Stem cells for spinal injury, and breast cancer breakthrough
In the Naked Scientists News this week, stem cell treatment using cells from the bellies of those with spinal cord injuries restores movement and sensation in phase 1 clinical trials. Also, Cambridge scientists build an 'atlas' of breast cells to better understand how cancer develops, and new analysis into dinosaur fossils reveals when they began to develop rapid growth rates...
In this episode
00:54 - Belly fat stem cells improve spinal injury recovery
Belly fat stem cells improve spinal injury recovery
Mohamad Bydon, Mayo Clinic
Could an injection of stem cells grown from your own abdominal fat be the key to improving outcomes for people with spinal cord injuries? In an early stage trial in America, scientists have found that over two thirds of the small group of patients they treated showed improvements. They think that the stem cells are boosting the blood supply to the injured region of the spinal cord, and helping to control inflammation, which may lead to reduced scarring and better prospects for recovering some of the lost nerve connections. Mohamad Bydon is a neurosurgeon at the Mayo Clinic and led the new study…
Mohamad - The historical teaching around spinal cord injury is you deliver surgery, you do physiotherapy, and that's basically it. And things haven't really advanced in a long, long time. So what we wanted to do was really impact the space and say, are there other treatments that we could add to augment the recovery, to aid the recovery, to improve the recovery?
Chris - And your intervention? What's the rationale behind what you're doing and how are you doing it?
Mohamad - So at a very high level, at a 30,000 foot view, the question becomes, what are the other things that we can add? And that's where we believe regenerative medicine will be a part of this paradigm. It's not going to be the only answer: you still need your surgery, you still need your physical therapy, there's other things like stimulation that are being discussed, but we believe regenerative therapy, specifically with stem cells, will be beneficial in helping to improve outcomes for patients.
Chris - So what stem cells? Where from and what do you do with them?
Mohamad - So stem cells are cells that can become a number of different things once they enter the body and they come from a number of different areas. Specifically in this study we used what are known as mesenchymal stem cells, adipose derived. Those words mean stem cells from your own fat, belly fat. I had a colleague who said to me recently, 'Who knew that belly fat could be so useful?' So, from your own belly fat, we remove that and expand the cells until we get to the right number of cells and then we proceed to reinject those cells once they're expanded and cultured into the spinal cord.
Chris - How many cells were you putting in once you'd grown them or expanded them and where exactly were they going? Were they going into the substance of the spinal cord or around it?
Mohamad - There were 100 million cells. Frankly, we need to work on dosing still, but a hundred million is the dose that we expand the cells to. Once we do that expansion, we proceed to inject it into the faecal sac. There's the substance of the spinal cord itself, and then there's a sac that surrounds the spinal cord - it's called the faecal sac or the dura mater - and that is a lining that surrounds the spinal cord. It also surrounds the brain. Inside that layer there's something called cerebrospinal fluid. So what we do is we put these cells inside the dura, into the fluid, and then the cells go to the area of highest injury and area of highest inflammation, which is the area of injury.
Chris - What do the cells look like? Are they still very much stem cells at this time when you're doing this? And then when they go to the areas of injury, is this only in people who've just had an injury or will they go to areas of injury that happened years ago?
Mohamad - Good question. The cells definitively are stem cells and there are certain markers and hallmark features that stem cells have. To your question on longevity, our current trial is in patients who've had their injury within a year. Many trials deliver therapy to patients who've had the injury right away; you had your injury yesterday, we're going to give you therapy today. This trial was not designed like that because some patients have natural improvement and so the earliest we injected any patient was at seven months. The latest that we injected any patient was at 22 months. Some of the patients that we injected out to 22 months had a very significant response. Now, we haven't done studies looking at longer, although now we're starting studies to look longer out. So what would it look like if we did patients after five years, ten years? What would that look like? Those are also things that we're evaluating and looking to treat.
Chris - Do you know for sure that the stem cells when you put them in actually go to the injury side or do they just go everywhere and some randomly crop up at the site of the injury? Have you actually followed them to see what happens to them and how long they persist for after you put them in?
Mohamad - We've done testing on this and we know that the cells go to the site of injury at the same time. The cells have an impact across the spinal cord and the brain and that's okay. The impact that we've seen has been positive or had no impact. So, we haven't seen it be negative. The cells themselves then work through a couple of different potential mechanisms once they get there. There's potentially a regenerative mechanism through the stem cells themselves regenerating that area, but the other potential mechanism is a vascular mechanism where the stem cells induce a more vascular area where scar tissue would normally be a very nonvascular area without blood vessels. Blood vessels are important because they deliver good nutrients, they take out bad nutrients, and so areas of injury tend to wall themselves off and lose their vasculature. These cells can be very helpful because they can reset the vasculature in those areas, allowing the areas to heal more properly.
