Marvellous Materials in Medicine
This week, Chris Smith and Izzie Clarke explore the helpful materials that keep us healthy. How are dental implants made and fitted? Bacteria-resistant plastic coatings; and what hip implants have in common with plastic bags. Plus, in the latest science news, why pancreatic cancer is so aggressive - and how we might stop it, signs that something ten times the size of the Earth slammed into Jupiter, and more...
In this episode
00:51 - New potential to stop pancreatic cancer
New potential to stop pancreatic cancer
Paul Timpson, Garvan Institute
Pancreatic cancer has a notoriously dismal prognosis; fewer than one in ten of those diagnosed survive for more than 5 years. Now scientists in Australia have uncovered part of the reason why this disease is so aggressive: the tumour secretes chemicals that subvert healthy cells nearby and turns them into a protective shield that nourishes the cancer and promotes its spread. But now that Paul Timpson, at Sydney’s Garvan Institute, has identified the signals that make this happen, it should be possible to block them, and improve the outlook for patients.
Paul - Fundamentally pancreatic cancer is a major killer. The disease is typically surrounded by tissue that typically protects it from chemotherapy. That surrounding tissue also acts as a super-highway to allow the cancer to spread. We wanted to understand two things: how does that work, and how could we target that. So we've done a very simple experiment: we've taken two types of mice that have pancreatic cancer; one that typically spreads all the time, and another mouse that grows the tumour at the same rate but does not metastasise.
Chris - Are these mice that naturally develop pancreatic cancers or are these the mouse equivalent of a human pancreatic cancer?
Paul - Yeah that's a great question.These mice have been genetically engineered to have the typical mutations that a human does. This mouse has pancreatic cancer that mimics the human disease. And so what we did was we asked a simple question: why does one spread and why does the other not. And so we took the cells, which are called fibroblasts, that surround the tumour and protect that tumour and we mixed them. We took the cells from their metastatic spreading tumour and mixed them with a non-spreading tumour, and suddenly that tumour could spread.
Chris - And when you say you took these fibroblasts, these are not cancerous cells, these are just in the normal tissue that's around the milieu of the cancer?
Paul - Yeah. They're called cancer-associated fibroblasts. A cancer can educate its surroundings to manipulate a cell that normally has a function of wound healing for example, and it tells that cell “I want you to produce X amount of molecules to help me grow, to help me protect myself against the chemo and to help me spread”. And so that's why we took these cells, mixed them with the tumour that could not spread, and suddenly that tumour could now spread. Clearly these cells that surrounded that tumour could educate that tumour to now be able to spread. They’re passing on some sort of information to a tumour that cannot spread, and that was something we were really interested in because obviously if it doesn't spread it's more likely to have surgery and you can actually take the primary tumour out before it spreads.
Chris - And do you have any leads yet to what the nature of that conversation may be? So the tumour is secreting something and that something is doing something else to all these surrounding cells and completely re-educating and changing their behaviour as you put it. Have you any insights into how?
Paul - Yeah. So that's a perfect question. We take the surrounding cells, these fibroblasts, and we ask what are they secreting back to the cancer cell to allow it to spread. What we found was that they secrete a molecule called perlecan and perlecan stood out to us because very recently someone had looked at prostate cancer and this was linked to this spread of prostate cancer. We attacked that molecule and assessed whether this was actually one of the key drivers. Interestingly, the cancer cell itself secretes a molecule to actually tell the surrounding cells to produce this molecule, so almost changing its architecture to say “now protect me from chemotherapy and allow me to spread”.
Chris - It's interesting though that this is almost like a switch being thrown whereby the cancer tells these cells to start doing this they start doing it and then they feed back on the tumour, it’s almost like a positive feedback loop.
Paul - So that's a fantastic point. So we call this the vicious circle because as soon as the cancer cell tells the surrounding tissue what to do and produce this molecule, that surrounding cell talks back to the cancer cells and says “yes, I’m producing more”. And it's a vicious circle and therefore a tumour becomes more and more aggressive more and more invasive and obviously more and more deadly.
Chris - Is it also possible then that you could because you make the area more propitious and fertile for cancer cells by doing this that the initial pioneering cells from the cancer that make this change then actually lay a road down which other less invasive cells can more easily flow? So actually you accelerate the progression of the cancer because it's not just these hardy pioneering cancer cells that then can leave and start to spread and cause further disease.
Paul - Yeah. So that's a fabulous point. It's like a domino effect. And this is exactly what we wanted to address. And for any given tumour, many times you will have a non-invasive cell and beside it an invasive cell that has this mutation and that can cause small amounts of the tumour to actually metastasise and spread. All the other cells then follow. It’s almost like the invasive cells create a burrow and therefore all these non-invasive cells spread as well. It's almost like the cancer cell is already looking for its next home. It's priming the next environment for its next home. And it keeps on going and going and eventually that's why it takes over the body.
Chris - On this basis then Paul, do you think that using this strategy can translate into a clinical difference for patients or is this just very early interesting observations that we've got to build a lot more on?
Paul - What we do believe is that this could be a treatment. The reason we believe this is because we allowed the tumours to fully grow, fully develop and allowed them to almost have some early stages of metastasis. We then inhibited perlecan and we could see a significant difference. So we actually used a fully blown disease to test this. And it does work. So we think that this could translate to the clinic. Yes.
06:60 - Ants befriend snakes to fight foes
Ants befriend snakes to fight foes
Eleanor Drinkwater, University of York
Nature is full of surprises, and this week’s no exception. Scientists working in Madagascar have discovered an ant species that can tell snakes apart, and work with friends to fight off foes. York University’s Eleanor Drinkwater, wasn’t involved in the study, but took Phil Sansom through the findings...
