Blood Under a Microscope

As we’re all aware, science rocks! But sometimes, science rocks a little smaller than normal, Adam Murphy found out about a rocking study in Nature Physics, from the Lancaster University's Edward Laird…

Adam - We all love a good guitar riff. Slash, Keith Richards, Rory Gallagher, Pete Townsend; everyone's got a favourite. I'm partial to a bit of Brian May myself. But it seems even quantum physics is getting in on the guitar. I spoke to Edward Laird from Lancaster University about the tiniest guitar that's a little bit different.

Edward - Yes. It is a single-stringed instrument and the string is a carbon nanotube, which is the smallest wire that we can make. It's about 100,000 times thinner than an actual guitar string and it's also much shorter, it's less than one millionth of a metre long. It is like a guitar string because it's suspended between two clamps, one at each end, and we pass an electrical current through it and then we measure the electrical resistance. When it moves that resistance changes. Like a guitar string it vibrates at one particular frequency; because it's so small and so light that frequency is correspondingly much higher than an actual guitar, so it's 231 million hertz, which is a high A. What is new about this particular device is that it oscillates by itself.

Adam - A guitar that plays itself, playing the highest of As. Rock stars around the world would be envious. But why do you want to do that?

Edward - Well there’s two interesting things. The first one is, I would say, the pure scientific motivation of studying the effects of quantum mechanics and of quantum measurements on small moving objects. The theory of quantum mechanics was developed 100 years ago to describe the behaviour of individual particles. In everyday life we don't see any of those things. So what happens in between? And we're now in a position that we can explore this experimentally by taking medium-sized objects - so medium-sized in this case means a million atoms or so, which is about the size of one nanotube - and trying to find out how quantum mechanics makes them behave differently. There is also an application as well which is that you can use small resonators for detecting small forces. Just like in a real guitar string, if you put your finger on it, even if you touch it very lightly, it's very easy to hear the change in frequency or the change in damping that changes the note. If you have our nano guitar it can measure a small force applied to that, and we can detect that by a change in the motion.

Adam - Which means by dragging it across the surface you could get a super powered microscope, or a weighing scale that can weigh atoms. But how on earth can it play itself?

Edward - Ah, okay. So what do you need to set up an oscillation is some kind of feedback effect between the motion and the electrical current.

Adam - Feedback, at least in sound, is where noise from the speaker goes through the mic, which goes through the speaker, which goes through the mic...

Adam - Real guitar players, though - some of them like it. So Jimi Hendrix uses feedback in some of his recordings: he points his guitar at a microphone, and if he sets the parameters properly then the feedback stimulates the guitar string, which stimulates the microphone, which then stimulates the guitar string again and so you amplify the oscillation. What we did was to have a feedback… we set up the feedback loop entirely within the carbon nanotube itself. There is then feedback between the motion and the electrical current that’s flowing through it. And the reason for that feedback is in the details of the way the electrons quantum tunnel down the length of the nanotube. But the effect is exactly the same. The feedback makes the guitar string hum to itself and that's why we call it the self-playing guitar.

Obesity is becoming more and more of an issue, and with that, there’s been a greater push towards healthy eating. More and more restaurants these days are putting nutritional information in plain sight for us all to see. But does that make any difference? A new study in PLOS One suggests that it does. Chris Smith and Adam Murphy were joined by Cambridge University Researcher Dolly Theis, who’s been looking into this...

Dolly - We have found something different to what the evidence base has looked at so far. So a lot of the evidence is focused on whether it impacts individual choice, whether having calories on the labels changes what people choose when they eat out or order in. And what we did instead was compare the restaurants in the top 100 by sales UK chain restaurants. We compared the ones that had nutritional information on their websites versus those that had it in store and found that those that had in store had 45 percent less fat and 60 percent less salt in the food and drink they serve. So this is new evidence for the U.K. they've conducted it in the States and it indicates that menu labelling potentially incentivises restaurants to improve the healthfullness of their food. So we don't even have to make the choice.

