Regeneration: How the Body Heals

18 December 2018
Presented by Chris Smith, Georgia Mills.

Share

This week, we are getting to grips with regeneration: how does your body heal itself, and what can science do to help?  Plus, in the news, the tech set to change our lives in 2019, the hidden perils of AI, and does a crossword a day really keep dementia at bay?

In this episode

Breast tumour

00:47 - Combined melanoma treatments improves survival

A new type of treatment uses your own immune system to attack cancer...

Combined melanoma treatments improves survival
with Howard Kaufman, Massachusetts General Hospital

Melanoma, or skin cancer, is the fifth most common cancer, and rising. Medical therapies have not kept pace, and in some countries melanoma is one of the top ten killers of people. Now, Howard Kaufman and his team from Massachusetts General Hospital have begun to develop a therapy that uses the patient's own immune system to attack the cancer. Chris Smith heard how...

Howard - The immune system protects our body from foreign invaders such as bacteria and viruses but it can also recognise damaged or injured cells. And so, when a cell becomes a cancer cell the immune system can tag it, and in some cases it can destroy it.

Chris - The problem is that cancers carry inbuilt mechanisms to deflect the immune system, so that they can grow unhindered. And so, to be successful a therapy needs to somehow surmount this natural immune defence and persuade the immune system to regard the cancer as hostile. To make this happen the Massachusetts team have developed a modified virus that can selectively grow in cancer cells. As well as destroying the tumor where it's injected, the growth of the virus also provokes the immune system to attack the cancer, and subsequently to then patrol the rest of the body ferreting out tumour that has spread elsewhere.

Howard - So these viruses are what we call attenuated, meaning they're a little bit weaker so they don't cause as many side effects as a normal virus would cause. This particular virus is a herpes virus which normally would cause a cold sore. And the genes that cause some of the pathology are removed, and it has the added benefit that it seems to be able to replicate more efficiently in a cancer cell. And it's not able to replicate in a normal cell. And this is the basis by which oncolytic viruses are particularly well suited to treat cancer.

Chris - On their own though, the viruses only trigger a successful response in about a quarter of patients. But what happens if the viral therapy is combined with other treatments that attack melanoma in different ways. One class of drugs already approved to do this are agents called immune checkpoint inhibitors. These block the ability of cancer cells to deflect the immune system making it harder for tumour cells to hide.

Howard - So the way I like to describe it to my patients, is that if you get a viral infection you need your immune system to eradicate the virus but then you want to shut that immune system off, because when you get a cold or the flu, the reason you feel miserable is largely because the immune system is being overactive. So there are a set of molecules called checkpoints and these turn the immune system off. And cancer, being the sneaky disease that it is, has learned how to use these checkpoints to turn the immune system off. And this allows the cancer to grow. So checkpoint inhibitors are a new set of drugs that block this kind of shut off switch. And when you shut that down the immune system stays active for a longer period of time and this allows then, the immune system to deal with the cancer.

Chris - And the combination of the checkpoint inhibitor drug with the modified virus can greatly boost response rates.

Howard - We combined the virus with checkpoint inhibitors, which are also approved to treat melanoma, and the early results of those clinical trials are showing tremendous promise, where we're seeing almost a doubling, if not more, of the response rate without an increase in side effects.

Chris - Which is great news. But it does still mean that a significant number of individuals nevertheless fail to make an effective immune response against their cancer. The same results are seen in experimental mice with melanoma. Part of the problem seems to be that the therapy itself triggers the cancer to increase its own production of other immune bypassing signals, including one called PD-L1. The good news is that drugs exist to block that too. And when these are added to the mix, at least in mice, the results are very impressive.

Howard - When we put the three drugs together, which hasn't been done before in humans, we actually saw almost 100 percent response in the animals. And this suggests that the three drug regimen might be a particularly effective way to treat patients. And all three of these drugs are already FDA approved as single agents. And another important point that we saw in the studies, was that because this was so effective we were able to lower the dose of almost all of the agents. And so it suggests that we might not have to use as high of a dose and that means we may not have to deal with as many side effects.

Lightbulbs

Bendy screens and hoverbikes: the tech of 2019
with Peter Cowley, Invested Investor

Now we’re getting to the end of 2018, let’s look forward to what awaits us in the bright new year in the world of tech. Georgia Mills spoke to Peter Cowley, techspert and angel investor...

Peter - Well first of all the Consumer Electronics Show which is beginning of January is where the launches occur for 2019. It’s huge, been going about 50 years, 200,000 people turn up. The launches aren't yet public. They sort of come out the weekend beforehand but the ones there seem to be rumours about, there are four of them. One is a transparent TV. That means you can see the wallpaper through the TV perhaps, not quite sure why that is.

Georgia - Why would you want your TV to be transparent?

Peter -  No clue. This is only a rumor. Secondly a foldable phone. Now of course that'll presumably be a screen with two sides but if you go back probably even before you were born there was foldable phone in the 80s from Motorola in 1989. Voice control of more devices this will be more useful. The fact I hardly ever use a TV in the lounge means I have no clue what the buttons do on the remote controls so voice control actually makes sense to me. And finally there's going to be homebrew kit for beer in the same way that you get coffee machines so you canput the ingredients in the capsule that would produce beer.

Georgia - Some of my housemates brew beer and it takes them a very long time and makes a massive mess. So how would tech help speed this up?

Peter - It’s just a rumour! I’ve seen a photo, that’s all.

Chris - Do you just add alcohol then? Do you put the booze in as a separate supply?

Peter - It probably actually creates the alcohol as is any Beer Kit would do.

Georgia - And when you say foldable phones like I'm imagining a flip phone...