Eleanor - This study seems to show that ants can tell the difference between different snakes. As far as I know, this could be the first study showing that ants react differently to different vertebrate predators.
Phil - Really? This isn't something that we knew ants could do before?
Eleanor - We know the ants can distinguish between different predators. There's some evidence in American ants that when they are confronted by another species of ant, who is intent on stealing or eating their brood, they can evacuate their nest. But applying this to vertebrates is something that's quite novel and exciting.
Phil - What vertebrates are we talking about here?
Eleanor - The species that this study focuses on is a Madagascan ant and in its range there are two different snakes which it has an interesting relationship with. The first of these is a blind snake, known as Mocquard's worm snake which is specialised in eating termites and ant brood. Then the other one is a Malagasy cat-eye snake which is known as the “ant mother”, which I think is lovely.
The reason for this is because it's often found around the nests of this particular species of ant. Interestingly, it's not hunting the ants but instead it eat these are blind snakes who prey on the ants. The researchers set out to try and work out whether or not the ants distinguish between these two different species.
Phil - How do you do that?
Eleanor - What they did is, first of all, found a whole bunch of these different colonies in the wild which is no easy feat in itself. And then what they did is they presented, for five minutes each, first of all the predatory blind snake, then the cat-eyed snake, then a control snake which is a frog eating snake.
Phil - And when you say presented, they were literally holding the snakes in front of the nest?
Eleanor - Yes, apparently that's exactly what they did. I hope they didn’t get too bitten…
The ants completely ignored the Malagasy cat-eye snake and attacked the predatory blind snake as well as the control snake. But the really interesting thing was specifically and only with the blind snake the answer ran back inside and then they had this amazing evacuation of all of the brood.
Phil - Woah...
Eleanor - That's really really exciting. So not only does that show this predator specific response to this blind snake but also the fact that they ignored the cat-eye snake. At this stage it's kind of unclear whether or not there's this amazing symbiotic relationship going on, where the ants allow this snake to live with them and then the snake will protect them. Or it could be the case that the snake is tricking them with chemical cues in order to sneak into these ants’ nest.
They suggest in the paper that the nests provide them with constant humidity and a constant temperature and a really good habitat for this snake to live. Whether or not they are ungrateful houseguests, or whether or not they are actually helping the ants to defend their nest as well, that's kind of unclear.
Phil - Now how do they tell the difference between the two snakes?
Eleanor - They don't go into it in this paper, and it would be really interesting to see some proper research on this, but ants are known to recognise other individuals largely through olfactory cues, so largely through smells. They can even recognize that an individual is from a separate colony, it might be the same species but it's from a separate colony.
Phil - And then also is it surprising? I know ants are complicated and have crazy societies but is it surprising that they have this level of sophistication?
Eleanor - By the stage I'm unsurprised by anything that ants can do. They have this incredible ability to do all manner of things; you have demonstration of teaching in ants. you have demonstration of “tool use” in ants and many other amazing complex abilities. It's one of these papers when you read something like “man, I wish I'd done that. That's really cool!”
Phil - I got to dangle snakes in front of ants’ nest.
Eleanor - I know right!
11:33 - Reversing ageing in the brain
Reversing ageing in the brain
Robin Franklin & Robin Chalut, Wellcome-MRC Cambridge Stem Cell Institute
As we get older, our muscles and joints start to stiffen, making us move a bit slower. This week, a study reveals the same is true for our brains, and this affects how well the brain’s stem cells can keep the nervous system in good working order. The good news is that this aspect of ageing it might be reversible. To explain how, Robin Franklin and Kevin Chalut from the Wellcome-MRC Cambridge Stem Cell Institute. First up, Kevin explained the stem cells they were looking at.
Robin - These are stem cells in the brain. Turns out actually our brain is full of stem cells, they're all over the place, but they're rather unusual sorts of stem cells in that they don't make all of the cells of the brain. So our brain consists of a variety of different types of cell: there are nerve cells which have these long extensions of nerve fibers, but there are also other types of cells called oligodendrocytes and they make the insulation around the nerve fibres. Now the stem cells in our brain are very good at making oligodendrocytes but they're not very good at making the nerve cells.
Chris - And because they can make these supporting cells that surround nerve cells and help them to function, they therefore are contributing, are they, to the ongoing function of the nervous system throughout 60/70/80 years of life?
Robin - Well the real significance of these cells is in the context of disease. So if you lose nerve cells - if you have a disease in nerve cells like Alzheimer's - they're gone forever because the stem cells don't replace them. The diseases of the support cells, the oligodendrocytes - such as MS - do at least in the early stages have the capacity to be regenerated, so your stem cells can make lost oligodendrocytes. The problem of course is that these cells become less and less effective at doing that as you get older, and so in diseases like MS of many decades’ duration there's a big problem of how you deal with the ageing phenomenon in the adult stem cell.
Chris - And Kevin what insights have you now got into why the older brain is less good at fixing itself with these sorts of stem cells than the younger brain?
Kevin - Well I think there is a lot of ideas about why that would be the case, but the finding that we made in this paper that was new is that we found that the brain is stiffening with age. And at the same time we found that if we could take these old stem cells and put them into a young animal, we found that they could be entirely rejuvenated. It’s as if they always knew what they could do but they just didn't know they were supposed to do it. So what we did was we put these two facts together - the fact that it wasn't irreversible, and the fact that the brain stiffens with age - and we made the hypothesis that perhaps it's about stiffness.
Chris - How do we know it's the stiffness that's important?
Kevin - So we have these synthetic scaffolds that we invented so that we could put cells onto a stiff or a soft synthetic scaffold, and nothing else was different except for the stiffness.
Chris - Right.