Adam - Now that's a massive difference especially in the salt content. Why do you think it's such a stark change from one to the other?

Dolly - We aren’t able to infer, because it's a cross sectional study, which way the association goes so it could be that the restaurants that already serve healthier foods were more inclined to voluntarily introduce menu labelling in store, but the indication shows that if we are able to see what impact it might have over time it might be that other restaurants that aren't even aware of the nutritional information of their own food and drink, that given that information they can know whether where the improvements are required.

So that is the big message from our paper that it's quite bonkers to think how many restaurants don't even know what's in their own food and drink, let alone the consumers.

Chris - How were they making the patrons aware of those food constituents Dolly? Was this a traffic light system like you see on sandwiches these days or was it just the raw numbers?

Dolly - Absolutely depended restaurant to restaurant. So it was everything from having it right by the pictures, they've got the calorie information alone, and then some only had it on the menus that they give out and others have it separately.

So it's a complete mixture which also again points to the fact that the inconsistency isn't always easy for consumers to know where to even look for it in the first place. So we don't know whether you were introduced, you would have something of a more consistent process and then you can start talking about whether you introduce traffic light labelling on top of it.

Adam - Now I don't know if anyone else has the same kind of morbid curiosity as I do but we were talking about how good restaurants can be, how bad can it get?

Dolly - Well we found one item that was almost six thousand calories! It’s a burger called the Apocalypse Cow. Fantastic name but not great for health! That had almost 6000 calories.

Chris - Who was selling that?

Dolly - Do I mention names?

Chris - It's just a restaurant chain?

Dolly - Yeah. Just a restaurant chain.

Chris - And what’s in it?

Dolly - I wasn't quite in the kitchen when it was being made. That was actually a restaurant that didn't have it in store, menu labeling in store. So a consumer would technically turn up and I'm sure that they would know it probably doesn't look like the healthiest thing…

Chris - I know that around the time that he died, Elvis is alleged to have been eating roughly the number of calories that would have.

Dolly - On the loo.

Chris - Well admittedly he did die on the loo. But when you realize he was eating roughly the number of calories that would have sustained an African elephant each day I think the intake was in the order of 21,000 calories a day. It's probably not far off a couple of those burgers!

Dolly - Exactly and that's the other thing is that we found so many items! That was an extreme example but there are so many items that are just over an entire adult's recommended daily amount. You know one menu item is just bonkers to think that that is the norm now. So it's not only about individuals being aware of it but it's the restaurants themselves, if they don't even have that information how you're going to target interventions?

Adam - So speaking of interventions, what recommendations do you have now going forward?

Dolly - So the government conducted a consultation at the end of last year on menu labeling and they had actually already committed to introducing it. So the consultation was much more about the detail of how they would introduce it.

And we are still, coming up to a year, waiting for a decision to be made. So I think first thing would be great to hear a decision and to understand what the government's thoughts are on this issue and perhaps a good place to start is exactly where we looked with the top 100 chain companies. Because there have been some issues around the capacity smaller companies have to introduce menu labeling and the cost on that. So yes we would like a response from the government.

Adam - Will making restaurants do this actually do anything to change behaviour of people going into those restaurants?

Dolly - We didn't look at this in our own study, so the evidence is pretty weak on the impact on individual choice, but potentially that might change if it's mandated so we have to wait and see.

We're taking a look at the messages you've been sending in...

Adam - And now it's time for the mailbox which is the part of the show where we look at what you've been sending us in, and we just wanted to say a big thanks to Schuyler Moore who's part of the most impressive of clubs which is people who have listened to all our episodes which must be a thousand plus going back nearly 20 years at this stage!

So thank you very much Schuyler. And just a reminder that if you're interested in any of the stories we've covered all the transcripts and papers can be found on our website.