Chris - For the patients, what were the outcomes like and in what ways did people improve in ways that you wouldn't have anticipated had they just been managed the way we normally, historically, have been managing spinal cord injuries?
Mohamad - What we looked at, in terms of safety, we found adverse events. Mostly, they were headaches or back pain that would improve over a few days. We never saw any significant or long-term side effects. On the effectiveness side, in terms of our secondary endpoint on effectiveness, what we found was that seven of the ten patients showed some improvement, three of them being very significant improvement, four of them being mild to moderate improvement, and the other three patients showed no improvement but did not get worse. Some patients who required a harness and multiple assistance to be able to bear weight and get up could now walk without that: they could walk on their own. Other patients had improvement in bowel and bladder function.
Chris - How do you know, though, that you didn't, just by chance, select people for this study who are that bit fitter? They're more likely to have a good outcome and, had they been just left to their own devices with the gold standard care they would otherwise have had, they would've ended up at the same endpoint?
Mohamad - This is a good question, and this is a question that we debated at length with the regulatory bodies. Most studies in this space treat patients right after the injury, in which case your question becomes very relevant. In our case, we waited. Most of the improvement after a spinal cord injury occurs within the first six months. Much less improvement occurs as you keep going over time, much, much less. The earliest we ever treated a patient was seven months and we had patients that we treated as late as 22 months and everybody had plateaued. Nobody was continuing their improvement. Remember, this is a phase 1 trial of ten patients. The definitive trial would be randomised controlled, which we're doing now, which is a phase 2 randomised controlled trial of best medical management versus our interventional therapy. But this is a signal and this is an important signal that will inform our future trials.
09:19 - Immune exhaustion linked to breast cancer in BRCA carriers
Immune exhaustion linked to breast cancer in BRCA carriers
Sara Pensa & Austin Reed, University of Cambridge
Thirteen per cent of women will develop breast cancer. It’s the most common female malignancy, accounting for a fifth of diagnosed tumour types. We know that family history and therefore genetics can play a powerful role in determining the risk of developing the disease, and some genes - particularly the BRCA1 and BRCA2 genes - can strongly load the dice. One in four hundred of us carry altered “high-risk” forms of these genes, which can give an individual a 70% likelihood of developing a breast cancer by age 80. Angelina Jolie famously underwent a preventative mastectomy ten years ago when she discovered that she was a carrier. What’s less clear is how these genes are tipping the balance towards developing cancers. To find out, a team at Cambridge University have picked apart, cell by cell, the make-up of breast tissue - including the immune cells found there - and interrogated what genetic programmes are operating in these cells among both healthy people and BRCA gene carriers. The purpose is to probe how the disease gets started. Austin Reed and Sara Pensa are the study’s authors…
Sara - One of the ways that we thought we could tackle this is by looking at how the healthy tissue looks and how risk factors; ageing, breastfeeding, and mutations in important genes that are called BRCA1 and BRCA2, would do to these otherwise healthy tissues.
Chris - Has no one, with all the years we've been studying this disease, actually picked their way through a breast and asked, well, what are all the cells that are in here?
Sara - There have been a few attempts, but we believe this is actually the biggest in the world. What makes it particularly special is that we've been able to collect donated tissues from women of all sorts of different ages and types, and the variety of the samples that we've been able to analyse have given us the ability to understand changes in response to different factors.
Chris - So what did you do with the tissue samples you had? You've got women who are healthy, you've got women who are carriers of some of these genetic conditions like BRCA - which we know increase your risk of breast cancer and other cancers - you've got some people who've actually got breast cancer, you've looked at the opposite breast. Austin, how did you then, when you were handed these samples, how did you process them?
Austin - Once we receive the donated tissue, we break it down into single cells and we read the genetic signalling for each of these cells for all of the donors. We then start to look at the patterns and trends and the gene signalling to try to give us insights into the changes that are happening in the breast and how they might link to the actual changes in risk that these donors might have.
Chris - Did anything leap out at you that might be linked to why certain people with certain genes get this disease?
Sara - Yes. One of the most important findings is we noticed that, in the tissues that were coming from individuals with these genetic mutations, we seem to have a very elevated number of immune cells in the tissue. Now, immune cells normally are there to protect us from disease from damaged cells, but what seemed pretty obvious is that these immune cells seem to be unable to function properly, they had signs of being, as we technically call them, exhausted.