Kevin - And so what we were able to do is put these old cells onto the very soft scaffold and know that the only thing that was changing was the stiffness.
Chris - And do we know how the cells are doing the cellular equivalent of the Princess and the Pea experiment? How they know they're in a stiff or a soft environment?
Kevin - We have a lot of ideas, and I suppose that one could expand on it, but one of the things that I suppose that we do know is that there's this thing called “mechanical signalling”: how cells are getting signals about how stiff their environment is. And one of the main proteins that's responsible for this is a protein called Piezo1, which is sort of a channel that sits on the surface of these cells and that basically tells the cell, “am I in a stiff environment or am I in a soft environment?”
Chris - And as the cell... because these cells start in one place, they're born in one place, they've got to migrate or move to where they're needed; and I presume as they move they're encountering this environment, they're sensing it, via the signalling from this Piezo1 signal...
Kevin - Yes.
Chris - And that has some effect on the cells telling them to either grow more or less, according to how much signalling is there?
Kevin - Yes, exactly. It's a combination of the environment stiffening, and they encounter all sorts of environment, but then they also have these signals that tell them how stiff that environment is.
Chris - Robin, why have we got a system in our brains then - that can stop the brain repairing itself as well as it could do when we get older - in the first place?
Robin - Yeah, that's a great question and I'm not sure we know the answer to that. I sort of think that once an organism has got beyond the age of being reproductively useful it doesn't matter what happens, and so this is just a function of wear and tear that, the brain starts getting stiffer, our stem cells don't work so well. Of course that's a problem for humans with chronic diseases.
Chris - Sure. And talking of chronic diseases, could you use your learning between the two of you to get these cells to perform better? If you know this signal exists, is it possible to blindfold the cells to the stiffness of the environment in which they find themselves, so they're fooled into thinking they're back in a young brain and they can repair better?
Robin - Well that's exactly what we intend to do. I mean I think that there are two very interesting implications of this study in terms of therapies. One is that if you transplant a fit, vibrant cell into an old environment it ain't going to work, because the old environment will make that into an old cell. But secondly what we found is that actually if you dissociate an old cell from its stiff environment it now works as if it's a young cell, so actually the translation implications of that, of perking up these old cells - that you really haven't clapped out at all, they’re just in the wrong environment - and reinvigorate them, then the therapeutic opportunities are really very exciting.
17:05 - Remembering Kary Mullis and PCR
Remembering Kary Mullis and PCR
Kary Mullis, Inventor of PCR
It’s been used to solve crimes, diagnose diseases, decode the human genome, trace our ancestry, and even find out who our parents are. It’s the technique called PCR - the polymerase chain reaction, that copies DNA and earned the Nobel Prize for its inventor, Kary Mullis. He died earlier this month, Chris Smith revisits their interview from years ago.
Chris - PCR, The Polymerase Chain Reaction, revolutionised the field of genetics. In a matter of hours, scientists could make millions of copies of a piece of DNA that they wanted to study. The technique was the 1983 brainchild of chemist Kary Mullis.
Kary - I was working in a company making these a little short pieces of DNA which we call oligonucleotides. They were very difficult to make. Then a really good friend of mine named Ron Cook brought a machine into my lab one day and he said “try this Kary, it'll replace your whole lab!”.
And in fact instead of needing about seven people to help me I figured I could probably get away with me and the machine and one other person and I probably wouldn't have to work too hard. So I was stuck with the problem of “do I fire five of my good friends here? Or is there any way I can think of increasing the market for oligonucleotides by a large factor?”
Chris - Widely regarded as a colourful character, Kary Mullis put his aptitude for science down to a childhood spent building rockets to fire frog astronauts since the high atmosphere above the family farm in North Carolina. En route to becoming a chemist, he dabbled in writing fiction, became a baker and took by his own admission plenty of LSD in the 1960s and 70s, remarking in one interview that “it was certainly much more important than any courses I ever took”. In fact he said an LSD trip helped him to dream up the PCR reaction process that led to his 1993 Nobel Prize.
Kary - I was driving up to my cabin up in Mendocino one Friday night. I just had in my mind this little picture which anybody familiar would say “hey, that's PCR”. One of the little oligonucleotides there was actually the business end and the other one was sort of a control. All I had to do was sort of say “you know what? If you did that and then did it again and did it again and then did it again you would start amplifying the piece of DNA that's between those two oligonucleotides”, and there would be no end of that process. You could do it forever if you wanted to.
Chris - What he'd envisaged was using two short pieces of DNA to flank the region he wanted to copy, and then using the enzyme DNA polymerase to shuttle back and forth between them to run off an exponential number of copies. But the idea could easily been killed off before it even got going.
Kary - The really critical next stage was getting me and my car and my new idea out of the highway because I had stopped right in the middle of a curvy two lane road up in Mendocino County. There were logging trucks using that road and I could have been slammed off the road and my idea and I would have suffered an ugly axe. I finally said “get out of the road for Christ's sake move over. Get onto this shoulder”. I got over on the shoulder I started making a few notes and as far as I was concerned by the time I got back to my cabin it was done. That was my job.
Chris - That discovery went on to change the world and the technique is now used everyday in thousands of laboratories and industries all over the world. Indeed in the early 90s Kary Mullis himself joined the bandwagon and used his own technique to found a jewelry business selling trinkets allegedly containing the copied DNA sequences of famous dead celebrities Elvis and Marilyn Monroe among them. But he also took pleasure in what others made of his contribution.
Kary - Nothing made me happier lately than - there's a song about it. It's like on YouTube if you look up PCR song you get this really well produced interesting song about my reaction.
Chris - His only regret he says was not capitalizing better on his discovery initially.
