terrible symptoms of the Spanish flu yet the virus was that was going around in those decades must have been derived from the original Spanish flu virus now I've been trying to get a costume that flu virus is able to change it's able to mutate every time it replicates it can undergo changes and the way evolution works is that the best virus in the scenario is always the winner for a virus to keep going in humans it's no good if the virus kills everybody because if everybody's dead there's nobody new to infect it's actually not very good for a virus to make people very very sick because people are very sick they stay at home and they don't go out and they don't breathe their viruses onto other people the best thing for a virus to do is to not make many people sick at all because that's really successful it can go from one person to the next nobody ever picks up nobody ever knows to to go home and take any medication they just go out walking around Sainsbury's and breathing on everybody and the virus spreads very well so these viruses in in the 1920s 30s and 40s are adult viruses they're the 1918 virus after it's grown up but that first early 1918 flu was the horrible one that didn't know how to behave itself and that's why it kicked off all those inappropriate cytokine storms and killed so many young healthy people with their vigorous immune systems that turned upon themselves so how severe will the next pandemic be I think that's going to depend very much on where that virus has been most recently if we think about 1918 we think that that virus was very recently a bird virus which just crossed over from birds to people didn't know how to behave itself and kicked off all of this horrible immune response if we think about what we see in people who unfortunately get infected with bird flu in Asia again we see humans infected with bird viruses and the case fatality rate there can be as high as 60% once again you get the cytokine storm you get hemorrhaging you get multi organ failure whereas if we think about how swine flu the last pandemic that we experienced thankfully it was mild and what we know about that is that the last animal host that that virus we can trace before it jumped into humans was pigs now pigs are much more similar in their behavior in their immune system in their cell in the make up to humans than our birds so that virus had learned how to behave itself in pig cells before it passed into humans and that's why it was not such a problem to us and in fact the case fatality was a hundred times lower than the 1918 flu which was a direct jump from birds so we can't predict at the moment which of those scenarios the next pandemic is going to be but as soon as that virus emerges we will be able to sequence it and tell where it's been most recently and what it's most like and that will be really important information in the early weeks of a pandemic to help us decide and plan what to expect in terms of hospitalisation deaf and other issues so what will our pandemic response be well it would be lovely to think that we would be able to control the next flu pandemic with a public health control system perhaps we could shut down the schools screening people at the airports stop the virus coming into the uk i'm going to tell you in a minute i think that's highly unlikely to work you could already see enough of the world i showed you in 6 of june 2009 that the pandemic would have reached our shores before we even know that it exists so what we like to do to control the flu and we know how to do it is vaccination so we will be able to make a vaccine fast enough in the virus and if we can't what will we do instead sars is another example actually of these animal viruses which come straight out of animals into humans and can be very scary very devastating so sars if you recalls your mind back to 2003 was a virus which emerged in Hong Kong spread around the world Canada and other parts of Europe and thankfully we were able to control sars with what's largely a public health strategy and the reason that was possible is that people who are affected with the sars virus it's a different virus and influenza and they are only contagious when they are showing symptoms so sars was a huge problem for healthcare workers sadly several doctors and nurses died looking after people infected with sars because those people were coughing and the virus is coming out and they were highly contagious when they were symptomatic in fact what we know about influenza is that influenza is contagious before you have symptoms and even if you don't have any symptoms at all you can still breathe out droplets loaded full of influenza virus and pass them on to someone else and that's illustrated here in this this graph so influenza 40% of infections are thought to come from people who aren't even showing any sign of illness that's why it spreads so very rapidly and very easily so it's not really going to be possible to use things like airport screening because the people walking through that screen are not going to show up as having a fever yet but they might be breathing out virus which can infect the the new city where they're about to arrive to the good news is though that unlike sars we have a lot of experience at treating influenza because we have seasonal influenza every winter we know that we can make vaccines that work against flu and we have some antiviral drugs that work against flu as well so we've already done the show of hands about flu vaccine I would imagine that everybody in the audience here put their hand up as having received flu vaccine will have received what we call the inactivated