Viruses and Vaccines

Four out of five patients participating in a recent kidney transplant trial in America have been able to stop using immune-suppressing drugs.

The patients, aged 22-46 years old, had all developed kidney failure for different reasons.  Prior to receiving the donor organ each of the patients received a course of drugs to partially destroy their bone marrow and the T lymphocytes, white blood cells that recognise and reject foreign tissue.  After this "conditioning" regimen was complete the patients underwent a combined transplant during which they received the new donor kidney and were also injected with their donor's bone marrow cells.

The results have been striking.  Between nine and fourteen months after each transplant all but one of the patients have been able to stop taking any immunosuppressive drugs, and their kidneys remain healthy without any signs of rejection up to 5 years later.  The scientists think that the transplantation of the donor bone marrow triggers the recipient's body to develop "tolerance" to the foreign organ, possibly by re-educating the recipient's white blood cells into ignoring what was previously viewed as hostile.

According to senior study author David Sachs from the Massachusetts General Hospital Transplantation Biology Research Center in Boston, "we are very encouraged by our initial success in inducing tolerance.  While we need to study this approach in a larger group of patients before it is ready for broad clinical use, this is the first time that tolerance to a series of mismatched transplants has been intentionally and successfully induced."

The findings will almost certainly come as welcome news to the thousands of patients who face a twice-weekly trek to their nearest hospital for dialysis whilst they wait for a suitable donor organ to be found.

Researchers have shown that caffeine exposure is linked to an increase risk of miscarriage.

De-Kun Li, from Californian health insurer Kaiser-Permanente, followed 1063 women during the first twenty weeks of their pregnancies or until they had a miscarriage. Amongst the details collected, the participants were asked about their caffeine consumption.  The data is published in the American Journal of Obstetrics and Gynecology and shows that women drinking more than 200 milligrams of caffeine per day - the equivalent to just over one cup of coffee - had a two-fold rise in their miscarriage risk.

But it wasn't just coffee that was to blame - all caffeinated beverages including fizzy drinks, tea and even hot chocolate had the same effect.  According to Li, caffeine might be triggering vaso-constriction - blood vessel narrowing - in the placenta, cutting blood flow and the delivery of oxygen and collection of waste products from the developing foetus.  Alternatively, he says, caffeine may be directly toxic to a foetus.  Either way he suggests that women avoid caffeine altogether during pregnancy. "It's not a big sacrifice," he says.

One big thing that's been in the news in the last weeks or so is a story about the blackest black that's ever been seen.  Using carbon nanotubes Professor Pulickel Ajayan from Rensselaer Polytechnic has developed a material that he says absorbs over 99.9% of all the light that falls on it.  That's 30 times darker than our current benchmark, or what we call black. 

Chris - Hello Pulickel, thank you for joining us.

Pulickel - Thank you.

Chris - So why have you done this?  What is this stuff?

Pulickel - Well, an ideal black material absorbs light at all wavelengths and all angles, basically.  There were some speculations published by Spanish and English scientists who said if you take these tiny carbon cylinders and organise them into an array you can get very high absorbancy and very low integral refraction.  Of course to get a very black substance you also need to minimise the reflectants on the surface and you can do that by creating a surface softness.

Chris - So how does your technique actually work?  If I was to zoom in with a very powerful microscope on the surface that you've created that is very back, what would I see?

Pulickel - Right, you will see nano scale cylinders of these carbon materials.  A nanometre is about a billionth of a metre so you have several of these structures that are just randomly placed on the surface.  That's what actually decreases the surface reflectance.

Chris - So you have these tiny tubes.  I mean, looking at the scale of them that would make them 400 or 500 times thinner than a human hair wouldn't it?

Pulickel - It would be more than that, about 3 orders of magnitude smaller than..[a human hair]

Chris - So you have these peppered all over a surface?  How do you make them..

Pulickel - There is a periodicity of these structures in the bulk of the material.  In the surface you have a random array so it satisfies both criteria: that you have a very highly absorbent material and also it reflects very little on the surface.

Chris - So how does it actually work to mean that so little light comes back off?

Pulickel - It's basically almost like the light enters this material and it gets trapped because of this periodicity.  That's why you have a very low index of refraction.

Chris - How would you see this being used?  It's one thing to get into the Guinness Book of Records for the World's blackest substance but how is this actually useful?