Kary - The one thing that I feel like would have been nice is if I’d have said “here it is but I'd like to keep one percent of it myself in terms of the profit from it”. I was young and foolish I guess. But I did get the Nobel Prize for it which is quite a fun thing to have happen to you.
21:43 - Massive planet slammed into young Jupiter
Massive planet slammed into young Jupiter
Ravit Helled, University of Zurich
This week scientists studying our Solar system’s iconic gas giant, Jupiter, think they’ve found evidence that something ten times the size of the Earth slammed into the planet way back in history, reconfiguring the shape of its core. As Izzie Clarke has been finding out.
Izzie - Jupiter is the biggest planet in our solar system, and it’s atmosphere is mostly made of hydrogen gas and helium gas - that’s why it’s called a gas giant. But this planet’s formation and structure has been a bit of a mystery…
Ravit - We thought that Jupiter could have a core, with the core being quite compact; a few tens of percent of the planetary radius. The composition is primary heavy elements so that means metals, rocks and ices
Izzie - That’s Ravit Helled from the University of Zurich in Switzerland, who has been using computer models to explore how the gas giant might’ve formed and whether this core really existed. Eight years ago, in August 2011, NASA launched Juno, a three pronged, almost claw-like probe to do some exploring…
Ravit - The aim of the mission was to really understand Jupiter as a planet, looking at different aspects. The gravity field, the magnetic field, the atmospheric variations… And by that better understand the origin of our own solar system and also better understand giant planets in general.
Izzie - Juno reached Jupiter three years ago and the mission is only halfway through. But Ravit has been interested in Jupiter’s gravity…
Ravit - The gravity measurements of Juno are essentially used to make new structure models of the planet. We can understand what the planet looks like from the inside; what is it made of, and how the material is distributed within the planet. New structure models of Jupiter that fit Juno data essentially tell us that the core of Jupiter might be fuzzy or diluted and rather large. Which is very different than this standard compact core that we had in mind before, before the Juno mission.
Izzie - I see. It's actually not like a little compact thing in the middle and then something else completely surrounding it. It's more diluted. How can that be possible?
Ravit - Exactly. It means that the core can be extended to a few tens of percent of the planet's radius. And it also means that the core is not very distinct within the planet. It can also consist of lighter material so it's not just pure heavy elements but it could also be mixed with some hydrogen and helium.
It can also be that you know it's distributed in a gradual way so you don't have a distinct core-envelope boundary. You don't just have the hydrogen and helium envelope above it but you somehow have a more gradual transition between the inner part of the planet and the outer part of the planet.
Izzie - What do you think could cause that? What would cause that?
Ravit - Yeah we didn't expect that. So we think it was a giant impact of a large planetary embryo that hit Jupiter right after its formation.
Ravit - What could that have been?
Ravit - If you have a giant impact which means that you have a huge body impacting Jupiter. In our simulations, that the body was assumed to be 10 Earth masses, so it's a very large object. And then if it impacts Jupiter in the right velocity and geometry, so it really comes head on, it can really penetrate all the way to the centre of the planet. Basically, it can destroy the core and lift the material to the outer part of the planet and then create this dilute core.
After the impact, we modelled the evolution of the planet and we asked “can we get something that looks like Jupiter today?” And the answer was yes.
Izzie - But we’ve seen this before. Impacts are important to understand other planets in our solar system; on mercury there’s a high metal-to-rock ratio, a lot of planets are tilted most likely due to impacts, and our own moon is probably a result of one. And as technology and space exploration advances, this insight into jupiter can help those discovering planets outside our solar system….
Ravit - I think we are in a great time now to do this kind of research because we can really explore the solar system planets in detail and at the same time have this huge great statistics of planets around other stars. The idea is to bridge these two aspects and get a better understanding of giant planets and planets in general.
27:05 - MAILBOX: Why does Titan have an atmosphere?
MAILBOX: Why does Titan have an atmosphere?
Time for a look in the Naked Scientists mailbox and Izzie Clarke received this question from Alistair in Gloucester,
"I'm interested in NASA's dragonfly quadcopter mission to Saturn's moon Titan. How can a moon with such a low gravity hold a thicker atmosphere than Earth? Is this the same mechanism to give Venus its thick atmosphere?"
Izzie - Alistair, this is a brilliant question. Titan is Saturn's biggest moon and it's similar in size and mass to our own Moon. The difference is that Titan is much colder, and the colder molecules move more slowly, which makes them easier to hold on to. Titan is minus 100 degrees Celsius. Our moon, however, is about plus 100 degrees Celsius when it's lit by the Sun. So Titan is able to hold onto that atmosphere which the moon can't.
Now looking at Venus, Venus is a much bigger body and has stronger gravity. So even though it's extremely hot, and it’s got these energetic molecules, it's this gravity that means it can hold on to its thick atmosphere. I hope that answers your question.
29:00 - Designing dental implants
Designing dental implants
Nick Williams, Dentist. Zoe Laughlin, University College London
Do you have a hip replacement or a dental implant? Or know someone that does? And do you know what they are made from, or even how they’re made? This week we’re exploring the helpful materials that keep us healthy. First, open wide! Emma Hildyard has been to see Nick Williams the dentist. Plus, Materials Engineer Zoe Laughlin from the Institute of Making at University College London.
Emma - Most dentists advise us to brush our teeth for two minutes twice a day. But the average adult only devotes around 70 seconds of their time to cleaning their teeth. Poor dental hygiene can result in tooth decay and gum disease which, if untreated, can result in tooth loss. I wondered what dentists are currently using to replace lost teeth. And what better way than to go to a local dentist surgery here in Cambridge to find out!
Nick - Hi Emma, welcome to Devonshire House, I’m Nick Williams. Would you like to come in and have a seat?