flu vaccine the injection into your arm of a small piece of that spike which was sliced off from that the particle of virus that I showed you it looks just like the virus it holds your immune system into making that antibodies that can block that virus but it isn't you don't get a dose of flu it's a it's a jab of a protein in your arm which is nothing like the virus so you don't get flu when you have flu vaccine you just get a tiny fragment of the virus part of which pulls your immune system into into making the right antibody response we're working on improving flu vaccines all the time they get a bad rap in the press some years they don't work terribly well last year the not last season but the one before there was a new vaccine on the market which was called an adjuvanted vaccine an adjuvant is a chemical that you can add to a vaccine to make even better immune response and that really seems to have worked well in the 65s and over and we managed to get flu vaccine up to 62 per cent of a vaccine so that means that you know you've only had a 62 per cent chance or whatever of 38 per cent chance of getting flu if you'd have had your vaccine. Inactivated flu vaccine we can make millions of doses the world health organisation has contracts with vaccine manufacturers to generate 100 million doses in the first week of the next pandemic or as soon as they can in the next pandemic um but there is actually another vaccine on the market which is being used here in the UK which is actually very exciting and what to tell you about because I think there's a lot more potential for it and that's uh a different sort of vaccine that we give to children so there is now available a live attenuated vaccine and this is really a virus this little girl is being infected on purpose with a flu virus but she's not going to get flu because this virus is a version of the virus which can't replicate at high temperatures of her body this virus can only replicate in her nose and because her nose sticks out from her face it's cooler than the rest of her body so the virus replicates in her nose she doesn't even get a cold she makes a response to that replicating virus which is very very robust and she is now protected against flu this vaccine is now being offered to all children up to age 11 in the UK uh the uptake is about 60 percent we wish it was higher but last year's effectiveness for those who did guess it was 87 percent so it's a really good vaccine now why is the UK even giving children flu vaccine when we're the only country in Europe to be doing this um and that brings us back to the pandemics one of the things about the last pandemic and the next pandemic is that we learn a lot in pandemics pandemics are like huge natural experiments a new virus is released on the world and we we can observe what happens what we observed in the UK was that in the first few weeks of the last pandemic in May and June lots of people started going to their GP and then in the middle of July it all went away and what happens in the UK in the middle of July the schools break up and what this told us is that children are the main spreaders of flu through our community and if we can only control flu in the children we can protect ourselves so the children go back to school in September and the flu comes back again okay so this was what persuaded the people advising Department of Health JCVI the joint committee in immunisation vaccines that vaccinating children against influenza can save money which is why they do it and lives and here's a public health England poster saying how successful it was in the year of the pilots but the graph I really like to concentrate on here this is one of the early pilot experiments where the UK was splitting into different regions where children of either primary school age shown in red or secondary school age were given the vaccine and then this graph down here is called showing all cause mortality in those different regions and what you can see here is that the winter comes on the people in the red region are less likely to die in the winter from outbreak syrpysbryd virus than people in the green or the yellow regions that got no vaccine at all so what that says is that primary school children are very mucky and dirty and they like to mix them around and then they go home and they give granny a big hug and they pass the flu around and it's a really really effective way if we could only increase that vaccination rate in the children from more than 60% it could be in a good way if we were to use that live attenuated vaccine in children at the start of the pandemic as the paper just come out from modellers in Hong Kong suggesting that the whole pandemic scenario could be controlled if you could make the children immune in the first few weeks of the pandemic to the new virus now how do we make these vaccines this is a very very old slide to emphasise that the way we make influenza vaccines is very old-fashioned and it's actually made by growing virus up in chicken's eggs whether or not if the virus is squirting up children's noses or the virus we're chopping up and putting in these arms we actually make vaccine in eggs if the next pandemic is a virus that's come straight from chickens into humans and is killing lots of chickens we could be in a pickle because there won't be any eggs okay that's a serious concern um it's a very very long and complicated procedure we know how to make flu vaccines we make seasonal flu vaccines every year we take viruses from around the world we grow them in eggs and then sort of mix them about to make them safe to make vaccines from lots of people