Chris - Does this mean then that the immune response is there? It would normally be trying to stop a cancer forming, but it's basically becoming tired or fatigued so it's not going to be as good at doing that?
Sara - That's exactly what it is. What it is interesting is that this is normally found at late stage disease. This is something that is very commonly found in cancer. But what we were seeing here is this is happening already, much, much earlier.
Chris - So people who have BRCA, this gene that gives them a higher risk of cancer, this is trying to form a cancer all the time. The immune system is trying to stop that happening, but eventually it gets worn down and then a cancer escapes.
Sara - That's exactly what we think is happening. This is a combination of what you just described and changes that occur in the cells that then will become tumour cells themselves. There is a little bit of a dialogue going on there, and the signals that some cells are giving to other cells is exactly what's going wrong at some point. Then it makes these dangerous cells hide themselves from the immune system and therefore the immune cells cannot kill them anymore.
Chris - What are the implications of this, then? You've spotted that you seem to have this chronic inflammatory process with the immune system, there. The immune system appears to eventually be overwhelmed by the efforts of the tissue to try to become cancerous. What does this tell us then about what we might be able to do to stop it?
Sara - What is particularly interesting to us is that if we see all of this happening before the tumour forms in the first place, then maybe we can think of targeting these cellular changes before and use some sort of preventative therapeutic approach. One of the strengths of what we are doing is that a lot of drugs that target these cellular processes already exist in the clinic, are already used for either breast cancer itself or other types of disease. What we were thinking then is potentially we could use these drugs to prevent the disease instead.
Chris - Austin, we know that the genes which are linked to what we've just been discussing BRCA, they're expressed all over the body and a range of other tissues also have a higher risk of cancer when you carry them. So could you do the same study again for other organs and see if what we've just been hearing might be playing out elsewhere as well, such as in the prostate gland in men, ovaries in women, and so on?
Austin - Absolutely. BRCA1 and BRCA2 mutations, for example, are known to have increased risk for prostate cancers and ovarian cancers. Similar studies could absolutely be applied to look to see if similar mechanisms are at play in these other organs. There's not a huge amount that we've seen that suggests this has to be specific to the breast, and I think that would absolutely be a very interesting avenue to explore.
Chris - Is one implication of this then that you will put patients on these sorts of drugs to try to stop the immune system becoming exhausted in this way and then see if that reduces their risk of getting the cancers that they might otherwise have been destined to develop. Is that the next logical step in this study?
Sara - So this would be the next logical step, yes. But because of side effects that come with using these types of treatments, it's important to understand a little bit more about how this would work in preclinical settings first. So what we want to do is use a model of this disease and then try and use all sorts of compounds that already exist in the clinic. We would give these drugs to these models before they actually form breast tumours and see if we can prevent the onset of these tumours, in these models.
17:25 - Did speedy growth spurts ensure dinosaurs' dominance?
Did speedy growth spurts ensure dinosaurs' dominance?
Kristi Rogers, Macalester College
For nearly 200 million years of Earth’s history, dinosaurs were the dominant force on the planet. And now we think that their early development might have played a large part as to why. It turns out that dinosaurs, and a few other reptile relatives, hit their growth spurt pretty early on in life. That may well have given them the edge over the competition, by making them rapidly much better developed, and possibly too big to eat. I’ve been speaking to Macalester College’s Kristi Rogers...
Kristi - When we think about the animals we have on Earth today, we can really think about them as reptiles, mammals and birds, as big groups. And we know that birds are actually just modern dinosaurs that have shrunk their body sizes and changed their biology a little bit. Birds actually grow incredibly quickly. When we push back down into the dinosaur fossil record, we can see that dinosaurs also grew quickly relative to other animals living in their landscapes, other reptiles especially. So we know that at some point when we go even farther back in time, we can see that some of the very first animals that were really living on land actually grew more slowly, kind of more like traditional modern reptiles. And so we wanted to see if there was a point at which dinosaurs flipped that switch and made the change to rapid growth. And whether or not anyone else in their ecosystem, that wasn't a dinosaur, did the same thing.
Chris - And you can tell this from the fossils?
Kristi - Exactly. So most of the time people imagine palaeontologists looking at the outsides of bones and measuring bumps and measuring the lengths of bones and characterising the outside anatomy. But there is a branch of palaeontology that cracks open the bones and looks at the insides, especially the microscopic structures that are present. So we use a method that we call bone histology, and we look for signals like the places where blood vessels stream through the bone when that dinosaur, or any other animal, was alive, or the spaces were cells that helped build and maintain that bone when the animal was alive. So we use microscopic structures like those which are really good proxies for relative speeds of growth in all kinds of backbone animals.