Emma - Whilst Nick cranked up the chair so that I wasn't lying down, I asked him to explain what a dental implant actually is.
Nick - Dental implants are the best way we have of replacing natural teeth. Historically, people would have had a missing tooth and you would have to prepare the teeth on either side to make way for a bridge which is quite destructive. The good thing about a dental implant is that it’s standalone so you don't have to destroy the natural tooth structure on either side.
Emma - Nick showed me an example of a dental implant, which looked like a normal white tooth that was attached to a metal screw at its base. Initially, the metal screw is placed into the mouth on its own and the crown is then attached at a later date. Very reluctantly I asked how the metal screw was secured in the mouth.
Nick - Where the missing tooth is, you drill a small hole to receive the implant, you put the implant in - similar to how you would screw into a piece of wood. A standard implant is around four millimeters in diameter, so you prepare a site that's three and a half millimeters, so the implant is very slightly bigger than the site you prepare it for. You put it in and a slow torque, there's a very slight amount of bone compression but you don't want too much, just so that it's stable enough to be gripped for that initial healing phase.
Emma - Nick then explained how your body responds to the implant being screwed into your mouth and how we use its response to make sure that it’s secure enough to not wiggle about.
Nick - When you break a bone for example, you get a blood clot into that area and over time that clot turns into new bone. You get a similar process for the site that's prepared for the implant. You get the blood, growing onto the implant and that then slowly turns into bone, Normally we’ll wait anywhere between six weeks to three months. The bone is then hard enough to take an impression of the implant fixture and get a crown made specifically to go on top.
Emma - The metal screw is made from a titanium alloy that has been designed specifically to be put in the human body. I asked Zoey Laughlin, a materials engineer from University College London why titanium is a good metal to use in medical implants.
Zoe - It's great to be used in the body because it's essentially described as bio compatible in that the body doesn't reject it. Imagine if you were to get a splinter or a bit of shaving of metal lodged in you through an injury, the body slowly works it out, it slowly rejects that foreign body. But it doesn't do that with titanium so it’s safe to implant it into the body and the body doesn't try to somehow eject it. It's also really strong and lightweight. If you're making a kind of hip joint, you don't suddenly double the weight of your right hand side by implanting it in.
Emma - Titanium is very corrosion resistant too, meaning that it won't begin to form rust like iron would. As a result of their unique properties, titanium alloys are used in a variety of medical implants ranging from teeth to hip and knee implants. These implants are often complicated shapes, like the screw. These require a special process of machining called CNC milling. These machines use rotary cutters to remove material from a bulk block of material.
Zoe - They'll have a computer generated CAD file that is the bespoke particular shape they want and then you would mill the titanium out of that shape. That often can lead to quite a lot of wastage because, you can imagine, you mill it out of a solid block of it. Lots of that material then gets lost. It can occasionally make things weaker when you mill them because you create lots of little tiny stresses and strains in the material that can later fracture. There's work now being done to look at 3D printing with titanium. This is a technique that essentially starts with titanium powder in a box. I'm slightly simplifying it, but imagine you've got a vat of powdered metal and you fire a laser beam at it and the metal will melt and fuse where the laser beam is focused. You go blast blast blast blast and you run the laser over a layer of the powder and it fuses together. Then you deposit another little layer of powder like you're sort of sieving flour onto the surface, then you blast it again with the laser and you just do that thousands of times and you start to build up these fused 3D printed titanium objects.
Emma - Once the screw has been made and implanted, what about the crown? The bit that is attached on the top of the screw that looks like a tooth. What’s that made from, and how is that made?
Zoe - That can be an entirely ceramic object that starts life as a little cube. They take a scan of your mouth and the tooth that they want to copy let’s say, and they can make a virtual model of what tooth shape they want and then they send it to a tiny CNS mill that carves out this perfect little tooth that can be made in a whole range of tones of white and beige to match exactly your teeth shade. So that it's really a very unobtrusive and unobvious tooth implant.
Emma - Well there you have it. It's nice to have an insight into the materials that help us chew. It's no excuse for not brushing your teeth for two minutes though.
35:53 - Bacteria-resistant coating for catheters
Bacteria-resistant coating for catheters
Andrew Hook, University of Nottingham
Each of us produces a couple of litres of urine a day, and getting rid of it isn’t normally a problem for a healthy person. But some people can’t pass water this way and need help, either in the short term or for longer periods of time. This is where a urinary catheter comes in. This is a flexible rubber tube that is inserted along the urethra to remove urine directly from the bladder. But a big problem with catheters is that, in doing this, they can introduce infection. But now researchers at the University of Nottingham have developed a bacteria-resistant coating for these devices to cut down the risk. Andrew Hook is one of the developers and joined Chris Smith on the show.
Chris - How big a problem is it that you're trying to solve here? How many people succumb to these sorts of issues?
Andrew - Yes. So it's a big problem. Generally speaking, there's about 3 to 5 percent for people who have to use a urinary catheter and this can be, hundreds of thousands of people will use a urinary catheter each year within the U.K. You can do the math there. This is a problem that affects lots of people, and it's also a big cost to the NHS. It's estimated to cost up to two and a half billion pounds per year to treat.
Chris - And why is it a problem? Why does this happen? Why should putting a catheter that is sterile, it comes out of a sterile packet into the body, why should that lead to a higher risk of infection?
Andrew - When you put a device into the body, what that allows bacteria to do is, usually the bacteria are what we call planktonic, or a single bacteria and the body's pretty good at dealing with these. And what happens when you have a device, this is a surface the bacteria are able to attach, they’re then able to form what we call biofilm. You may have come across a biofilm before actually we're just talking about dental hygiene. Actually dental plaque is a type of biofilm, and when bacteria form biofilm they’re up to a thousand times more difficult to treat by antibiotics, or your host's immune system. And it's the ability of bacteria to attach to medical devices that causes this biofilm. This is what causes these persistent infections associated with these devices.