then do lots of standardisation this is sort of a graph of the world health organisation every year making flu vaccine and it takes about six months from start to finish to find the virus you want to make the vaccine against work out how to grow it well enough for the eggs make enough of it package it ship it out and get it into people's arms and indeed in the last flu pandemic making a vaccine against the new pandemic virus took six months or more so here's that epidemic on religion curve again the children breaking up from school the flu vaccine coming back and the first vaccines in the UK went into people's arms in about first week in November by which time the second wave of this pandemic was almost finished so we we don't have the capacity nor the knowledge at the moment nor the manufacturing prowess of your life to make a flu vaccine to a newly emerged pandemic virus fast enough to really make the difference that we like to make that leads us to the dream of a universal flu vaccine so if we if we knew what virus was going to be the next pandemic we could just make that vaccine now and stop pilot but we don't know what virus is going to be we don't know whether it's going to be a bird flu from vietnam or a pig flu from north america and they're all different they all need their own specific vaccine but they're all flu virus and so maybe there's something in common with amongst them all we could only work out that what that was we could make one vaccine that we gave to people at the start of life and they would never get seasonal flu and they would never get pandemic flu when the next pandemic came either the troubles we just don't know how to do it the virus is very very clever the bits of it that we respond to are the bits which are changing all the time and different between all the different strains and the bits which are the same in the virus if you make antibodies against them you don't protect yourself against the virus so it doesn't do you any good so at the moment there is a huge amount of effort and money going into trying to make a universal flu vaccine there are lots of dark top companies the US government is plugging lots of money into this but we do not yet have such a vaccine and meanwhile we are in a pickle because if the next pandemic comes along we won't have a flu vaccine for six months so what on earth will we do when everybody's panicking in the daily mail is predicting that you know 100 000 people are about to die of this new pandemic we will have to have something to give people in the meantime while we get ready and make the new vaccines so the best hope would be an antiviral drug a medication pill to give people that will at least fight the virus off in their body and stop the virus from winning that battle stop those hundreds of thousands of copies of virus from accumulating and maybe even stop the virus passing from one person to the next now of course we have antiviral drugs already we've had antiflu drugs actually since the 1980s but the most popular antiviral drugs that we have at the moment the ones that are licensed and mostly used around the world are Tami Flu and and its sister Relenza so these are neuraminidase inhibitor drugs so they're very specific for flu they don't work against other viruses they've been very very cleverly designed based on the three-dimensional structure of the protein that's essential for the virus and when bird flu first started infecting people in China back in the early 2000s governments like the UK government and other European governments first world governments started thinking there was a new pandemic cover which could be very dangerous and they needed to start stockpiling these drugs and as you can see here more than 500 million pounds were spent in that decade in the first decade of 21st century in the UK alone stockpiling enough Tami Flu for everyone of us to have one week's course as shown here in the event of the pandemic and that these drugs are stockpiled in secret warehouses whose location none of us can know but if and when it's necessary the warehouses will be opened up and the Tami Flu will be distributed to the appropriate people so Tami Flu is a controversial drug it was licensed back in the 1990s based on a series of clinical trials which was submitted to the licensing authorities the FDA in EPA and it was trialled properly in people with mild flu and it showed an effect however not when a drug gets licensed not every single piece of information that the drug company uncovers during its clinical research goes into the licensing package the drugs companies are about to put their licensing package together and choose what they want to show in order to persuade the authorities to give them a license to sell their drug and Ben Goldaver who's a very eminent and very vociferous medic feels along with the British Medical Journal and some other people that this isn't right and that all the trials that a drug company ever performs when it's developing a drug should be public knowledge and should be taken into account during the licensing um so he persuaded the Cochran group an independent group to reanalyze all the data that was provided by Roche and Glaxoson applying the two manufacturers of these drugs and they were reanalyzed and indeed they confirmed that taking Tami Flu when you have influenza illness does shorten your illness by about a day 17 hours in adults 29 hours in children so it works but it's not a lot right you still get sick it still takes you four days to get better whereas otherwise it would take you five days to get better and some people feel nauseous and vomit when