Peter - No I think it'd be more than that. I think the LCD screens are becoming flexible more and more, in time we will have packaging on the side of our cola cam which will actually have your own message on it. Hello Peter. Drink me.

Georgia - And what about out of the home? What about travelling? Is there any big changes coming?

Peter - Well outside the home autonomous vehicles are moving on. There's still a lot of societal and regulatory work that needs to be done before they become adopted.

Georgia - We are constantly hearing though autonomous vehicles are sort of they're coming they're coming they're coming but do you reckon 2019 will be the year?

Peter - No, there’ll be a lot going on in the background, there's a lot of work going on in terms of vision systems etc., where we went to see progress but not that much. About 18 months ago I was on the programme talking about taxis in Dubai. These are effectively drones. They still haven't arrived yet.

Chris - They’ve got hover bikes though because I was asked to comment on this recently. They're equipping the police with these things which are basically a motorbike with 4 fans one, two on the front two on the back and it looks like a really good way to take someone's head off actually if you were to come in a little bit low. They're un-enclosed fan blades, if you fell off you would mince yourself.

Peter - They're actually Wankel engines and in there, four Wankel engines. Whether they’ll get adopted I don’t know, but he's really working that project for many years.

Georgia - I'd like one of them for Christmas.

Chris -  You wouldn’t want to fall off Georgia I'm not kidding because literally these massive blades going around thousands of revs a minute. They’d mince you.

Georgia - Are there any sort of other fun toys you've got your eye on?

Peter -  I’m a very early adopter, so a couple of things I really would like would be some pair of earphones that Bluetooth that you can sleep on. You know that will protect the ears for ride noise cancellation but also you're not going to be totally discomfort but by themselves you can listen to the naked scientist where you're going to pay the extra fee.

Chris - You do know Peter at this conference you're talking about the tech conference. You do know what gadget headlined there couple of years ago don't you? It was some it was radiation repelling boxer shorts.

Peter - Haven't you got some?

Chris -  No no I haven't actually but I toyed with the idea. They've got this sort of silver thread in the material and the idea is this mesh work of silver thread soaks up radiation from your mobile phone in your pocket might be incident on your manhood. Yeah. And because it's silver, the anti microbial effects of silver also mean that you'll keep down the germ load in your boxer shorts as well!

Georgia - What about on a society level? Is there a huge amount going on there?

Peter - Yes, for instance it's said that three countries will ban autonomous or semi autonomous vehicles during the next year, but the same time some rubbish collection will start actually start to be autonomous. This Duplex voice chat bot. That's a bit of a mouthful. I talked about that some months ago. This is Google duplex actually where you're talking to a computer that's umming and erring and pausing and etc. There's got to be some work on that to stop people being conned by that. Drone regulations, We know that's got to happen because we will have more more drones and there's likely to be more accidents. And of course the big one  - fake news  - something's got to happen about the way that media is distributed to our feeds.

A newspaper with a crossword

11:06 - Crosswords can't save your brain

Will it help if we keep our minds sharp with plenty of puzzles?

Crosswords can't save your brain
with Duncan Astle, Cambridge University

We’re often counselled to “use it or lose it”, particularly when it comes to keeping your mind sharp as yet get older; sayings like “a crossword a day keeps dementia at bay,” are common. But is it true? A new study published in the British Medical Journal says not. Chris Smith spoke to psychologist Duncan Astle, he wasn’t involved in the study directly, but he does work on similar research projects at Cambridge University and he’s been taking at look at the findings...

Duncan -  It's been done by a group in Aberdeen led by Roger Staff at the Institute of Medical Sciences and with his colleagues...

Chris - And what were they seeking to find out?

Duncan - Well they recruited a group of 64 year olds and then they followed those individuals over the next 15 years seeing each person five times each within that time period, and each time we saw them they measured different cognitive skills like short term memory and attention skills and they also conducted a questionnaire which they called the intellectual engagement questionnaire. It asks questions about do you enjoy reading? Do you enjoy problem solving crosswords? Are you curious, for instance do you want to learn about new things like social media? And what they wanted to explore was how the relationship between these two different types of measures changes over that 15 year period.

Chris - And does this give them the power, critically, to control for people who start off from a good point because if taking the idea that, if I do lots of crosswords this will defer dementia. If I'm starting from a higher point then another person, it may just be that I was always good at doing crosswords and I'll just keep doing crosswords and I'll have a low risk of dementia anyway versus someone who doesn't do many crosswords and starts from a low point and the dementias manifest more obviously sooner.

Duncan -  So that's a very good question. So the perennial problem with studying cognitive ageing is that it takes a very long time to study it. And so you often end up studying people over a relatively short period of time, so 15 years sounds like a long time but of course and within the age span that's even that's relatively short period of time. But there's something very special about these individuals and that's that all of them took part in a study in 1947 when they were all 11 years old and as part of that study they conducted a cognitive assessment, so they had this very good baseline of cognitive ability for many years before the study even started. What they initially hoped to see was that the trajectory of decline in the cognitive skills would be altered by the degree of intellectual engagement from the questionnaire. So those people who are more intellectually engaged might show a reduced decline in cognitive skills as they get older but what they found actually wasn't that the responses on the questionnaire moderate the rate of decline. They just found that people who were more intellectually engaged had better cognitive skills overall and everybody declines at roughly the same rate.

Chris - So the whole idea of Use It or Lose It is therefore it's a myth. It's not gonna work that way.

Duncan - It's not so much that it's a myth. It's the myth part I guess is is about the trajectory. So, what this study and some other previous studies have shown is that essentially what predicts good cognitive health in older age is good cognitive health throughout the lifespan, essentially those people just start off further from some kind of functional threshold so they have further to drop before they start experiencing cognitive difficulties.