Chris - So in an ideal world we would like some kind of catheter, or material to make catheters and other plasticware that we put into the body, that does not allow bacteria to cling on in the first place, or assemble these protective biofilms that insulate them from either the body's own immune system, or the antibiotics that we try and get rid of them with.
Andrew - Yeah. So that's exactly the strategy that we were trying to take, we'd like to prevent the bacteria from being able to form these biofilms at all. And then that would allow the immune system to be able to deal with the bacteria, if the bacteria are able to invade the body at all.
Chris - And you reckon you've got something that fits the bill?
Andrew - Yeah. So we've been able to develop a polymer coating, or plastic coating, that we can put onto medical devices and we've been able to test it. We're able to reduce, in the lab, biofilm formation by up to 99 percent. So it's really exciting that we can see these results, and yeah we're really excited about this technology.
Chris - This works in clinically relevant bugs does it? The kinds of bacteria that cause urine infections, if you have a surface which is coated in your new material, those sorts of microbes can't gain a toehold.
Andrew - Yeah. So we were focused on the urinary catheter and so we were testing this particular polymer, we were testing it on the bacterial species associated with those infections, so things like e. coli, and on a bacteria called Proteus mirabilis. And we've tested it with these bacteria, and that's exactly the ones we were able to show a reduction in this biofilm formation.
Chris - What is the new material and how does it do this?
Andrew - So it's a synthetic polymer, so it's a plastic coating that we can put onto the medical device. The particular polymer that we are using has a special property which we call amphiphilic. So materials are usually either able to dissolve in water. We call that hydrophilic, or they prefer to dissolve in things like oil which you call hydrophobic. Our polymer actually is amphiphilic. So it's both water soluble and oil soluble. And this particular property is what is able to disrupt the bacteria's ability to form biofilm.
Chris - And is it actually any good at doing that? So if you if you make a surface with this, you said that it suppresses the numbers down, but it only takes one or two microbes to then trigger an infection. So if you actually do this clinically, have you got data showing that this protects patients?
Andrew - Yeah. So we've begun clinical testing in March, earlier this year. So we're still in early days of the actual clinical testing. We've tested it in about 100 people. The results look pretty good. It looks like we are reducing the amount of bacteria associated with the particular devices, and what we're really interested in doing is reducing the infection rate. If you have a catheter it's a 3 to 5 percent infection rate associated with using that device. And we'd really like to just be able to reduce those sorts of infection rates. But it looks really promising in the clinical trials we've done thus far.
Chris - And could you just very briefly could you translate this do you think, beyond the bottom end of the body, to plasticware and devices going into any part of the body? Because anything we put into the body; hip replacements, heart valves, whatever, is susceptible to infection by circulating microbes isn't it? Could you prevent that?
Andrew - Urinary catheters have really, the highest rate of infection of any medical devices. They’re the obvious place for us to start, but once you've been able to demonstrate efficacy, that it works with this particular device, then absolutely we would like to be able to explore other particular devices. We are particularly targeting preventing that biofilm formation. And so there's those devices such as endotracheal tubes where you get ventilator associated pneumonia, that sort of device is absolutely suitable for this material as well. And yes, in fact, all the medical devices.
41:42 - Improving hip replacements
Improving hip replacements
Sophie Williams, University of Leeds
If we did the recommended 10,000 steps a day - that equates to 3.65 million steps every year, a quarter of a billion in a lifetime... It’s not really surprising that, as we age, the cartilage that provides the slippery shock-absorbing surface inside our joints begins to wear and can become painful. Eventually, the only option may be a hip replacement. This is probably one of the most successful surgeries - in terms of quality of life improvement - ever invented; Even so, Sophie Williams, from the University of Leeds, is trying to make things even better, as she explained to Katie Haylor.
Sophie - The hip is a ball-and-socket joint. So you have the socket in your pelvis, we call that an acetabulum. And with that in the top of your thigh bone there’s like a ball, and that sits inside this hollow of your acetabulum. And both of those are covered in cartilage, and that's really smooth and that is lubricated really well. So as you walk along it all sort of glides, very low friction.
Katie - Considering this design then, why might someone need a hip implant?
Sophie - In the UK it's really because of osteoarthritis. So that's when your cartilage is effectively worn away, so you don't have that lovely soft cartilage layer there that makes it frictionless. You end up with bone against bone and that starts to cause pain.
Katie - So we know what a hip joint looks like. What does an implant look like?
Sophie - Very much like that ball and socket. So the head is just going to be a round sphere, a ball. Think about a very smooth golf ball. They tend to be smaller than the natural hip: so the natural hip may be around five centimetres in diameter; hip replacements tend to be smaller, so fairly common is something that is 28 millimetres. And then the socket most likely will be a white plastic that is then also fitted into a metal shaft, so you have a plastic liner and then a metal outer and then that all fits into the socket of the hip.
Katie - Why metal and plastic?
Sophie - That was sort of a combination that was found by chance back in the 1960s and we haven't hugely deviated from that. Those materials are quite low-wearing; we've been able to choose metal-on-plastics that don't have a huge reaction from the body; and very much looked at more natural alternatives, but actually not found anything that is wear-resistant that would meet the demands of the job.
Katie - So by wear are you talking about, if you get any two surfaces and rub them together over time, that's going to become worn right? You might get bits breaking off and causing... well I guess in the body do they cause trouble?
Sophie - They can do. And this is one of the things, we're always looking at materials that wear less. So in the body, as you walk along, then you will get that metal head rubs against the plastic and you get very, very tiny plastic wear particles.