Chris - Thanks very much to Ed Wilson who's tweeted @nakedscientists and sent us a wonderful picture of an Apocalypse Cow burger. That does look like actually it would sustain me for about a week. Probably about 10 inches tall that burger and that looks like it's one two three four five six seven seven or eight burgers? And that's not including the chips which fill the entire tray that it's on!

After you go for a blood donation, you get a little letter through the post, telling you, among other things, your blood groups. But what are those, and how did we find out about them? Chris Smith was joined in studio by Elise Burton, an historian with an interest in genetics, at Cambridge University...

Elise - Well, the first blood groups to be defined was the ABO blood group system, which is the most well-known. And it was discovered right around the turn of the century by a scientist working in Vienna named Karl Landsteiner. And what he found at that time was only three blood types, because he was working with only 22 people and his sample didn't include the AB blood type.

Chris - Oh. So how did he actually fathom that there might be differences in blood groups in the first place? Because it's not intuitive to think that, when you see this red stuff coming out of people, that there may be differences.

Elise - That's right. The science he was working with, the context he was working in, was when blood transfusion was not at all a common thing to do and it was not a very successful medical procedure. What he did was try to understand why sometimes, when blood transfusions were attempted, the blood would coagulate or clump together and cause really severe reactions that would make the transfusion fail. So what he did in his first experience was really just take samples from two different people at a time, and mix them together to see if he could find a pattern; you know, some sort of logic for when the blood would coagulate or not.

Chris  Obviously this is a bit of a volte-face from earlier medical practices where people were really keen on getting blood out of the body. So when did that switch-around happen, and people realised it's pretty important to keep hold of your blood, and rather than blood-let and take it away, actually we wanna put some back? When did that happen?

Elise - That was really in the 19th century, especially later in the 19th century, when people started having a better idea of how blood pressure worked, and the importance actually of maintaining constant blood pressure; in the event that too much blood was let out, that was recognised as a serious problem. But at the time, in the 19th century, people didn't actually agree necessarily that you should be putting blood back into people. They would actually inject people with things like milk with saline solution, that was a popular one, and worked well for some reasons; and sometimes they would try to inject non-human blood as a replacement.

Chris - I was going to say, did they go down the animal route? Because they'd say, “well this looks the same,” and they had microscopes, they would have been able to see there are cells in there, and they would have looked grossly the same. So it was presumably something that people logically tried, “well let's put some pig blood or sheep blood into a person and see what happens”?

Elise - They did indeed try that out. And it really wasn't until World War One when blood transfusions using human blood became an increasingly routine procedure, and everyone came to an agreement that in fact human blood is the best thing to use in a transfusion.

Chris - And were they adopting those techniques of knowing which bloods were compatible or not at that time, or was it still very much a potluck thing? Where people would say, “this guy's bleeding to death, he needs blood, we’ll just give him some,” and take the first person they come to and just say, “hold your arm out”.

Elise - Well this is an interesting story. So in the lead up to World War One, between 1900 when they were first discovered and 1914, Landsteiner himself recognised that it was probably very important for a transfusion that you should test the donor and the patient and try to come up with compatible matches. But a lot of physicians didn't necessarily agree that that was important, because usually the rare conditions under which they would even consider a transfusion were so dire and so time sensitive that they didn't have time to check for compatible blood type. The test that Landsteiner developed would take an entire day to get results.

Chris - And so what would they do? Just literally couple one person up to another?

Elise - Yes. In fact some of the early techniques for direct blood transfusion, they would literally sew together the artery and the vein of a donor and a patient.

Chris - Goodness. How long did... how did that work out? I would have thought that the donor wouldn't last terribly long either, because you're going to hose out most of your circulating volume!

Elise - Well it was an extremely dangerous procedure, and delicate.

Chris - I bet it was!

Elise - And it required a very well-trained surgeon to even link up the blood vessels in the first place. And yes, it was found that this was not at all sufficient for an emergency medical situation.