they take this drug as well so should the UK government have spent 500 million pounds stockpiling these drugs in the event of a pandemic the academy of medical sciences was asked to investigate and they looked at all the evidence including what we call retrospective analyses where the drugs have not been trialled in in um random control trials but have actually been used in hospitals when people got sick and turned up to hospital did they get Tami Flu or not and did they get better or not and the evidence is very clear when a person is sick enough to go to hospital if they get Tami Flu within 48 hours of turning up they get better much more likely than if they don't so there are clear benefits if you're ill enough with influenza and you need to be in a hospital then Tami Flu is obviously beneficial nonetheless this whole controversy has really clouded the use of this class of drugs there is not I think it's going to say a lot of confidence out there in the medical world about this class which meant that there has been a race towards getting more drugs and different drug one that worked in a different way one that worked better faster more reliably and this is the newest kid on the block in that race this is Zofluza so Zofluza is not yet available in the UK it's not licensed yet in Europe but it is licensed in Japan and the United States and for the first year last winter it was used in Japan and six million doses of it were used in Japan which is a lot because Japan is a huge country and Zofluza works in a completely different way than Tami Flu but and it works very potently it inhibits the replication of the virus by targeting the very machine that the virus uses to copy itself people who take Zofluza or Biloxemia as it's probably a chemical name is seem to stop shedding their virus within 24 hours of receiving the drug whereas people who take Tami Flu continue to shed their virus for three days and people who don't get any drug at all shed their virus for four days so once you've got virus in your body you're going to carry on being ill so stopping the virus is good but this is also suggested in the early wave of a pandemic for example giving people this kind of drug could really interrupt transmission because if people aren't shedding virus they're not so likely to pass their virus onto the next person that will slow down the pandemic and then we might buy enough time to generate that vaccine which we'd love to be able to give everybody so that's that's the plan but using antivirals in the early waves might slow us by us time slow the virus down but who who should be first in line I mean okay we could buy enough doses for everyone to have one dose but we can't buy more doses than that and people will start gaming we already saw evidence of gaming drugs in the last pandemic so people went and phoned the NHS phone a friend um flu line and said oh i'm ferio i've got flu and then you can go online you know and find they're selling boxes of Tami Flu for 100 pounds each so we we're going to have to work out how to give people and who to give people their first doses. Talk about flu pandemics we are in the middle of an obesity pandemic the world is experiencing an obesity pandemic and obesity is a problem for many many reasons but with infectious disease obesity is an issue because obese people have an altered immune state obesity is a is a chronic inflammatory condition as well as having many other problems along with and actually in the last flu pandemic which was the first flu pandemic where there were a significant number of obese people in the world it was very obvious that obese people infected with flu were more likely to go to hospital more likely to get severely ill and more likely to shed out lots of virus so we need to identify the new risk groups in the 21st century and plan our pandemic strategy accordingly. The other thing that we discovered in the last pandemic was that there are some people who are unfortunately for them genetically predisposite disposed to fare badly with flu so we already know that some people will fare badly if they're asthmatic or if they have heart disease flu is a problem and they're on the at risk list but the last pandemic in 2009 was the first time ever when we could analyse the genetics of people and we were able to look at people who ended up in hospital with what was otherwise quite a mild virus versus everyone who'd got the virus that hadn't gone to hospital and by sequencing the genomes of the people who ended up in hospital we could find very rare variants because we're all different so some of us have got this variant in a particular gene this particular gene here is called iFit M3 and it helps protect you against flu and if you are a European then only 0.3% of us have that rare variant but of the European who ended up in hospital six percent of those had the rare variant gene variation and interestingly in China 25% of Han Chinese have that variant anyway and you still see this massive enrichment in the severely ill people who went up in hospital so in China more than 60% of the people in hospital had the rare variation so maybe in the next pandemic will be in an era where everyone is sequenced at birth and we'll know that all the people with the iFit M3 SNP need to get their vaccine first or their antivirus first because they can't help their genetics and they're the ones who are going to end up in hospital even if it's a mild virus but that brings me just to the very end this is all what we'll do when it happens but could we now we really understand where these pandemics come from could we prevent the next pandemic even