Katie - What happens then if they get into your bloodstream? Do they get into your bloodstream?
Sophie - The particles do tend to stay fairly locally. While I say that they're really tiny, they're not tiny enough to start flowing around the body. But cells will come along - and they're kind of around the size of bacteria - so cells will come along and see them as something foreign and try to eat them up, and will cause a reaction. Those cells want to get rid of those particles because they don't think they should be there. So they'll send out some chemical messengers, and those chemical messengers then change the behaviour of the bone cells in that area. So you start to get a wearing away of the bone, so actually the hip replacement can become loose. This is quite a long-term process, this tends to happen sort of 15 years after the joint was put in the body. Our plastics have changed; while we still use metal and plastic like we did back in the 1960s, we've changed our plastics so we get even less wear with them, so you’re even more unlikely to have issues with wear.
Katie - So what things do we still need to work on when it comes to hip implants? Because that sounds like it could be quite a complex issue to solve. So how can you go about getting less wear?
Sophie - So we've already done quite a lot. It's a polyethylene that’s used, and that's what your plastic carrier bags are also made of, but it's ultra-high-molecular-weight. That means it's really, really big, long polymer chains that are in that material and then really closely packed together. We zap these implants with gamma radiation that causes cross-links in the material, so chemical linkages between those chains, and that actually reduces the wear of the material quite significantly. So you have that hip head going backwards and forwards over it. You need to put in a lot more energy, if you like, into that system to get those chains to break down and the particle to be released.
The problem is it also makes the material less ductile, so that's less stretchy. Now it's not massively stretchy anyway, but it becomes much more brittle. So let's think about a bar of chocolate on a hot day, and it has a bit of give to it, you could bend a little bit. That's a good thing in a hip replacement: just a tiny bit of bend in that plastic socket. If you put it in the freezer it’s then going to be really brittle. So if you put lots and lots of gamma radiation into your polymer it will become more brittle. So as material scientists we do need to think about what that offset is; that you want to reduce the wear but you don't want to cause the material to become too brittle. So there is a compromise between those two. Lots of research has been done and we've found the region that we need to be in so the materials aren't too brittle but that they will be low-wearing.
Katie - Gamma rays… this doesn't mean that a hip implant becomes radioactive, does it?
Sophie - It doesn't, no. Not radioactive at all. And in fact gamma radiation is something that's used to sterilise all sorts of medical implants and instruments before surgery.
Katie - And it's part of your job to try and help the surgeon to reduce the chances of anything going wrong then?
Sophie - Yeah. You know, we work with surgeons and we also work with implant manufacturers. We have simulators in our lab, so these act like pseudo-patients, someone walking along for millions of millions of steps, and we see how those materials wear. And then we'll also change things a little bit, like maybe how the head in the socket has been positioned, and see if that changes the amount of wear we get. So we can really understand how those materials are working before we put them into patients.
Katie - How good are these metal-on-plastic hip implants? Are they as good as the real deal?
Sophie - No, it is always going to be a replaced part of your body. But the vast majority of patients really do talk about their forgotten joint that they don't really know it’s there. They can certainly continue to have the kind of lifestyle that they want to be having.
48:44 - Skin substitute to repair burns
Skin substitute to repair burns
Malavika Nair & Tricia Smith, University of Cambridge
Skin is one of our most important - and largest - organs. It keeps out unwanted invaders, regulates our temperature and prevents us from dehydrating, or swelling up in the rain! But, it is very much in the firing line, sometimes literally, meaning it can succumb to severe burns. And these may require healthy skin to be transferred or grafted from another body area to repair the damage. But, when the burn covers a very large area, obtaining sufficient skin for such a graft can be difficult. Now researchers at the University of Cambridge have developed a technique to create repair materials made from collagen, the connective material that gives skin its strength. Tricia Smith and Malavika Nair brought some into the studio to show Izzie Clarke.
Malavika - What I've given you there is a collagen scaffold, and it's basically 99% air and 1% collagen. It's a scaffold material, which is basically what we're used to seeing in terms of building; so they're just temporary structures that we put up so that the people who are doing the construction work can weave through, and lay down the foundation to the building, and repair it. And in a similar way within the body what we want is the cells to recognise these scaffold areas, weave through them, and lay down new tissue and regenerate this tissue.
Izzie - So how do you make one of these things?
Malavika - To make a collagen scaffold we go through a process known as freeze-drying. So what we're freeze-drying here is essentially a suspension of collagen and acetic acid, so that’s just vinegar and collagen put together and blended up. When we then put this into the freezer, we allow ice crystals to grow. Now ice is quite particular because it actually doesn't like a lot of foreign bodies within its crystal structures. So collagen is a foreign body; as the ice crystals grow, the collagen would be excluded off to the side of the ice, but it allows then the collagen to pack around the ice and be templated by these ice crystals.
Izzie - I see. And so how do you get rid of the ice?
Malavika - To get rid of the ice we go through this process known as sublimation. Now sublimation is a process where we go from the solid to the vapour and just skip the liquid phase entirely. If we were to drop the temperature back up to room temperature then we'll just melt it, and it will just get rid of all this beautiful structure that we've created and we're trying to keep. We reduce the pressure in this freeze-dryer and we allow these ice crystals to then go to vapour, and then we are left just with the empty space with the collagen packing around this empty space. These empty spaces basically serve as the channels for the cells to move through when we put cells onto these scaffolds or when we put the scaffold into the body.
Izzie - This one that you've given me is quite spongy. Because we’ve got so much different tissues in our body, can you change the properties of it?