Chris -  Does this mean then that if you've reached old age and then you've never been that, well, the sharpest tool in the drawer is too late or are you saying actually you've got to make the most of what you have got.

Duncan  - I think you probably have to make the most of what you have got. So it's very hard to demonstrate that doing crosswords and so on will cause you to have better cognitive health. But it certainly can't hurt. But we do know that there are lots of other factors that are very good predictors of cognitive health in older ageing, so for instance having good cardiovascular health is a great predictor of having good cognitive health.

Chris -  So lead a healthy life from the get go and have the best likelihood of preserving your intellect into old age. The bottom line isn't it.

Duncan -  Having good cognitive health in older age starts young.

Computer chip

15:14 - The hidden dangers of AI

Are the dangers of AI much closer to home than we think?

The hidden dangers of AI
with Vivienne Ming, SOCOS

AI or artificial intelligence is rarely out of the news at the moment, with all kinds of claims about how it will change the world: either by being a revolutionary technology making the world a better place, or that a super smart computer’s going to take over. So what are the risks of AI? Georgia Mills caught up with AI entrepreneur Vivienne Ming at the Royal Society’s “You and AI” event in London...

Vivienne - No one has invented a technology that thinks like we think. That understands the world. There is no AI that, given enough processing power, will have an opinion about Brexit or will prefer coffee over tea. Nothing like that exists. And in fact, anyone who says they know when it's coming is essentially saying they can predict when a truly novel invention, that no one yet has made, will happen. So maybe it will be tomorrow. I doubt it. And maybe it'll be 20 years and maybe it will never happen.

I don't think there's any theoretical reason to think we won't have very intelligent AI out there, someday, but it's coming no time soon and therefore it's not a technology that can take over the world. I think what we're genuinely afraid of is people and what people will do with immensely powerful tools in their hands. AI can truly do some terrifying things; autonomous weapons, the use of artificial intelligence by autocracies to maintain power. Those are things we really need to worry about.

Georgia - When people want to use machine learning or AI for problem solving, where can that go wrong?

Vivienne - I have been coming at artificial intelligence for a very long time from the perspective that I want to solve problems. The problem is the success of my work has come from a deep understanding of the problem. When I was the Chief Scientist of, perhaps, the very first company to ever use AI for hiring, the first thing I did was I read 100 hundred years - very literally - of research papers about what makes a great employee. Then we built AI to look for those qualities in people. By contrast many notorious cases, most recently Amazon, built a very complicated deep neural network and they threw it at the hiring history of Amazon. And guess what? It didn't want to hire women. It turns out that getting hired at Amazon tends to mean you're a man. That happens a lot together. So that AI learned to associate the two things.

That probably says something unpleasant about Amazon but it also says something about the naivety of turning over some of the most challenging problems in human history: Who should get a loan? Who should they hire? How do we take bias out of the judiciary? Who even gets into our countries?

All of these things put together are now being put in the hands of some very young people that have come out of university and they've learned to do something incredibly challenging. They have learned how to build and tune the meta parameters and deep neural networks and architect these elaborate models. But, in the end, all of artificial intelligence, as it exists today, is a tool. And that I think is one of the most immediate problems with artificial intelligence. Thinking it will solve our problems for us when, in fact, all it can ever do is reflect our own ethical choices back in our faces.

Georgia - Do you think it's going to make society a more or less fair place?

Vivienne - An interesting truth in my experience with almost all technology, not just artificial intelligence, is when it first comes out it invariably helps the people that need the least help. Because people like me with very fancy degrees, living in elite places, we’re the ones that can actually make use of it. This is true of the Internet. This is true of educational technology. Turns out it's immensely true of artificial intelligence. Artificial intelligence increases inequality. We tend to make tools that make life a little easier. And it turns out that the people that are able to make the most use of it are the people in large companies and, for them, making life a little easier is driving wages to zero.

And when they look at what an AI can do it can read a contract and find all the loopholes, it can take a spreadsheet and analyse all the risk in a financial investment, it can write code. It can do all these expert judgements that have, for up until this moment of time, been solely the domain of humanity and it can increasingly do them cheaper, faster and better than people can. And if you're the CFO of a Fortune 500 company, your first reaction to that is “Why the hell are we paying for all these software developers and lawyers and financial analysts? I can't fire them all but maybe I can replace them with people that never even went to university. Combining them with an AI, we can create something that is 80 percent as good as that very expensive college graduate we used to hire.”

We can do so much better than that. We can makes a choice that actually draws people into the creative economy instead of what I call de-professionalising. I hope we make those choices because 10 years from now it'll be too late to say, “Oh my goodness, that was a bad idea!”.

Yellow-banded Poison Dart frog Dendrobates leucomelas

Frogs are sexy in the city
with Wouter Halfwerk, Vrije Universiteit Amsterdam

When looking for a partner, animals have to adapt to their surroundings. And the Tungara frog, from Central America, is no exception. New research from Vrije University has found that frogs living in cities have evolved to call more often, and make a more complex sound than their forest-dwelling counterparts. Adam Murphy heard all about it from Wouter Halfwerk...

Wouter - They're much smaller than you would expect. They're about two centimetres big. Different brownish colours and normally during the day they're very camouflaged on the forest floor. But, when they start to call, it's a very impressive sound. They call very loud. They call in big groups, so they're hard to miss. If you compare their call to us, they have the same fundamental frequency as our voice and more or less the same amplitude as when we are yelling at each other. So they have a very impressive mating signal, or mating display you could say.

Adam - So they are tiny frogs screaming at our volume looking for a mate?