starting in the first place so we think before we know it really that pandemics come from wild birds and the wild bird viruses pass usually through farmed animals with which humans are having close contact and then the virus is mutated in such a way that they can pass through the air from one person to the next what if our farmed animals could not be infected with influenza virus then they wouldn't pass on their virus to us and our contact with wild animals is so infrequent that the chances of getting the pandemic from them is very small so we now have a new technology in the world which is called CRISPR technology this is a way of genetically editing genomes of animals and we have CRISPR edited genomes of various animals including chickens and pigs so we can generate chickens now that are different genetically so a couple of years ago during the research that I've been doing in imperial we discovered for example one particular host gene that encodes a factor inside host cells with all influenza viruses have to use so when these viruses get inside cells they take over our own machinery and then turn them for their own use and make all these thousands of copies of themselves so what if chickens didn't have that host factor or had an altered version of that host factor that the virus couldn't use anymore then those chickens would be resilient or resistant to human to infection with the flu virus so we're now working with the Roslin Institute just on the other side of this lovely country where they of course created Dolly the sheep the world's first clothed animal and at the Roslin they already know how to use CRISPR technology to edit chickens and pigs and we are in the laboratory under very controlled conditions gene editing chickens to lack this particular piece of a small protein which means that they won't be infected by flu viruses anymore um of course we've been all we've been changing chickens for years we just don't know how this chicken here is 60 years ago and this is today's chicken they are not genetically the same they have been randomly bred for traits like big fat legs and lots of breastbeats what we're proposing to do is to make chickens that would still look like this so the farmers will be happy because all the traits that the farmers like will still be there but one gene or one part of one gene will be different enough in that chicken that if it's exposed to a flu virus it won't be infected with that virus anymore and that I think could protect us from the next pandemic but also of course give food security because around the world there's a demand for protein and chicken is the fastest growing protein source to feed the world so with that controversial proposition I'm going to round up and say there will be another flu pandemic this severity could be anything from very mild to not and I think that will depend on how it reaches us as humans what its root from animals birds through various animals is we have got antiviral drugs and there are more coming along and we do know how to make vaccines but it takes us a long time so in the meanwhile in the past we've had nothing okay what we would love to have today would be to have universal flu vaccines that we would stop by now a battery of other agents that would work cross-reactively against any flu virus that emerges combinations of drugs because one thing I haven't had time to touch on is the sad reality that using single antiviral drugs just in the way that we see with bacteria and antibiotics now leads to resistance and we have lots of flu viruses out there that have become resistant to the drugs we've got we have to use them in combination otherwise we're going to be in problem and I would propose to you that in the future we might farm gene edited chickens and pigs that are altered in these essential post factors so that they can't be the conduits through which the virus will pass from wild birds into humans so thank you very much for listening to me I really do want to acknowledge a wonderful team of young people that have the privilege to work with in my lab you do lots of hard work and are funded by these sources and we have collaborators from public health England and the Institute of Animal Research at Perlbright and of course the Boston Institute as well thank you for listening


The decision over whether or not to use the terminal is of course a choice that you need to make on your own, but I've talked many times over the course of the last three years over the merits of actually learning how to use the terminal. Even if you're just going to learn the basics, I've always said it's better to learn a few things on the terminal than to learn nothing at all because eventually on Linux you're going to come across something that you have to do in the terminal or that it's at least easier to do in the terminal and knowing just a little bit can get you a long way. One of the questions that I get most often when people talk about the terminal is how do I learn? Where are the best resources for me to learn from? What are those resources? How do I find them? What's the best way of learning something when it comes to the terminal? All these questions mostly centering around the fact that when it comes to anything on Linux there's multiple ways of doing something and when that's true and it's almost always true on the Linux side of things. Anyone who writes a tutorial on this kind of stuff does it in a slightly different way. You can get on Google and search how do I do whatever and you're going to find six different ways of doing it. What do you consider the best way? It's really hard for a new user