Much A-Flu About Nothing (Post 3 of 2 - a little add on)

I’d just like to make a little add on to my previous post, as I’ve just read about some very interesting work regarding influenza that hasn’t even been published yet and is currently under review. This work is causing a huge amount of controversy because of the implications it could have if published. The study was conducted by Ron Fouchier of the Erasmus Medical Centre in the Netherlands, in which he managed to create an H5N1 flu virus capable of host-to-host transmission, which if you’ve read my previous post, you’ll know is the main thing stopping that strain of Avian Flu becoming a pandemic.

Fouchier’s work looked to create a virus capable of transmission between hosts; obviously he can’t use humans, so he used ferrets which are the closest model available to study the virus. He first attempted to create mutations to the virus which he thought would allow host-to-host transmission but was unsuccessful in this approach. He then moved on to the tried and tested method of simply passing the virus from one ferret to another over and over again. This passaging process causes the virus to adapt and make it better at transmitting between hosts. After only 10 generations, the virus had become airborne and could pass from one ferret to another simply by them being in close proximity to one another. Subsequent analysis of this new mutant form of the virus showed that only five changes had been made to its DNA, and these affected just two proteins. What’s more worrying about this is that all five of these mutations have been seen in nature, just never all five in the same virus.

Herein lies the controversy: this man-made virus, in theory, has the ability to spread from person-to-person and it is estimated that it could kill over half the global population as a result! If the work is published and the mutations are freely available for anyone to view, it is not too difficult for anyone to re-create this virus and use it for a bioterrorist attack, for instance. This work has started the ball rolling on an intense debate over scientific freedom and whether so called ‘dual-research’ (research which has the potential for good and evil, for want of better terms) should be published. The good that comes from this work is twofold: firstly we will be able to look for these mutations in the wild and get a very rapid response if it ever looks like the virus may form, thereby potentially limiting its fatality, and secondly by having the virus in the lab we will be able to study it and look for novel ways to treat it if ever it does form. The ‘evil,’ as mentioned above, is the possibility of bioterrorism.

Personally, I feel that the work should be published. With the information available about the mutations that are key to allowing it to spread, we will be better able to understand the virus and find novel ways to deal with it, should we ever have to. Yes, there is a risk of the information getting into the wrong hands but if we are able to find ways to deal with a natural form of this virus then we will also be able to deal with a man-made form. Science doesn’t move forward without a risk or two along the way.

Much A-Flu About Nothing (Post 2 of 2)

I left the last post touching on the fact that we would look into 3 historic pandemics in more detail. We’ll start with the furthest back, and the most deadly, this being the Spanish Flu pandemic of 1918. In the 2 years this pandemic lasted, it managed to infect an estimated 500 million people (that was about third of the population at the time), furthermore it also managed to kill between 50 and 100 million of those it infected, meaning that between 3% and 6% of the global population died due to this virus. Additionally, instead of targeting those of advanced age, as seasonal flu does, it caused deaths in younger, healthier individuals, making the burden of disease far greater. The Spanish Flu pandemic was the result of an early avian virus managing to infect humans due to mutation, not re-assortment. This virus was an H1N1 virus.

A pretty famous image form the Spanish Flu pandemic. All are patients.

Fast-forward to 2009 and we hear from H1N1 again, something I’m sure many readers will remember. This was the Swine Flu pandemic, which lasted a little over a year. This H1N1 virus came from a quadruple re-assortment of strains from swine, avian and human flu viruses. So couple the terror of the possibility of a second Spanish Flu outbreak with a quadruple re-assortment and you can hopefully understand why there was plenty of fear surrounding this outbreak. Swine Flu had more than just letters and a number in common with Spanish Flu, in that it was more contagious than seasonal flu and was seen to target the young more than the old. Fortunately, however, the virus seemed to cause only a mild illness; of the 375,000 lab confirmed cases there were only 4,500 deaths.

Our final virus to consider is Bird Flu (aka Avian Flu), another outbreak which many people will probably remember hitting the headlines. This virus is yet to reach pandemic level, unlike Swine Flu, however there is a close eye being kept on it as there is a high potential that it could soon manage to become pandemic. The Bird Flu virus is an H5N1 virus that can pass from birds to humans and from 2007 to 2010 there have been 26 outbreaks resulting in human infection. The reason that H5N1 has failed to live up to the media hype of being a huge global killer virus is that its transmission from human to human is very limited, so any outbreaks rapidly burn out. The reason for this lack of transmission lies in our lungs. As a reminder, flu viruses have HA on their surface, which binds to cells and allows the virus to enter them for infection. All HA molecules target a receptor on cells known as the sialic acid receptor which is (in parts) made of sugar molecules. Avian HA targets sugar molecules which are linked in a certain way, known as an α2,3 linkage. However, human HA targets α2,6 linked sugar molecules. Both of these types of linkage are found in our lungs, but not with an even distribution. In our upper respiratory tract we have many α2,6 receptors, whereas in the lower respiratory tract we have α2,3 receptors. Flu is an upper respiratory tract infection and going to the lower respiratory tract means it will not be coughed or sneezed out as it is too far down, thus stopping human to human transmission. Here in lies the fear though, in order to switch from targeting α2,3 receptors to targeting α2,6 receptors the H5N1 HA only needs to pick up 2 mutations. Mutations are a rare event, but picking up 2 is not beyond the realms of possibility and is something that is constantly being looked for.