Wouter - Yeah they're tiny frogs and they really scream at the maximum capacity. They also have a very big larynx, a voice box, very similar to what we have. But in their case, their voice box is much bigger than their brain. And in humans it's the other way around. It just shows you that sexual selection has operated on their voice and not on their brain.

Adam - What did you find then when you look at these frogs?

Wouter - We compared frogs in 22 urban sites and forest sites. We recorded up to 100 males. On average we see that frogs in the city call at about 25 percent higher call rates and about 40 percent higher complexity. So what you should know is that in this species males always make this first part of their call, that we called a ‘tun’, that sounds like “boom”. And that's how they start. We call that a simple call. But then when they get really excited they start to add elements known as ‘chucks’ and that sounds like “ah” or “ah, ah”. And if you get “tungara” - that's why they're called tungara frogs. And when they do that they make themselves more attractive to females. But we also know from previous studies that predatory bats and parasitic midge are also paying attention to these ‘chucks’. And if you give them a choice they prefer to attack males that make more of these so-called ‘chucks’. That was the first thing we found - we found that these urban males make more of these ‘chucks’ and then we thought, okay, that must be related to on the one hand attractiveness to females but also on the other hand related to predation risk.

Adam - Can the city frogs, could you take them into the forest and they'd revert back to being rural frogs and vice versa? How would that work?

Wouter - Yes so that's also what we tried. So when we found out that there are these differences, we wanted to know: how flexible are urban or forest males in changing these calls? We put an urban frog in a forest environment and then immediately saw that it would change back its call to match that of a forest frog. And that way it adjusted its calling behavior to match the predation risk in these forest environment. But when we did the other experiment, where we moved a forest frog to the urban environment, we saw that they could only partly change their calls and they could not make as much of these ‘chuks’. They had less complex calls than the urban frogs in the same environment. And this suggest that we are looking at an evolutionary response and that the urban males have been selected by the city for their increased complexity.

Adam - So this is witnessing the start of natural selection onto evolution then?

Wouter - Yeah, this could potentially be to start off of a new species as a result of changes in sexual and natural selection pressure. You're right. So the key question here what we really want to find out is whether these differences are heritable - whether this trait this calling behavior is passed on from one generation to the other. That's what we are planning to do next summer. We are planning this large-scale breeding experiment where we keep forest frogs together and urban frogs in the same kind of lab environment and then see if their offspring have the same differences in calling behavior.

Chopping peppers

25:58 - A scar is born

How does a scar form when you cut yourself?

A scar is born
with Matt Hardman, University of Hull

Our body is constantly making new cells and tissues to replace those damaged by ageing or an injury; often the repair process isn’t perfect and leaves a scar. And most of the people you meet in the street have one and a story to go with it. Georgia Mills spoke to Matt Hardman, of the University of Hull, to find out how scars form.

Matt - Well, like any biological process it's actually quite complicated. So the first thing that happens is platelets in your blood clot together to form a clot - that stops you bleeding to death. Then immune cells are recruited from your circulation to the sites of injury. And their job is to get rid of any debris or get rid of any bacteria that are in the wound that shouldn't be there, and then stem cells become activated locally and they replace the cells that are missing in the void. And the key thing is that void has to be filled with matrix, a matrix is kind of like a biological polyfiller. And the way that that is sculpted is what causes the scar.

Georgia -  is that kind of a scaffold across the hole in your finger trying to bridge the gap? And what is that made of?

Matt -  So it's made of all kinds of different components essentially long proteins that bind together in kind of a mesh work and that mesh work is what restores the function of the tissue. The key thing is a scar is actually quite different to normal skin.

Georgia - Why is that why don't we get a lovely new fresh finger again. Why does it leave a scar.

Matt - It's evolutionarily programmed so we've developed over thousands of years to actually heal in in a dirty environment. So we have to heal rapidly and quickly and close that wound. But actually these days most injuries happen deliberately in operating theatres. And so that's a much cleaner environment so you don't necessarily need to heal so quickly and with such a prominent scar.

Georgia - Right. So it's because we're we're trying to heal so quickly that it is like different from our usual skin.

Matt -  Yeah. And the immune cells themselves actually drive the scarring process so if you have a really exuberant immune response that releases loads of factors which actually activate the scarring response.

Georgia - So why does the tissue look a different color as well?

Matt - So scars are completely different to normal skin: they like hair follicles, they lack sweat glands and they also tend to be less pigmented.

Georgia - It doesn't happen all the time does it. We don't always scar. So why does it happen sometimes and not others?

Matt -  Essentially the depth of the wound decides whether you're gonna scar or not, if you have a very superficial wound like a paper cut that's not going to scar. If you have a full thickness wound all the way through the skin then you're gonna end up with a scar.

Georgia- And yet the paper cut hurts more.

Matt - Yeah exactly. It is interesting that not everyone scars the same. And actually the way you scar changes over your lifetime.

Georgia -  How so?

Matt -  I'm sure you want to realize that younger people tend to heal faster but also with less scarring but also older people don't have sex exuberant scarring mainly because their immune response is dampened so as you get older your immune cells lose a lot of their ability. And that means that your wounds heal less quickly but also with a better quality of scarring.

Georgia - That's really interesting. So it slows down and that means it doesn't scar so much. Could we trick younger people into doing that too to avoid scarring?

Matt - Yeah but the danger there is that then you'd move onto a wound that wouldn't heal. So it's a fine balance you don't want to delay wound healing too much because then you could end up with a much more serious problems.

Georgia - I see you could get infected and then you'll look great but you'll be about to die.

Matt - Yeah.

Georgia -  What about you mentioned younger people don't score so much what about in the win.