or even someone who's just never used the terminal before but has used Linux for a long time. It's hard for anyone to decipher what's the best way of doing anything. What's the best source of material for me to learn from? There is actually a thing that you should use or some group of things that you should use to get that information and those are man pages. Now man pages have been around for a very very long time and I forget constantly that they exist. It's a stupid thing to forget about because like I said they've been around for a long time and they're essential when it comes to learning anything in the terminal but I forget about them a lot because I don't use them as often as I should so that's a personal failing on my part and I would suggest that you don't make the same mistake because man pages are awesome. They're amazing. I'm going to show you today the amount of information you can get when it comes to man pages. Now before I jump in and show you what a man page is, how you navigate them and all this stuff I do want to say that man pages just like documentation everywhere varies in quality. So you're going to find some programs slash commands on the terminal that have man pages that are really really good. A good example of this is Vim. Vim's man pages are really really good. Same with Bash. The Bash man pages fantastic. Then you're going to find some applications slash commands on the terminal that have man pages that are awful that are really bad. Maybe they're five or six lines or maybe it's a really simple command but it has you know 50,000 words. You know you'll find both situations well a lot of situations like that when it comes to man pages simply because the man pages are written by the developers and the amount of effort they put into them is going to vary. Some developers consider it a very essential part of their program to provide you documentation inside of the man page. Some developers don't want to do a man page at all. So they just do a simple one and put all their documentation everywhere or elsewhere I should say. And some developers put all of their documentation inside of man pages and then don't put it anywhere else. I'm looking at UBS PWM. Anyway, so the quality of man pages will vary and you'll find yourself disappointed sometimes and very mightily impressed sometimes. It's really kind of luck of the draw. Unfortunately, there's no consistency across developers. It's just the way it kind of is. So let's go ahead and jump in and I'll show you a few man pages and we'll talk about them. Okay, so the best place to view a man page is in the terminal. Now it doesn't mean that that's the only place of course you can usually find man pages on the internet somewhere for whatever command or program you're looking for if you prefer to look at the man page in a browser but if you've installed the application, the man page is almost certainly have been included in the install somewhere on your system. And the best way to access that man page is with the man command. Now you can find a man page for basically any program that you've installed or that is installed in your system. So for example, man CD does exist. It's just these few lines. There's not anything more to the man for CD. All that stuff is here. Now the reason why I know that this is all there is for the CD command is because I had this idea for a video. Five secret ways you can use the CD command. Turns out there's nothing more you can do with a CD command other than change directories. That's all you can do. There's no extraneous like flags or anything for CD. So the man page is obviously therefore not all that complicated. There's 32 lines here. That's literally all there is. Now when you're inside of a man page, the best way to get out of a man page is to press the Q button. That's the best way to do it. It's very simple. And if you ever forget that, usually along the bottom here, it will say type Q to quit. If you need to figure out any of the other commands or key bindings that you can use while inside of a man page, you can use the H command. That'll show you all of the key bindings for less, which is the viewer that you're using when you use a man page. So just hit Q, hit Q again, we'll quit that. Now let's take a look at a more complex man page. So I'm gonna do man kitty, which is the terminal that I'm using. And this one here has a whole bunch more lines to it. There's obviously a whole bunch of documentation here for you to go through if you wanted to learn about kitty. The best way to move between lines and pages inside of a man page is to use the VIM keys. So J goes down, H goes up. So if you've ever used VIM before, you'll be perfectly well at home moving around a man page. You can also use the slash key to search for if I wanted to search for config, I can do that. And then I can just use the N, the letter N to go back and forth between different entries in that search. So most of the VIM movements here work just fine inside of less, which is again, the viewer that you use when you're viewing a man page. So the benefits obviously to a man page is that it gives you information over how to use the command or the terminal application. So the biggest reason why you'd wanna use this, especially is if you're going to look for options that the command or the application have. So in the case of kitty here, if I say I wanted to use a specific kitty configuration file to test it or whatever, I could use the dash dash config flag when I run kitty from the terminal. Now, obviously you're not usually going to run kitty from the terminal, but you can. This dash dash config option