Pulickel - It was done mostly from an academic curiosity but something that absorbs a lot of light would be useful as a solar collector.  Again, in order to make this into an appropriate device you would have to worry about some other losses from material as a result of light.  Certainly it'll be a very strong absorber.  It could also be useful in areas where you want a very black background so that you can have a high definition of the areas which are light and black.

 Chris - So you could use it to trap sunlight which would make solar cells more efficient.  What about other things?  Does it work outside the visible spectrum of light?  Of course, there's much more to light than just what we can see: things like radio waves, microwaves and at the other end of the scale x-rays and gamma waves.

Pulickel - Absolutely, that's our hope.  We have not done these things yet but we are in the process of doing the high end IR and other wavelengths.  That'll be much more interesting from various points of view.

Chris - Thank you very much, Pulickel.  Good to have you on the show.

You're on the right lines there, George. The reason is that if you think of a heart as almost a sphere and the volume of a sphere is given by the mathematical formula 4/3πr3. That's the volume of blood that a heart could hold. You could work out how much output's coming out of your heart by multiplying the number of times per minute the heart beats (the heart rate) by what's called the stroke volume (how much blood the heart squeezes out with every beat). Given that a heart that's small, instead of it just decreasing its volume by a small amount when you shrink the heart a bit it will actually decrease the volume of blood proportionately by the radius cubed. For every shrinkage of the heart, if the heart gets smaller and smaller - in fact there's a very big decrease in the amount of volume it can pump. You can compensate for the reduced volume by increasing the rate at which you pump. If you have a smaller heart you have to make it go faster. A mouse's heart, for instance, can be pumping at two-four hundred times a minute whereas a big whale could have a heartbeat of say 20 or 10 times a minute but it has got a heart which is the same size as a Volkswagen beetle. That's why.On a related note, if you've got a very big heart it's going to be almost impossible to empty that very, very quickly. It'll be impossible to empty a whale's heart which is several feet across 400 times per second. You just couldn't shift the blood quick enough. It's likely that the dynamics of muscle contraction wouldn't be able to occur fast enough to make the muscle get shorter quickly enough en masse to move that amount of blood at that speed. It is a phenomenal thing to have achieved.

We're talking about infectious diseases and foremost among them the thing which surprises most people actually kills about twelve thousand people every single year and that's influenza. Ed Hutchinson's a researcher from Cambridge University, so Ed, what is this beast that we all succumb to on a regular basis?

Ed - Well, for starters it's a virus and like all viruses it's incredibly small: 100nm across. That's about a quarter of the wavelength of visible light. Because it's so small it can replicate incredibly quickly but also because it's so small it really can't do anything. It really has to take over cells and get them to do all the jobs it needs.

Chris - So you mean, because the virus is so tiny it doesn't have the machinery to copy itself so it needs to invade us, or things like us, to do that?

Ed - Exactly, it's traded off that ability in order to replicate very quickly.

Chris - Is it just us that get the flu?

Ed - No, it comes in several different types. The one we really worry about we call Influenza A and that infects a huge range of different creatures. It infects people but it also infects birds, we worry a lot about bird flu. It infects seals, it infect whales.

Chris - If you could see the flu what would the virus look like?

Ed - It looks a bit like a kidney bean really, or a baked bean floating around. It's this little oval thing. You would need a very powerful microscope, you'd need an electron microscope because it's far smaller than the wavelength of [visible] light. That's most viruses. Now some of the influenza viruses as well, stay the same width but extend out great, long filaments. The ones we spend most of our time studying are little baked bean-shaped things.

Chris - Why do they form these filaments?

Ed - That's not really very well understood. We know this happens in clinical isolates. It doesn't tend to have them when you're looking at them in the lab. But when they're growing in your throat sometimes these viruses grow out these big strands which extend upwards into the mucous which is covering the cells in your throat. We think it might have something to do with getting the virus coughed out and spread on from person to person. The way this virus spreads is that it gets into the mucous. You cough or you sneeze and if a handkerchief doesn't get in the way it then gets breathed in by someone else and they get infected.

Chris - Are handkerchiefs actually useful as a way of stopping it because it sounds like it's so tiny that a handkerchief which you can physically see through if you hold it up to the light, it doesn't seem like much of a barrier.