Matt - Yes so that's really interesting. So actually whereas most mammals do scar quite a lot. Most mammals when they're in the womb don't scar. So there's there are changes biological changes that occur at the point of birth that lead to scarring and it's thought that it is mainly the immune system. So when you're in the womb you have a less developed immune system.

Georgia - And I've heard that some animals don't actually scar at all, like a fish. Is this true and how are they doing it?

Matt - Yes. So flies worms fish even some lizards don't scar and they can actually regenerate whole limbs. And the answer is we don't really know why those less developed organisms are able to heal them regenerate whereas with humans aren't.

Georgia - that sounds really handy. I mean being like a regular Wolverine I mean could we could we find out what they're doing and then apply it to us, do you think?

Matt -  Yes absolutely. And there are lots of groups around the world who are actually looking at understanding regenerative healing and in less developed animals to be able to implement that in a human's.

Georgia - That sounds great. And finally this is something everyone who's ever had a skull will know. Why do they itch?

Matt -  So the nerves in your skin are actually stimulated by the cells that are healing a wound. So as they're moving around as they're releasing chemicals that stimulates your nerves but actually the nerves themselves are regenerating. So within the tissue there are underdeveloped nerves and they're sending out kind of scrambled signals to your brain which are sensed as itch.

Alcohol bottles

32:21 - The extraordinary regenerating liver

How does the liver completely regenerate when damaged?

The extraordinary regenerating liver
with Martin Boughen, Meritxell Huch, Cambridge University

The liver is an incredible example of an organ that can regenerate when it’s injured; in fact, it’s so good that live liver donations are possible where a person gives away up to 80% of their liver to a new recipient and then regrows themselves a new one! Martin Boughen has personally experienced how well the liver can regenerate.

Martin - My adult son suffered from a complex and rare immune condition that progressed to end stage liver failure just four years after diagnosis. The transplant was only chance for life. Despite being on the active transplant list, my son's condition was approaching critical and he may not have lived long enough given a shortage of suitable organs and patient priorities. I was carefully assessed both physically and psychologically before the transplant unit was given permission to transplant some of my liver into my son. I donated 61 percent of my liver. It was the most I could safely offer and the effect to my body and potential to save my son's life was measured. I was in surgery for six hours followed by 24 hours in ICU and released from hospital after just 10 days. My liver regenerated to its near original mass and function within twelve weeks. My liver is a strange shape now and uncomfortable at times but works. The living donor transplant worked long enough to save my son's life. Sadly he needed a full transplant just three months later due to serious complications with the original disease. Six years later is living the life he so richly deserves. For me live liver donation is a very important issue. Advancements in medical and surgical procedures make a living donation a very viable option in the right circumstances and in my opinion this option could be offered earlier rather than waiting for the patient to be so ill that it may be the only option left open to try.

But why does the liver have this extraordinary regenerative capacity in the first place?  Eva Higginbotham heard from Meritxell Huch, who's trying to find out at Cambridge University’s Gurdon Institute...

Meritxell - Because the liver has this property of detoxification every day it gets injured. The liver has evolved to have a very huge capacity to restore these cells back and restore their normal state of the liver.

Eva - How does it do that? How does it grow back?

Meritxell - That's very interesting and is actually very important question to address. We know that it does it and it does it very well. The molecular mechanism how the cells know they have to regrow how the cells know they have to stop growing because the liver is regenerated, we know which factors are important, but we don’t know all of them and we don't know how they do it. There is a lot of investigation on that area. Obviously we think that if we understand how the liver regenerates well we might be able to apply it to other organs and understand why the other organs cannot do it.

Eva - What about when things go wrong in the liver?  You hear about people damaging their liver with alcohol for example, what happens there?

Meritxell - Yeah. We get many patients that have what we call alcoholic liver disease. Their livers have been damaged because of drinking alcohol and liver disease is actually one of the diseases that is increasing because despite you can injure the liver in a daily basis and it can to grow, is not an infinite capacity.

That means that at some point for reasons that we still don't understand, it will stop regenerating. And when the tissues stop regenerating it has only two options. Either it undergoes a scar, the function is lost and is replaced by cells that do not have this detoxifying function of the liver. Or the other option is that actually it grows cancer because in regeneration the mechanism is that the cells have to sense the damage and respond to the damage by proliferating in order to make a new pool of cells. If you have a lot of proliferating shells on the liver you are susceptible to that mutations and therefore you're susceptible to cancer and alcohol has a huge influence on liver disease because it's a constant damage to the tissue.

 

ECG Trace

36:42 - A mechanical heart

How a mechanical heart can save lives when our own lets us down...

A mechanical heart
with Stephen Pettit, Royal Papworth Hospital

Heart attacks can be devastating, and the scarring that's left makes it difficult to live a normal life afterwards. So what can be done? Chris Smith spoke to Stephen Pettit from the Royal Papworth Hospital, he’s a cardiologist with a speciality in advanced heart failure, after first hearing from Sarah Miles, who's recovering from a heart attack.

Sarah - I was working as a nurse but became unwell. I was diagnosed with diabetes and angina. My symptoms got worse and I was repeatedly told the cause was anxiety and depression. But I suffered a heart attack, which led to a cardiac arrest. I was only 38 and the damage was severe. Most days just washing and dressing is enough to exhaust me. I spend more hours asleep than I do awake. The whole body fatigue and breathlessness is overwhelming and I'm no longer able to sleep in my own bed as the stairs are just too much to manage. I've been referred for a transplant or possible LVAD, a mechanical heart. My GP of over 20 years manages most of my care, which is an incredible support. The British Heart Foundation has been incredibly supportive too and I work voluntarily with them to raise awareness, which I think is very important especially with the younger generation. I always felt I had a story to tell, an experience to share and a voice to be heard. They have given me that opportunity and now a purpose for which I will be forever grateful.