allows me to specify a path to the configuration files that I wanna use. And it tells me all the information that I could possibly want about this specific flag. Same thing about setting a custom class for kitty, I could do that. Or, and this is useful, not if I just wanted to launch kitty from the terminal, but also if I wanted to have a key binding inside of say a configuration file for Qtile or I3 or SXHKD or whatever. And I wanted to have a specific instance of kitty with a specific class name. Obviously I would not know this existed unless I came to the man page and learned what that is. So all of the information you want for a particular program is going to be located inside of the man page if it has one. Now that's a big proviso because there are some applications that don't have man pages. Either the developer decided that they didn't wanna create one or they just decided to put all their documentation online somewhere, whatever. But some applications you'll come across don't have man pages and that always makes me a bit sad because as you can see in the case of kitty, it can be very, very useful because it gives you options over how to use it. It gives you examples. So we can take a look at another one. So Qtiquit will do man bash. This is the man page for bash. Now if you're going to learn how to script in bash, I highly recommend you come here and read this man page. And I also will tell you this right up front. It's gonna take you a while because this is a very, very long man page. If we wanted to scroll up here from the bottom, we'd be scrolling for quite some time. In fact, I don't think we could probably do it all in this video because it's very, very, very, very long. And it tells you a lot of stuff if you'd need to know how to not only use bash, how to script bash, but how to use some bash commands instead of the terminal. Another really cool thing about man pages is that oftentimes, not all the information you need is inside of this singular man page. Sometimes you have other man pages. So if I show you the man page for Paru, which is an AUR helper, and if we go to the bottom, we can actually see a place here that says see also this line right here. So if you enter into a man page and not all the information you expect to be there is actually there, jump to the bottom and see if it has a section that looks like this. Because for example, the Paru man page just tells you how to use the command. It doesn't tell you how to configure Paru. So I always wondered where are all the documentations for how to do the configuration? Well, it's in its own configuration file. So if you see this, this is what the Paru man page looks like. If I do man paru.conf, which I found from looking at that see also section, this is the man page for the configuration file. And there were all, there were other ones as well. So if you see the see also, and this actually doesn't look like they included the see also in this particular man page. So if we do man paru again, like so go to the bottom. You can see there are other man pages that it suggests you take a look at, including make package, make package.conf, package build, pacman, pacman.conf and so on. So a lot of man pages will not only give you information about the command itself, but it will also give you information on other man pages that are related to whatever you're looking up. So if the information you have, or the information that you need rather is not there, check out some of those other man pages and you might find the information that you need. You'll also oftentimes find URLs to different places where you can look for help. So in this case here, it's telling you where you can report bugs if you needed to report bugs and Paru. A lot of times it'll give you links to further information where you can find more documentation. If it's not on a man page, it'll give you contact information for the developer. If you needed to contact the developer, a whole bunch of information here right inside of the man page. And it's just incredibly useful if you need to learn how to do something when it comes to a terminal application of some kind or a command inside of the terminal of some kind. So if we wanted to say a man LS, this is the man page for LS and there's a ton of stuff that you can do with LS, right? Show different permissions, show who the author is, a whole bunch of different commands and flags and stuff like that that go along with the LS command and this shows you all of them. You can come right here, it tells you what the flag is that you can use and then exactly what the flag does. A lot of times the man page will also point out directories on your computer that are important. So in this case of ZSH here, this shows you a whole bunch of paths and files and stuff on your computer that are important to ZSH. So if you're ever trying to locate a default configuration file for something or a global configuration file, a lot of times at the end of the man page, you'll find a section that says files and it will list all the files that are right that are important to that particular application right there. So let's just say you wanted to set a global environment variable for ZSH. This is the path of that file that you'd need to go visit if you wanted to do that for ZSH or for your system. And the same thing for the ZSH-HRC. If you wanted to create a, if you needed the default ZSH-HRC file, that's where that's located. You could go there, copy it into your home directory so you can make changes. So man pages are incredibly helpful for you if you're trying to learn any number of things. Now, like I said at the