Malavika - Absolutely. So collagen is quite ubiquitous in our body and we find it in tissues that are very different mechanically and biologically. So we find collagen in the skin, in the heart, in the cornea, and even bone; so we can tell that we don't really want the same collagen that we have in our bone in our skin, or vice versa. So in the same way, what we do is we can tailor both the chemistry and the mechanics of this collagen scaffold through various processes, one of which is cross-linking. So cross-linking allows you to improve the mechanical properties and to stiffen it. So that would prevent us from putting something that's more suited for the skin into the bone, for example.
Izzie - And Tricia, how does this collagen scaffold help skin - or burnt skin - to heal?
Tricia - So what it actually does is instead of allowing the burnt area to heal, it interrupts the healing process; because when normal skin heals, when you have a big area that's damaged, what happens is the skin will contract so that you have as small an area as possible, and then a scar will form. And that scar doesn't have the same mechanical properties, it doesn't have the same structure as healthy skin, and therefore it doesn't perform the same function. And if you have a large area that's damaged actually what can happen is you lose mobility of that area, you lose temperature control, you lose all of these things you listed at the beginning. So what the scaffold does is it blocks the contraction of that wound and that promotes something called regeneration rather than scar formation.
Izzie - If I had a particularly nasty burn, this would get introduced to that damaged area, then what happens? Does it just stay in the body?
Tricia - So what happens is that cells will be recruited into the scaffold and will start to lay down their own healthy tissue and their own collagen, and at the same time break down that scaffold so that in three weeks’ time, four weeks’ time, it will be gone. And all you'll have left is regenerated tissue which functions correctly, and none of the original scaffold.
Izzie - So how well does it work? What results have we seen?
Malavika - So one of the examples of successful collagen implants being put in is in cartilage repair. And cartilage repair, this can pertain to the meniscus - so this is in the knee - or even just anywhere where there's a join between lubricating joints and the bone. So one example of this is where they've tried to have a bridge between the bone, which is filled with minerals and a lot stiffer, as opposed to the cartilage which is a lot more spongy and it's a lot more fluid in some ways because we want to try and lubricate that joint. And this has made it out into a commercial application.
Izzie - So it's really important that actually it's not just these burns that we're talking about. This could repair a lot of areas of the body. Could this do internal organs should one of those get damaged or need help in the future?
Malavika - Absolutely. Anything that is based on collagen, which is pretty much every organ in the body, could be serviced by collagen scaffolds as long as we put the right chemistry in it. If we can tailor all of these properties, including the mechanics degradation, then we might be able to tailor it just for pretty much any organ in the body.
Izzie - And Tricia, what are you currently doing to improve how these scaffolds can help that natural healing process?
Tricia - So we already know that the scaffold itself - when it has the right degradation properties, the right mechanical properties, the right pore size - can stop contraction and promote regeneration of the skin. But one of the ways in which these skin grafts fail is that they're not nourished correctly in the centre, and that is because there's a failure for blood vessels to grow in from the edge of the wound into the center of the graft and provide the oxygen needed for the cells to proliferate there. So what we're trying to do at the moment is retain some structure which promotes that regeneration, so the right pore size for that sort of thing, but also add in regions to the scaffold where we can promote that ingrowth of blood vessels from the edges of the wound to the center.
55:40 - Why does wildlife thrive in Chernobyl?
Why does wildlife thrive in Chernobyl?
We received this question from Bill. Phil Sansom asked Victoria Gill, a BBC news correspondent who reported from Chernobyl early this year, to shed some light.
Phil - We put your question on the forum. User RD pointed us to a 2007 paper showing higher frequency of abnormalities in barn swallows around Chernobyl. Alancalverd said there’s a big spectrum between surviving and thriving. Others were more interested in the new Chernobyl vodka. Focus up, people.
To answer the question we needed someone with first hand experience. Victoria Gill is a BBC news correspondent who reported from Chernobyl early this year.
Victoria - The Chernobyl exclusion zone. That’s the name of the 4,000 square kilometre area that was abandoned after the 1986 disaster. And you’re exactly right about all that wildlife. Since most humans moved out, researchers moved in, at least for short periods. And they’ve recorded an increase in the population of all kinds of species: wild boars, bears, and even wolves in the zone. Apparently some species that used to live there historically but disappeared when the place was populated by people have come back.
Sir David Attenborough himself was even there for his recent Netflix series, Our Planet. So yes, wildlife seems – according to most research - to be thriving throughout the zone. That is for multiple reasons, but primarily it’s the very little human activity that there now is in that area. And crucially, the contamination isn’t as widespread and as ‘blanket ground-poisoning’ as many people believe. And in simple terms, the vast majority of the zone is relatively low in contamination.
So you can measure that as a dose. The dose per hour of radiation is often measured in a unit called microsieverts per hour. The average dose for someone in the Chernobyl exclusion zone – unless they spent a great deal of time in a very contaminated hotspot for some reason – their annual dose would be about 1,000 microsieverts. You would get about 60 microsieverts from one London to Los Angeles flight. And you’d get an instant dose of about 10,000 microsieverts from a whole body CT scan.
So now most of the zone, for wildlife and people, is relatively safe. And a few people called self-settlers who refused to abandon their homes in 1986 still live there. There’s no agriculture allowed or any developmental building of this officially contaminated land, and the locals there are actually fighting to have those restrictions lifted.
So there’s a huge amount of misunderstanding about how dangerous the zone is. But it’s something that scientists are still working to get to the bottom of, so that people in Ukraine and Belarus can be armed with the facts, and get on with their lives.
Phil - Thanks Victoria. Next time we’re answering this question from Anthony. Anthony - penne for your thoughts?
Anthony - When pasta or rice is added to boiling water, there is a sudden surge of the boiling water, to the point that the pot boils over with bubbles. Why is this?