Chris - And how far back in time did you look?
Kristi - We looked back to 230 million years ago. And this is just at the very end of a period of geological time in which dinosaurs were just getting started.
Chris - Right. So they weren't the kingpins at that time. They were part of life's rich tapestry, but they certainly weren't the main part.
Kristi - They were really 'living in the darkness and screwing around' kind of animals at this time. There were other groups of reptiles closely related to dinosaurs. You can kind of think of them as almost like dinosaurs, distant cousins. The ancestors of today's living crocodiles. And those organisms were really ruling the world at this time period.
Chris - And did you find that these animals, this far back in time, appeared to be growing very quickly?
Kristi - Every early dinosaur that we could sample, all of them are growing at elevated growth rates, more similar to the growth rates of living mammals and birds than to modern reptiles. But the really interesting thing is that so were a lot of other reptiles that lived just alongside dinosaurs.
Chris - So do you think that this is just a reflection on what the environment was doing that selected for animals that grew really fast? Or were they growing really fast because everyone else was growing really fast and to keep up and to fend off the opposition they had to?
Kristi - Yeah, we have to think about it in the context of what was happening in the world when these early dinosaurs and their non-dinosaur sidekicks were evolving. The Earth had just experienced, 30 million years before, or 20 million years before the worst mass extinction that the Earth has ever seen. Earth's life almost went extinct. And so these organisms are the descendants of the things that recovered, that survived. And what we've learned is that in order to survive mass extinction, you're going to be more likely to get through an extinction filter if you're relatively small bodied, if you are an ecological generalist who can eat lots of different kinds of things, basically if you're not very specialised, you're more likely to make it through because you can adapt in that changing and fluctuating world. So we think that elevated growth rates work relatively common because the Earth was changing so much and so rapidly at this time. And in the times just before we find these dinosaurs and their non dinosaurian relatives.
Chris - I think it's amazing that you can see this much information in what isn't even the real bone. It's a fossilised impression of that bone from hundreds of millions of years ago.
Kristi - Yeah, it's one of the things that I think is, is such a fun part of palaeontology because we have the beautiful skeletons, the outsides of these bones, but when you crack them open and begin looking at the internal anatomy, the microscopic structures, you can learn so much more about how dinosaurs and all kinds of backboned animals lived. And that is such a fun part of my job.
22:59 - Sporting success from faster eye frame rates
Sporting success from faster eye frame rates
Kevin Mitchell & Clinton Haarlem, Trinity College Dublin
The ability to react quickly is a crucial part of most organisms' lives. In the natural world, a split second can make the difference between living and dying. Us humans have it a bit easier than that, but it’s undeniable that fast perceptions can be hugely advantageous in fields such as professional sports, or on the battlefield. And now scientists at Trinity College Dublin might have an answer as to why some people can react quicker than others. It turns out that every individuals’ eyes have a different ‘temporal resolution’, that is to say some people literally see more frames per second than others. And if your eyes have a finer frame rate, your brain can see and react to things faster. Will Tingle has been speaking to Kevin Mitchell and, before him, Clinton Haarlem.
Clinton - We took a little light bulb that could flicker at different frequencies and when you flicker at really, really high rates, then there's a certain point where you can't actually see the flicker anymore and the light just looks still, but the exact frequency where that happens is different for different people. So we just made a whole bunch of people look at this light and recorded the exact point where they stopped seeing the flicker.
Will - So how much variation was there across all the people that you measured?
Clinton - Yeah, it varied quite a bit. So we measured this in Hertz, so in flashes per second, and on the lower end of the spectrum, people saw about 30 flashes per second. But people on the higher end saw more than 60.
Will - To bring you in. Kevin, could you talk us through why that might be happening?
Kevin - Any kind of trait that is typical of a species will also vary within the species. So if you think of height for example, humans are about yea high on average, but there's lots of variation around that. And what's really interesting is that a lot of that variation we're generally kind of unaware of, especially when it comes to perception because it's such a subjective sort of experience. And we may not realise that we are seeing the world literally differently than other people do.
Will - Does this access to higher frame rates in certain individuals allow them to do things that perhaps others might not be capable of?
Kevin - My gut feeling is that actually most of the time the variation that we've seen probably won't affect people in most of their daily lives, except maybe some people will see some things flickering and it might bother them. But where we do think it might come into play is in things like high speed sports where the need to be able to track very fast moving objects, for example, might make the difference between being a top tier baseball player or a cricketer or hurler as opposed to not.