Chris - Sarah Miles. Thank you Sarah. So why can't the heart regenerate like the liver does? With us is Stephen Pettit, he is from the Royal Papworth Hospital in Cambridgeshire. He is a cardiologist specialising in heart failure. When a person has a heart attack, Stephen, what actually happens to the heart muscle?

Stephen - The medical term is myocardial infarction and occurs when a coronary artery becomes blocked. This is normally recognised one would hope quite quickly and great efforts are taken to reopen the artery and restore blood flow to that part of the heart. But if that isn't done or if that's not successful then that part of the heart unfortunately becomes sort of irreversibly damaged by the heart attack.

Chris - And that means you lose heart cells from that part of the organ?

Stephen - Yeah absolutely, so heart muscle cells are not able to sort of divide and regenerate. The heart heals, but in healing scar is formed and scar cannot contribute to the sort of contractile function of the heart. So the pumping function will go down and scars can cause other problems in hearts as well.

Chris - So you end up with a stiff scar which is presumably a compromise - I need to heal this damage up quickly, so I lay down a fibrous scar, which seals the breach in the heart, but you've lost the contractile part, the heart muscle. So as you say the heart loses its pumping ability and that's why patients, like Sarah whom we heard from, get heart failure. Their heart just can't produce enough effort to push enough blood fast enough.

Stephen - Yeah absolutely. I mean to a certain extent there are medications that can mitigate against this sort of progression of heart failure, but absolutely there is no way back at the moment from that process of scar formation in the heart.

Chris - What can we do for people in that situation at the moment then?

Stephen - The mainstay of treatment for people who have developed heart failure is tablet treatment. Tablets can produce enormous improvements in how people feel and also led to a revolution in how long people survive with heart failure. But at the extreme end of the spectrum, when tablet treatment is not enough and despite that people are feeling awful and people's outlook is poor, then we turn to more extreme things, such as heart replacement therapy.

Chris - What sorts of things can you offer people?

Stephen - Well there are all sorts of options that are open now. Areas of scarred heart muscle are potential source of rhythm disturbances, potentially life threatening rhythm disturbances, so people with large areas of scarred heart muscle are sometimes offered implantable devices called defibrillators. They're a little bit like pacemakers but they can act to automatically identify and treat rhythm disturbances that would otherwise be fatal. At Papworth Hospital we also undertake heart transplantation, which for many decades now has probably been the gold standard treatment for very advanced heart failure.

Chris - Before someone reaches the stage of having a heart transplant or perhaps even while they're waiting, is there anything apart from tablets you can offer that gets them slightly better function in the meantime and a better quality of life?

Stephen - Yes. For a proportion of people we will turn to something called mechanical circulatory support and that is using a mechanical pump to sort of maintain blood flow around the body while a person is waiting for a heart transplant. And the type of pump that we use most often are called Left Ventricular Assist Devices or LVADs.

Chris - Is that what you've got there in front of you?

Stephen - Yeah absolutely. So this is a an LVAD. There are three main bits to this. The pump, and the pump is implanted by one of our cardiac surgeons and it actually sits inside the chest. It sits right at the apex of the heart.

Chris - It's about the size of a small computer mouse.

Stephen - I mean it fits in the palm of a hand. They're really pretty small now compared with what they used to be.

Chris - Can I have a feel of it?

Stephen - Of course.

Chris - So this is metal. What’s it made of?

Stephen - Yeah. Its metal and inside it basically looks like the propeller on the back of a boat. In the most modern VADs that propeller is magnetically levitated, so there's no axle, there’s no ball bearings, there is nothing that would create friction. So blood cells flow incredibly smoothly through the VAD.

Chris - As I said this is about the size of a small mouse that you would use to use your computer with. It's got several portholes on it. One's in the front face. One's in the one side of it. So is that where the blood goes in and goes out.

Stephen - The blood gets sucked into the VAD through a very short metal pipe and there's then a flexible pipe through which the blood is pumped along and that flexible pipe, it gets called the outflow graft, is attached to the aorta of the patient. Then the third essential thing is a power supply. So the VAD needs a constant power supply and there is an electrical power cable that is tunneled along the anterior abdominal wall and exits through the skin. Then patients have a controller and battery packs they're attached to, so when they're connected to power they've got as much freedom as you or I - they can just go about their business.

Chris - So it pulls blood out of the left ventricle the main pumping chamber of the heart and then shoves it into the aorta. So the heart can continue pumping as normal it's just some of the stuff that it would pump is being taken off its shoulders if you like and put through this VAD device and into the main blood vessel instead.

Stephen - Exactly. And that's why they're called Left Ventricular Assist Devices. These do not take over the function of the heart completely but they do a substantial proportion of the heavy lifting.

Chris - How much juice does this use? I mean how energy hungry is this thing?

Stephen - Not particularly. I mean they'll typically have a power consumption of sort of three or four watts.

Chris - And the power supply - do people wear that or can that be implanted or how does that work?

Stephen - At the moment the power supply is outside. A person has normally a waist belt that will have the controller for the VAD and then two batteries. But this is all fairly small as well. If a person had a jumper on or was wearing a coat you wouldn't know that they were attached to all this. You need to be a little bit careful going through airports.

Chris - How much function can this make up for? I mean how good are these in practice?

Stephen - We typically see them pumping somewhere in the region of four to five, sometimes even six, litres per minute of blood, which would match the cardiac output at rest. .

Chris - Indeed. I remember seeing on Star Trek. because Jean-Luc Picard, he actually had an artificial heart and the heart that he had that was displayed once was bigger than that. So it's amazing to think you know, here we are about 20 years after that program was made and we're looking at a device that looks a very very similar to that but is smaller and clearly can do what they were saying was sci fi.