beginning, the helpfulness of the man page is really going to depend on the developer of the program because some developers do a fantastic job of creating a man page. I've shown you several that are fantastic. Some developers don't have a very good man page at all. So your mileage really is going to vary. Even the man command itself has a man page. So if you were ever wanting to learn more about man, you could come to the man page for man and take a look because there are other things that you could do with man in order to view the file. So you could change the way it's displayed and all this sorts of stuff. And I didn't even know this existed before just now. So surprisingly, there's a lot of stuff here when it comes to how you configure and can view man pages using the man command. So that's the general overview of man pages. Now, there are other tools like TLDR and stuff like that that do a different job when it comes to giving you documentation of commands in the terminal. Those tools do exist and maybe I will make videos on those in the future. But I believe that the best place to find documentation for commands in the terminal or terminal based applications is man pages. You go there, you find information and it's just a very good resource. And I would say that man pages are actually essential resources for anyone who wants to learn anything in the terminal. You go to a man page, you get the documentation, it tells you precisely what the terminal application or command is capable of doing. And it's just something that, and usually it's written in such a way that you can understand it. Now, you will find man pages that are very technical in scope and pros. So for example, the bash page that we looked at before, it's not going to make a lot of sense to you if you have no idea what you're doing. Unfortunately, it's written for people who are more technically minded and stuff like that. Now, it doesn't mean that there's nothing inside of that bash page that you will understand, but you'll probably find yourself stuck in the mud the further you go in because you're going to kind of be over your skis a bit. It's just going to be a little bit difficult if you're brand new to whatever it is you're searching for. And that's not just bash, but a whole bunch of other things, right? The more you get into a program, the more you're gonna learn, but you're obviously going to find some things that you just failed to understand because a lot of times, you know, it just gets more complicated, right? And that's more true of man pages than you probably would expect simply because they are written by developers. And a lot of times, the developers don't do a very good job of considering that new users might view their man page. Some of them, I'd say probably do a pretty good job, but you'll find some man pages that are just overly technical and they make a lot of assumptions on prior knowledge. And you know that those man pages probably aren't as useful as they probably could be. I find that those are fairly rare, but that's also might be my perspective because I understand and have been inside of man pages many times before. So my prior experience is probably coloring my judgment over whether or not man pages are more for new users or not. So, you know, it's an issue. But as I said before, your mileage may vary on the quality of the man page and the technological advanced knowledge that you'll need in order to actually read the man page. Sometimes you'll find that you'll need more. Sometimes it's written for new users. It really does depend. I find that man pages are really, really useful for me, but I also, like I said before, forget that they're there quite often, despite the fact that I know about them, right? It's a weird thing. It's like a resource that I understand is very useful, very valuable, but I also oftentimes use Google as a crutch. I think that that's my biggest issue when it comes to man pages is that oftentimes for me, it's just easier or more, it has become a habit, I should say, of instead of going to the man page of just going to Google and searching for the thing that I need to find on Google because it just seems to be easier. Despite that being the case, I still say that man pages are better simply because usually they come straight from the developer's mouth. You know what I mean? All the stuff that the developer tells you you can do with their program or command or whatever is right inside the man page and that means that the information is not going to be biased by other users. Now that doesn't mean that other users can't have good perspective on a command or an application and show you different ways of doing things. That's still a good thing to learn and to seek out, but the so-called official way of doing things is always good to learn too. So those are man pages. I highly recommend if you are learning anything in the terminal, search out a man page and you'll probably be happy that you did that. So that's it for this video. If you have thoughts on man pages, you can leave those in the comment section below. You can follow me on masses on our Odyssey. Those links will be in the video description. You can support me on Patreon at patreon.com slash linuxcast. Thanks to everybody who does support me on Patreon and YouTube, you guys are all absolutely amazing. Without you, the channels will not be anywhere near where it is right now. So thank you very much for your support. I truly do appreciate it. You guys could just seriously close my mind if you guys continue to support me. Thank you so very much. Thanks everybody for watching. I'll see you next time.