Will - So this is the reason why I was so bad at sports at school, do you think?
Kevin - Exactly you can blame your slow eyes, Will.
Will - Clinton to bring you back in? We've spoken so far about the potential advantages of having a high frame rate, high temporal resolution. Do we think there's any use to having a low one?
Clinton - Well, I don't exactly know if that would be the case in humans, but what we see from the animal kingdom is that nocturnal animals tend to have really low temporal resolution and that's really so that their visual system has more time to collect these light particles and and make up an image for them to see. And the other thing might also be that animals that need to be aware of very slowly moving things in their environment, they might need that longer integration time. So for example, if you think about a flower blooming and we look at that, we don't actually see that happening because it's so slow and takes so long for that movement to happen. But if you were to take a snapshot once per hour, then you definitely see that movement and that's something that animals might be able to do
Will - In nature, we see the highest frame rate of any animal that we know to date is the peregrine falcon. That's a predator. Our ancestors were predators as well. If a higher frame rate makes you a better predator, why do we think then that there is a limit?
Kevin -I think part of the answer to that is actually that there's a cost to it. So if we're collecting all that information, we have to capture it, we have to transmit it within the brain, we have to process it. All of that has a lot of energetic cost. So for organisms who are in a niche where they don't need to do that then they won't have those high frame rates just because the cost is too high. And Clinton has found differences between predators that are active predators like a peregrine falcon versus ones that are ambush predators that just sit and wait. And the ambush ones have much lower frame rates basically because they don't need to be tracking the fast moving things. They just wait for something to come along.
Will - Fascinating, isn't it? Everything is a trade off in evolutionary terms. Where next then for this fascinating piece of study?
Kevin - We're sort of speculating about the idea that this temporal resolution will map onto motion tracking ability. And there's some good reason to think that based on animal studies and other human studies, but we really have to explore that in much more detail and also see whether, you know, speed of perception is matched by speed of action. Whether people's reflexes are also faster. If they can see the world faster, maybe they can act on it faster. We don't know if those things are coupled in individuals or if they vary independently. So there's a whole host of questions that this study opens up.
Will - That'd be remarkable, wouldn't it? If after all this time the source of most people's clumsiness is the fact that their frame rate doesn't match their ability to react.
Kevin - Absolutely. Yeah.
29:08 - Can glucose spikes be avoided by eating in a certain order?
Can glucose spikes be avoided by eating in a certain order?
James - Glucose spikes are not something most of us have to worry about, but for diabetics they can be quite dangerous. I spoke to Giles Yeo from the University of Cambridge to help find your answer, Steve.
Giles - A glucose spike is not just a slow rise, but a really sharp mountainous, Himalayan like spike in your glucose levels immediately after you've eaten an item of food. Type 1 diabetics don't have the insulin naturally in them to actually handle it, so they want to make sure that their glucose doesn't spike too much by postprandially, after a meal, injecting insulin. Now, type 2 diabetics want to make sure that they control their blood sugar levels because they can't control it properly either. Their tissues in their body tend to be insulin resistant.
James - What foods are most likely to bring on a glucose spike?
Giles - For sure, anything with refined sugar in it. So, added sugar, and this includes not only the powdered white stuff, but honey, maple syrup, agave nectar, all of these supposedly better sugars. They're not better sugars, they're the same sugars: they taste better, but they're the same sugar. And any kind of refined complex carbohydrates. So these are starches that don't actually have any fibre in them, so if you're taking white flour, for example, or white rice. Fibre prevents the sugars from being released so freely in complex carbohydrates. So if the fiber is not there, then there's only one step away from converting starch into glucose, just one little cut, because starch are strings of glucose. So those are the two types of food you want to avoid.
James - Because this seems to be the crux of what Steve's potential workaround to blood sugar spikes, that if you front load your meals with those foods, vegetables, these fibrous foods, and then you save your carbohydrates and sugars until the end of your meal, you might become less susceptible to these dangerous blood sugar levels.
Giles - And he's absolutely right. Wherever he is getting his information from is correct. So undoubtedly, once your stomach has items of food that don't spike your glucose readily... they all will put your glucose up, but anything with protein, anything with fat, anything with fibre, slows down the release of sugars. Even in a potato, if you ate a boiled potato, your blood sugar levels would go up, a spike. If you had a roast potato, so in other words, a potato that's been sympathetically exposed to hot fat, which no one would claim is healthier for you, your blood sugar levels are not going to spike. And the reason for that is because the fat within the potatoes prevents or slows down the release of sugar.
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