Stephen - Yeah. I mean there's some other sort of fascinating things about them. Early VADs used to generate pulsatile blood flow, but people quickly realized that actually that was traumatic to the blood and left patients at risk of things like stroke. So now VAds are continuous in flow. Once a patient has got one of these VADs implanted, the vast majority of them loose all pulsation.

Chris - So you have a pulse-less patient in front of you.

Stephen - Yeah absolutely.

Chris - That's a bit disconcerting isn't it.

Stephen - Blood flows continuously around the body and actually measuring things like blood pressure becomes really challenging because that normally relies on pulsatility.

Chris - Given how good you say these are. Do you think we're almost in an era then where actually, when someone with a heart problem comes to see you in the future, you're not going to bother with heart transplants you're going to give them the next generation one of these.

Stephen - Well that's a very very interesting question. Certainly the most modern LVADs have outcomes, you know two years post implant, that are pretty much the same as outcomes after heart transplantation. But we've only been using these pumps for a couple of years, whereas we know what happens 10, 15, 20 years down the line following heart transplantation. So certainly they're short and medium term outcomes are getting to a point actually where they're almost as good as heart transplantation, but in the long term, at the moment you know, there's a lot more uncertainty.

Chris - I mean it looks pretty basic. I'm sure the engineering in here is humongously expensive. How much does one of those cost?

Stephen - You looking in the region of sort of 80 to 90 thousand pounds for the LVAD itself and then there's all the sort of associated costs of implanting them as well. These are not cheap by any stretch of the imagination.

Chris - To contrast that how much does it cost to heart transplant somebody?

Stephen - Probably in the region of 20 to 30 thousand pounds for a heart transplant and the first year of care that follows. A heart transplantation is, at the moment, cheaper than support with the Left Ventricular Assist Device.

Chris - But given how common we think that heart disease, heart failure and so on is going to be in the future and given how few transplant organs we have at the moment, that we have access to, it looks like these are definitely going to be a big part of what we do in the future these Ventricular Assist Devices.

Stephen - Yeah absolutely. I mean if you look at National Statistics, the number of Left Ventricular Assist Devices that are being implanted is just going up year on year for exactly that reason. So I think these are gonna be a big part of the future of advanced heart failure.

Mouse brain

47:23 - Biogel can heal brain after stroke

A new biomaterial has helped mice recover lost areas of the brain after a stroke.

Biogel can heal brain after stroke
with Tom Carmichael, University of California, Los Angeles & Kativa Basi

Having a stroke can have devastating effects on your life, especially as damaged parts of the brain can't recover after the fact. Or can they? Georgia Mills spoke to neurologist Tom Carmichael University of California, Los Angeles, about research he’s pursuing to regrow brain tissue after a stroke, after hearing from Kavita Basi, who survived a brain haemorrhage.

Kavita - In 2015, when I was 38 years old, I was taken into a A&E with a life threatening illness: A subarachnoid brain haemorrhage. Prior to this, I was leading a happy, healthy lifestyle. I just didn't expect that something like this would happen to me. The night it happened, I had come home from work a little earlier with a headache and watched some TV, and I woke up then approximately 11 p.m. screaming with huge pain, as if a sledgehammer had hit the back of my skull and I had a seizure then, and collapsed. I was then treated at the Salford Royal Hospital in Manchester with various operations over the next few weeks. My life now is adapting to this new me. I have trouble with short term memory loss, severe headaches, difficulties with certain noises, claustrophobic, high anxiety, and also a personality shift.

I now have very straightforward black-and-white thinking and this is difficult for people who know me to understand.

Chris - Kavita Basi, who recently published a book on her experiences called Room 23; Surviving a Brain Haemorrhage.

Georgia - Having a stroke can have a devastating effect on your life and recovery is especially difficult because the damaged areas of the brain are permanently dead, or are they? I spoke to neurologist Tom Carmichael of the University of California, Los Angeles about research he's pursuing to regrow brain tissue after a stroke.

Tom - The key cell types in the brain, the neurons, that send the signals really are fixed after a certain age in humans. Somewhere between 2 and 5 years old, we don't get anymore brain cells and so we can't as a result, regenerate new brain cells themselves in large quantities. And so when there is an area of dead brain you can't regrow into that area normally. From the brain next to it because the brain cells themselves, the neurons, are what we call in in the scientific field, postmitotic. They can't divide and form substantial quantities of new cells.

Georgia - Would you call this scarring then, these dead cells?

Tom - Yes, what happens is the area dies and then some of these cells called glia, proliferate, and wall off the area of damage, and they participate along with other cells in the formation of a scar that helps contain the damage, but may also have a second effect of limiting some of the repair in recovery.

Georgia - How would that reflect in, sort of, the treatments you can give people?

Tom - Currently, as many will know, there are no medical therapies for recovery in stroke. The treatment is activity based; physical therapy, occupational therapy, or speech therapy. These are very limited in their efficacy. And so there are no therapies that stimulate recovery in stroke. And what we've been focusing on is the science of what the cells do after stroke, and how we might develop medical therapies that enhance that recovery.

Georgia - Right. Yeah. How is your lab investigating this?

Tom - We're very interested in what the brain starts to do, and then gets stuck and doesn't progress fully. So we've been investigating the molecules that stimulate brain cells to form new connections, or the molecules that stimulate blood vessels to grow and branch out in the tissue adjacent to stroke. And our reasoning is if we can understand those molecules we might understand why they don't produce a more full recovery, and then develop drugs that boost those molecular systems and boost recovery.

Georgia - How are you testing out the properties of these?