Ed - Yeah, but bear in mind you're not just coughing up a virus, you're coughing up a whole ball of snot as well so it is going to stick in your handkerchief.

Chris - I should point out at this point there's a wonderful article on our website this eek. It's been written by Becky Poole and it's all about why snot is green. If you go to thenakedscientists.com you'll see it's advertised there: all about the science of mucous to give it it's proper name. But Ed, carrying on with your guided tour of flu, what are the key points about it?

Ed - What you've got is really a box which has got the flu genes on the inside. On the outside it's got some proteins, the thing the virus is built of. These allow it to get in to cells and to get out again. These proteins grab on to cells and the virus gets inside. Within about 12 hours it's copied itself hundreds and hundreds of times. It's incredibly quick. Like I said, very small, very quick replication.

Chris - The incubation period of flu is incredibly short. When you think that most air travel for example, can bring you to the other side of the world and it takes 24 hours to do it. If you picked up flu on one side of te planet you could be infectious for it during touchdown.

Ed - It's a scary thought when you put it like that, yes.

Chris - How does it get into the cells that it needs to invade and then how does it take them over?

Ed - On the outside of the flu it's decorated with a little stalk called hemagglutinin. Now we tend to abbreviate that to HA or even H. That grabs onto the surface of the cell and pulls the virus inside. Once the virus is inside that box that holds the genes inside it opens up. The virus genes fall out into the centre of the cell.  Then they just take the cell over and turn it into a factory for making more flu. When the virus gets out again as it assembles it uses another protein that decorates the outside of the virus called neuraminidase which we abbreviate to NA or N.  That cuts it off from the cell and gets it out again. The reason I'm mentioning the hemagglutinin (the HA) and the neuraminidase (the NA) is because these cover the outside of viruses, they are protein building blocks recognised by the immune system. It's these things which antibodies stick to. It I for this reason when we talk about viruses we tend to categorise them by their hemagglutinin type and their neuraminidase type - their H type and their N type.

Chris - Like H5N1?

Ed - Exactly.

Chris - When this genetic virus goes in what's the genetic material it uses because people talk about the flu continuously coming back? If it was just the same infection every time people would be getting immune to it but we don't. Why is that?

Ed - Flu mutates very, very rapidly. This is partly because it's genome, instead of being built of DNA (that's what we use), it's built of RNA. That's if you like a far more primitive thing to build a genome out of and is absolutely hopeless at copying so rapidly so flu is constantly mutating all the time. Because of this the vaccine which we use against flu needs to be constantly updated. There's another side to this as well. Every so often, we're talking a few times a century, flu will suddenly change. The H type and the N type will change to something completely different. That can be catastrophic. This is a disease which normally will kill 250-500 million people globally every year.

Chris - What you're talking about is a new pandemic. You get an epidemic which gently changes and turns into something that is devastatingly different.

Ed - Yes, exactly. These completely new viruses will sweep through the population.

Well we've already heard about how flu actually causes disease, how it invades us, how it hijacks our cells and makes us feel generally grotty but how do we actually prevent it? John Wood is from the NIBSC, that's the National Institute of Biological Standards and Controls which means he works with flu vaccines. Hi John.

John - Hello.

Chris - What's in a flu vaccine that prevents us from getting sick and does it actually work?

John - Most of the flu vaccines are produced by growing the virus in hens' eggs. The viruses are purified from the hen's egg fluids. They're chemically treated so they're no longer capable of infecting people. These purified virus particles or components of them are used to give to patients by inter-muscular injection. This, in turn, stimulates the body's immune system into thinking they've been invaded by flu.

Chris - You're showing this viral shrapnel to the immune system so that it gets a sneaky preview of what the virus looks like. It makes an immune response: does it make as good an immune response as if you actually catch the flu?

John - It's thought not. The best way is stimulating a robust immune response which will give you protection for months and months to come is an infection itself.

Chris - We had an email from Mark in Bletchley who says, 'I've been in contact with someone who's had the flu quite badly but I didn't catch it. Why would that be?'

John - Well, I don't know the particular circumstances. It's possible, I hope, that maybe he had a vaccine but maybe not. He could have been exposed to flu in the past which gave him some immunity. Maybe he didn't know he'd been exposed to flu in the past. It may have been a kind of sub-clinical infection he didn't notice. I expect he had some kind of immunity.