Chris - So when did things become more standardised and organised, so that actually we had an idea as to what these blood groups were and what you could and couldn't do in terms of donors and recipients; and also having blood banks, so we store blood, along the lines of common practice today?

Elise - World War One was an incredibly important time for the development of all of these things. So it was in the context of war where you had a lot of guinea pigs, in the form of unfortunately maimed soldiers, where these physicians could do a lot of experimental work. For example, how to keep blood from coagulating through the addition of chemicals like sodium citrate, for example; much, much faster ways to test for blood types so that you could test it within a minute, for example. Those were all things that were developed during the war. And also indirect procedures, where you could withdraw blood using syringes and later have it available for other people to accept as a transfusion. That all happened in the later war period, 1916 to 1918.

Chris - And then what happened since then to bring us to the present era? Because obviously this field has exploded since then and we know the value of blood, but we've learned a lot more about it: we know a lot more about certain diseases that can be inherited that can affect the way the blood works; we know a lot more about certain things that you can be exposed to when you're pregnant, for example, which will affect your likelihood of having problems later.

Elise - Well it was actually in the 1930s and 1940s, with the addition of certain mundane technologies like refrigeration, that we were able to develop institutions like blood banks that would enable you to study blood for longer periods of time without constantly needing fresh infusions from a ready stream of donors. So it was technologies like that in the 30s that were really important. And also the development of an idea of medical genetics which really boomed in the 1940s and after. The blood groups are important to that story because in 1910, that was when it was first found that the ABO blood types are inherited according to a Mendelian pattern. Until then no-one had proved that Mendelian genetics actually apply to any human characteristic.

The volume of blood needed every day by the NHS, and around the world, is staggering. But what about growing blood in a lab, could we do that? Chris Smith was joined by Cedric Ghevaert from the department of haematology at the University of Cambridge, to find out more about lab grown blood...

Cedric - So platelets are one of the three main blood components. They’re actually the smallest cell in the body, if you look at a millimetre on a ruler you can line 250 platelets in that millimetre. The interesting thing is that some people argue they're not even a cell, because they don't contain a nucleus, they don't have DNA.

Chris - When I was learning biology at school they said platelets are bits of cells.

Cedric - That's absolutely true. They are fragments of a parent cell that lives in the bone marrow, and called a megakaryocyte, and one megakaryocyte will release about 1000 to 2000 of these little fragments called the platelets.

Chris - Every day?

Cedric - Every day we produce 10 to the 11 platelets

Chris -  100 billion Every day?

Cedric - That’s right.

Chris - And so these cells are just budding off little bits of themselves, which then go circulating around in the bloodstream.

Cedric - That's absolutely right.

Chris - And what are they doing there? What is their role?

Cedric - The main role of the platelets is to monitor your blood vessels, so they contain two things: Their outer layer, which is called the membrane. And on that membrane they have all sorts of little receptors, and these receptors will tell the platelets that the blood vessel has been damaged. When the platelet detects that it does two things, it will attach to the damaged blood vessel, and it will become activated and by that, it will then tell other platelets around, “you need to come and help.” These platelets will then stick to each other and form a plug to literally block the hole.

Chris - Do they change shape or anything? Do they become, sort of spiky or anything, to become more jagged so they jam in the hole.

Cedric - So they do become spiky, indeed you see that under the microscope when you activate the platelets. They go from a disc to this sort of spider, and that allows them to indeed interact with each other even better. The thing that they also do, is to then pull. They literally pull the wound together to try to stem the blood flow.

Chris - And they're presumably the first responders when you have a wound. They're there first because they're at the scene of the crime already because they're in the blood. And then as more come along, they're recruiting more of their mates from the numbers that come in the blood flow, and what do they provide the initial foundation of a blood thrombus or a clot.

Cedric - That's absolutely right. So once they become activated, inside the platelets there are granules, and those granules contain things that tell the blood, “you need to clot.” These things are released when the platelets become activated. And that leads to an amplification of the blood clotting that proteins are linked together, they form a polymer, and that polymer is a sort of a mesh that will capture more platelets and really plug the hole.