Tom - The first test is just a discovery process to get an idea or a hypothesis on a specific molecular pathway or molecule that might have a role in recovery. So in the example I just cited, we might identify a molecular memory system and say, we think this might have a role in stroke. And so the first test is a discovery test just to see in an animal model of stroke, like in a laboratory mouse, does this molecule enhance recovery.

Georgia - How have you put in the molecule to the mouse and what did you find?

Tom - There's a couple of ways we've done that. The most translationally relevant way is to deliver a drug that would interact with these systems, a candidate drug. We've partnered with pharmaceutical companies who have early stage discoveries that we might test. And we've also developed some of our own. And you can deliver that systemically to a mouse just like you would do a human. There are other more specialised ways. One exciting way is to develop new biomaterials that might enhance recovery and stroke. I mentioned that the stroke causes a cavity. That's a space in the brain that we might fill with a biomaterial, that could release a drug or that could have a molecule in it that promotes recovery. So delivery just like we would in a human systemically, or local delivery using new technologies like biomaterials.

Georgia - Wow. So like you'd put a plaster on a wound on your skin you, sort of, put the bio-plaster inside the damaged part of the brain?

Tom - Exactly.

Georgia - What happens then, when you tried this in mice?

Tom - Lots of times we have failure and that should be expected. It's discovery science and if you're not making mistakes you're not casting your net broadly enough, but in several instances we've had really substantial success and some of these have led to clinical trials, and some of these have really defined a new direction that we might then, in a sort of, iterative way, tune towards producing a human therapy.

Georgia - And when you say success do you mean parts of the brain that have died coming back online?

Tom - That's a very good question. There's probably two ways I might answer that. The first is to directly answer it, and that is yes we've developed what's called a biopolymer hydrogel, basically a jello-like material that's made of naturally occurring molecules in the body, and that can promote regeneration of new tissue after stroke. So in published accounts we've shown that it can cause axons, which are the connections of neurons, and blood vessels to grow into the damaged cavity and form essentially, new brain tissue that enhances recovery. And then a second answer to your question is what does it look like when the tissue recovers. Growing new brain with a bioengineered material is really a heroic feat that took years of work. Another approach is to simply enhance recovery of the existing but partially damaged circuits next to the cavity, and so recovery there might look like a circuit that originally say, was involved in moving the leg can now move the leg and the arm.

Georgia - Wow that's amazing. Do you know how long before maybe you start to see human trials?

Tom - There are various efforts that could go, in five years into clinical trial. The roadmap is well established for those. For others it may take seven to ten years. And that's particularly true for the more experimental therapies because there are a number of daunting translational problems. For example scaling up. Most of the processes that work in mice or in laboratory rats produce small quantities and to get into a possible human application you have to scale up in a very pure way to a large quantity and that's demanding and so there's a lot of, less interesting from a scientific perspective, problems that have to be solved to move many of these biomaterials efforts forward.

If you are in the UK and have been affected by stroke, you can get in touch with Different Strokes, a charity that supports younger stroke survivors at www.differentstrokes.co.uk

Bubble Floating in Air

55:30 - What happens to an air bubble in microgravity?

What does an air bubble in a blob of water do if you take away the gravity?

What happens to an air bubble in microgravity?

Adam Murphy spoke to Stuart Higgins from Imperial College London, and to David Kinahan from Dublin City University, to get an answer to this weighty question...

Malcolm - After watching the Sony film passengers and seeing what happens to the swimming pool after a loss of gravity. I'd like to know what happens to an air bubble inside a mass of water when there's no reference to where Woods is

Adam - In the science fiction film Passengers, Jennifer Lawrence's character, Aurora, has a pretty unnerving experience. While she's swimming in the spaceship swimming pool, the gravity cuts out and thousands of gallons of water rise up with her still trapped inside it. But what if instead of an acclaimed actress, it was a bubble of air instead?

The thing that makes this question so interesting is how difficult it is to wrap our heads around a lack of gravity, as Stuart Higgins, Researcher at Imperial College London, points out...

Stuart - We’re used to bubbles rising to the surface of a volume of water. On Earth, an air bubble at the bottom of a swimming pool experiences an upward buoyant force thanks to the fluid pressure of the water around it. This fluid pressure is caused by gravity pulling down on the water and depends on the height of all the other water above it. So the parts of the bubble nearest the bottom of the pool experiences a greater force than the part near the top. This creates an unbalanced upward force. Air is less dense than water so the gravitational force pulling the bubble down is less than the buoyant force pushing it up and the bubble rises.

In a weightless environment, where the effects of gravity aren't felt, there's no overall buoyant force to make the bubble rise to the surface. It just sits in the water.

Adam - But that is that the whole story? David Kinahan, researcher in micro-fluidics from Dublin City University, had a little more to add about why this happens.

David - There are two things to think about here; the gravity force acting on the water and the surface tension force acting on the water. Engineers figure out which is strongest by calculating a ratio called the Bond Number and it isn't 007.

Adam - If gravity is 0, the bond number is 0, and surface tension, which is what makes water pull together into droplets on a windshield, is all that matters.

David - Imagine the swimming pool room is left with the large volume of water floating freely in the middle of the room. Over time, with surface tension dominant, it will deform to minimise the surface energy and the shape with the smallest surface-to-volume ratio is a sphere. So you'll end up with a large spherical blob of water. If there was an air bubble within the spherical blob of water, it would also form a sphere in order to minimise its surface energy. You will end up with a sphere of air inside a sphere of water

Adam - So there you have it, sorry to burst anyone's bubble. Next week, we're keeping things bubbly with this question from William.

William - When a bar of soap gets used a lot and gets smaller, it seems to struggle to form suds properly. Is something other than just a smaller surface area going on?

Comments

Add a comment