Hopefully now you’ll never consider flu in the same way. For so many people it is essentially just a severe cold, but spare a thought for those who suffer much more from the threat of flu. And the next time the media pick up on a global pandemic that will “kill us all” hopefully you’ll be able to fully understand the aspects of the virus in question and understand the real dangers it may or may not pose, as the case may be.

Much A-Flu About Nothing (Post 1 of 2)

Everyone knows of flu, or to give it its full name, influenza. For most people it’s nothing more than a passing illness characterised by symptoms such as fever, fatigue, coughing, sneezing, aches and pains. However, for some people, it can be a much more serious disease, with estimates from the World Health Organisation believing it to cause 250,000 to 500,000 deaths a year. Those people at the highest risk have probably already been contacted with regard to receiving the flu vaccine, which is an annual occurrence around this time of year (in the northern hemisphere). What I’d like to talk to you about in this blog is what flu is and why every couple of years there seems to be a huge scare about a pandemic outbreak, the most recent of these being Bird Flu and Swine Flu. I don’t want this to be a scare-mongering blog about how there could be a pandemic flu outbreak that could kill us all (as the papers like to report it) but just to help people understand what is going on next time there are reports of a potential outbreak.

First things first; flu is caused by a virus. One of the defining features of viruses is that, unlike bacteria, they are completely unable to replicate without a host, and the aim of any living thing is to replicate. So without something to infect, viruses would just sit there as a ball of DNA, proteins and fats doing nothing. The influenza virus has 3 main hosts, these being humans, pigs and birds. The virus must therefore infect one of these animals, replicate inside their cells and then spread to new hosts. In humans, the virus infects cells in the upper respiratory tract, which is why we cough and sneeze a lot when we have flu.

Now for a bit of virology. A virus is unable to replicate without a host because of the fact that, in general, all a virus consists of is genetic material (either DNA, like us, or RNA) and a particle which transports this material, made up of proteins and fats. This particle is known as an envelope. In this envelope there are proteins, which stick out (see the picture) known as haemagglutinin (HA) and neuraminidase (NA). Both of these have very important roles for the virus. HA allows entry into the cells and without entry the virus cannot live. NA on the other hand allows the virus to leave the cells and spread to more cells. And yes, if you were wondering, these are where names of flu viruses such as H1N1 come from. These notations refer to which distinct type of HA and NA is on the surface of that flu virus. We currently know of 16 HA variants (numbers 1-3 infect humans) and 9 NA variants (only numbers 1 and 2 infect humans).

The last bit of background regards the influenza genome. The genetic material of influenza is RNA and inside each influenza particle there are 8 different segments of RNA. This is like having a jigsaw of 8 different pieces, all of which have different detail to them and all of which are necessary to have the final image. Each of these 8 RNA molecules will produce different proteins that enable the virus to replicate inside host cells and then spread.

Now that we’ve got the background down, things start to get interesting. As long as the flu virus has all 8 of the RNA segments it needs in the genome, it doesn’t care where they all come from. So let us think of a typical human flu virus with its 8 RNA segments. If segments 4 and 5 (for example) are exchanged with a flu virus that infects birds, we have a whole new virus that may be capable of infecting humans. We can take this idea further and include pig viruses as well and get what is known as triple re-assortments, where we form a completely new virus with RNA segments from human, pig and bird viruses. This is what scares virologists and epidemiologists the most.

Most people never get anything worse than a severe cold from flu infection due to the ability of our immune system to fight it off. This system of cells and molecules can detect the flu virus by means of molecules known as antigens. Our immune system is essentially blind and has to fumble around feeling for things it recognises as being an invader before it can destroy them. The main antigens that we use to detect flu are the HA and NA proteins I described earlier. Now let us consider recombination: if a flu virus recombines the segments of its genome which code HA and NA, then there is the potential to produce a flu virus with completely different HA and/or NA which in turn will be completely un-recognisable to our immune system, the system won’t know what that feels like so will ignore it.

Being that this new flu virus has a whole new set of antigens, no-one in a population will have immunity to it, which allows for the very rapid spread of a highly infectious virus. This will start as an epidemic and spread from there to eventually become a pandemic. A small caveat to this is that it is not always necessary for there to be recombination for a pandemic to occur; sometimes flu viruses which infect animals can simply mutate to aquire the ability to infect humans instead, bringing with them a whole new set of antigens.

So the question is: what, potentially, can the consequences of all this be? And why are we so scared? In the next blog we will look in detail at one of the worst global pandemics in history and also at two more recent examples of a pandemic and near pandemic that never really lived up to the hype, and why they didn’t. So come back soon to learn more…