Chris - So the platelets are pulling more raw materials that are dissolved in the blood into that wound site, and then turning it into this dense mesh work that's gonna be a stable repair.

Cedric - That's absolutely right.

Chris - So they're really critical aren't they?

Cedric - Absolutely.

Chris - We can't do without them. And what's the problem with just growing them in a dish, because we can grow loads of things in dishes these days. We can you know, cells grow in dishes easily. So why can't you just churn out platelets in a dish?

Cedric - The main challenge with producing platelets in a dish is to do it so efficiently that actually we have a product that can be used, for example by the NHS and cost efficient. So if you look at a bag of platelets which we give for a transfusion, it contains three times ten to the eleven.

Chris - So 300 billion platelets.

Cedric - So where the platelets score as it were, is that we only need to produce one megakaryocyte, to produce a thousand platelets. And we can grow the megakaryocyte from stem cells. So the idea is that we can take stem cells, grow them into a megakaryocyte, and then right at the last stage of production, suddenly you have this massive amplification, a thousand times more platelets than you had megakaryocytes.

Chris - But if it's that easy to just grow these things in a dish, why are we not doing it? What is the what's the problem at the moment.

Cedric - The main problem is that particular last step. When the megakaryocyte is in the bone marrow it gets its cue from its environment. And it will detect the blood flow. It will be talked to by the cells that are around it, and that, it's very difficult to reproduce in the dish. If we produce megakaryocytes in liquid, in a culture dish they can produce 1 to 10 platelets, so we are at least a hundred times below what a megakaryocyte can do.

Chris - So you've got to have some way of recreating that very specialised three dimensional relationship in the bone marrow, where all these cells are in contact in a particularly special arrangement which seems to be the cue to them, to churn out platelets with the efficiency that they do when they're inside the body.

Cedric - And that's exactly the challenge that my group and several other groups across the world are trying to answer. And there are two ways to do this. First we need to tell the megakaryocyte there’s a flow. They sense the flow, and that makes them release the platelets. So we put them in a bioreactor where they're exposed to shear, which is basically fluid going along them.

Chris - That's kind of mimicking the blood flowing through the bone marrow. So that would normally be bending and distorting the cells a bit, I presume, and that's what makes them churn off or snap off bits.

Cedric - That's right. So they produce these long digits which we call proplatelets, and these long digits elongate in the bloodstream and then snap off these platelets.

Chris - And when you make them, having mimicked this as best you can, do the platelets that you produce in the dish look like, and critically work like, the ones that are made naturally in the bone marrow?

Cedric - That's the critical thing that we are trying to address at the moment. They are bigger when we produce them in the dish, and they don't seem to quite react like normal platelets. However that doesn't mean that it won’t work really well. What we need to do is to test them through a range of assays to really make the statement; these platelets are good, they will monitor your blood vessel, they will last in circulation.

Chris - Is your aim to make platelets bespoke for a patient? Or would you make off the shelf platelets, a bit like we'd currently do with transfusion medicine, where we just make a big bag of platelets collected from a range of donors?

Cedric - So at the moment we can produce platelets from either four donations, from four different donors, or we take them off a special machine where we have one pool of platelets coming from one donor, but we've talked the blood group before, one of the challenges with platelets, is that some people are immunised and they need platelets of a very specific blood type.

Chris - When you say immunisation, you mean that they've made an immune reaction to certain types in the past, so you've got to basically restrict what types you give them?

Cedric - Exactly. The beauty of working with stem cells is that we can edit the DNA somewhat, and because we can edit the DNA we can actually make platelets that don't express blood group, that are universal platelets. The one we produce in the dish can go to anyone. And that's one of the beauties of this technology.

Chris - And are you far away?

Cedric - We are not that far away. We are looking at human clinical trials in the next two to three years.