Chris - Ed was saying the flu mutates as it goes around the world and this is why we get consistent outbreaks year on year. How do you make sure the vaccine is going to work every year?

John - This is a big problem and the WHO has a worldwide network of laboratories. They have over 120 so-called national influenza centres around the world. They monitor the newly emerging flu viruses. They analyse them and compare them with the previous years' flu viruses. Specifically, they're looking at the surface proteins to see how much they vary because these are the hypervariable part of the virus. The activities of these national centres are coordinated by four collaborating WHO centres. We have one here in the UK at Mill Hill in London, one at CDC in Atlanta, one in Tokyo and one in Melbourne. The directors of these centres come together twice a year in Geneva, the headquarters of the WHO to analyse all the data. I'm unfortunate that I'm asked along because they like to have some of the key regulating laboratories as well. We have to deal with the fall-out from any new strain. We look at all the data, we look at how the immune system was stimulated by last year's vaccine, recognises the vaccine. We look at the genetic properties of the new viruses, how these viruses react with the immune system and we make a prediction of which strains are likely to cause flu next year.

Chris - Is this based on viruses that are doing the rounds in the southern hemisphere? So when it's their summer and it's our winter here we're collecting viruses at the moment. Are we going to send them to their flu season next year so they can make vaccine?

John - It often does happen like that, yes. I said the WHO experts meet twice a year: once for the northern hemisphere recommendation and that's coming up in the next month and one for the southern hemisphere recommendation which is usually September. If you monitor very carefully what happens in the other hemisphere it's a very good indication what we're going to get next year.

Chris - Lots of people are saying if we're going have a pandemic of flu why are people worrying about antiviral drugs that are, at best, not very good? Why aren't we making a vaccine against pandemic flu?

John - We are making - we are trying to develop vaccines against pandemic flu. There are huge problems in trying to make the vaccines against pandemic flu. If we think it's going to be H5N1 there are lots of different varieties of H5N1 that are causing infections, lethal infections in birds. Well over six genetic groups have been recognised of H5N1. You will expect that a vaccine produced from one of these genetic groups may not give you protection against another one. There's no way of knowing which one would actually cause a pandemic in the future.

Chris - It sounds like a horrible pun but you don't want to put all your eggs in one basket; put all your vaccine into one particular type that might not end up being that type which causes the infection?

John - That's correct. You don't even know that it's going to be H5N1. It could be an old pandemic virus such as H2N2 from 1957-68.

Chris - I've got an email here from Ryan Bradley who says, 'I try to hold my sneezes in at least to have the air coming out of my mouth as opposed to my nose. The reason is I don't like spewing mucous out of my nose, onto my hands and other people.' The pressure doesn't bother me so I was wondering if this practise is at all detrimental to my health or if it defeats the purpose of needing to sneeze.'

John - I think it sounds a little bit dangerous practise to me.

Chris - We've had a call from John in Colchester who says, 'what about long haul flights when moving viruses around the world. This must be a major consideration and are there steps taken to sterilise the air on aeroplanes and things like that?'

John - I don't think steps have been taken to sterilise the air but certainly talking to people who've been on long haul flights they often complain of respiratory symptoms after the flights because the air is re-circulated. The tourist class syndrome, they think they're getting worse air than business class. I really don't know the mechanics of this.

Chris - Thank you very much, John.

We put this question to Cambridge University Researcher Ed Hutchinson...

In the case of flu, you've got the fact that flu will spread from organism to organism so although we're worried particularly about a human virus, or a virus of livestock as well, it actually starts off as a virus in waterfowl. Things like ducks, where it's not really a pathogen at all - it just lives in there and gets along with them. That doesn't really tell you where a virus has come from. We know that they can spread from organism to organism. 

In the first place viruses probably evolve as just bits of the genetic sequence which just get out of hand and start copying themselves, moving to places they shouldn't and acquiring more and more abilities along the way. There are quite a few examples of this where thing start jumping around inside genomes eventually will get the ability to jump from cell to cell as well.

Chris - In the answer to what came first, chicken or the egg, the virus-cell situation has to be the cell came first, the virus came later?

Ed - Remember, the defining feature of the virus is that it's absolutely dependent on taking over a cell to work. Without a cell the virus isn't going to do anything at all...