Optogenetics: Lighting up the Brain
Could a light in your brain cure epilepsy, or send you to sleep? This week we investigate the mysterious field of optogenetics, and the treatments it promises to bring. Plus, news of a cancer-detecting AI and a vaccination to fight fake news.
In this episode
00:55 - Artificial intelligence detects skin cancer
Artificial intelligence detects skin cancer
with Andre Esteva, Stanford University, and Sancy Leachman, Oregon Health and Science University.
Engineers in America have developed a computer programme that trains itself to spot skin cancers in photos from a patient's skin and, in tests, it does it as successfully as a panel of trained skin specialists. Stanford PhD student Andre Esteva is the inventor…
Andre - What we’ve done is to build a computer algorithm, like a computer programme that can match the performance of board certified dermatologists at identifying whether or not an image of a skin lesion is benign or malignant. And we’ve tested it across three really important medical diagnostic use cases, which include identifying carcinomas, including basal and squamous carcinomas from their benign counterparts as well as identifying malignant melanoma from normal ordinary moles.
Chris - And you do this by showing the computer programme images of these respective lesions?
Andre - That’s correct. We use a data driven approach which, in contrast to previous computer programmes where you would tell the computer do step one, do step two, to step three, instead what we do is we feed the computer a massive amount of data. We show it images and we tell it what those images are of, for instance, malignant melanoma and it learns through a training process how to distinguish between benign and malignant all on its own.
Chris - Now when you say you feed it a massive amount of data, just define what does that mean in practical terms how much data?
Andre - We’re using about 1.4 million total images. We use about 1.28 million images of normal everyday objects. You see, training this algorithm is split up into two steps and the first step you’re sort of teaching the algorithm what the world looks like. You show it images of everyday objects like cats and dogs, and tables and chairs. In the second step, you show it images of skin disease and there we’ll use almost 130,000 images of skin disease over 2,000 different disease types.
Chris - So it then learns what it’s looking for as a first a priori thing, and then once it knows what it’s looking for - ah, that is skin, that is a skin lesion and then it begins to extract the corresponding data that tells it what the diagnosis might be, benign, malignant, and what sort of malignant disease?
Andre - that’s about right, yes.
Chris - How does it know it’s got it right?
Andre - We know the ground truth. So we have a tessat of images that the algorithm has never seen before. And after we train the algorithm we test it on just under 2,000 different images, all biopsy proven, which means that a pathologist has confirmed that they’re benign or malignant and so we can gauge its accuracy.
Chris - And how accurate was it? In other words, how good is it?
Andre - What we did in this work was an image by image comparison. We showed to the dermatologist and image of a lesion and then we showed to the algorithm an image of the exact same lesion. We asked them do you biopsy or treat this lesion or would you reassure the patient and that allowed us to determine a sensitivity and specificity for each. What we found is that the algorithm performed on par with all tested experts.
Chris - In fact it performed as well or better than a panel of 21 dermatologists or skin doctors. So what do the experts make of it.
Sancy - My name is Sancy Leachman. I’m the Chair of the Department of Dermatology at the Oregon Health and Science University.
What we struggle with in dermatology is not being able to quickly see enough patients who have something that might be concerning. What this particular machine does is it allows their moles or their skin lesions to be checked really quickly by an objective source without necessarily having to have a dermatologist on hand to do it.
Chris - Do we know whether a picture of a particular skin complaint is as good as showing the dermatologist the skin complaint literally in the flesh?
Sancy - We actually do have some data on that. There have been some papers published at looking at whether or not digital images are just as good as a human exam in person. And it turns out it’s not perfect, it’s not quite as good but it’s very, very close. It’s close enough that’s it’s probably good enough to triage people. To be able to tell people do you really need to see a doctor or is this clear enough that we can avoid that office visit? That’s huge when you have an overburdened health care system.
Chris - We should know all about that with the NHS. But what do you think the scale of the problem that it can can solve is? How big is this?
Sancy - Well, I mean when you’re talking about just this first step, thinking about all of dermatology if you really use it to detect all kinds of skin diseases, that would be pretty big. But if you think about getting it to work for dermatology and then having it extend to radiology, or pathology, or ophthalmology, then you’re talking about it extending throughout the entire field of medicine and it’s huge, it’s absolutely huge!
Chris - Are you comfortable with that though? Do you not think that there might be some shortcomings here because you are replacing a human being with a computer programme and computer programmes don’t have emotions, they don’t have human instincts but, moreover, they may also not spot other glaring diagnoses that a person with a mole that’s actually benign needn’t worry about, but the other thing that will kill them next week will be completely overlooked?
Sancy - Yes, that’s obviously a concern. It’s not that different from how we use automatic flying systems (guidance systems) in an aeroplane. You still need that pilot there to be able to override. I think it’s similar with this kind of technology that you want to have a backup person and I do think that the false sense of security part of this is that you still need a person to decide what lesion needs to be examined by the machine. So you might end up having a person who wants to check something that they think is bad but it turns out they have something that's much, much worse on their back that they don’t even know about and, if they’d gone in to see the doctor in person, that might have been detected.
07:37 - Do roast potatoes give you cancer?
Do roast potatoes give you cancer?
with Jasmine Just, Cancer Research UK
The UK Foods Standard Agency have recently issued a health warning about the chemical acrylamide - found in starchy foods such as bread and potatoes - saying that it may cause cancer. The warning coincides with the launch of a new health initiative called ‘go for gold’ which encourages us to only cook foods to a golden yellow, rather than brown or black, to help to reduce the amount of acrylamide. Tom Crawford spoke to Jasmine Just at Cancer Research UK…
Jasmine - Acrylamide is essentially a naturally occurring chemical so that means we don’t add it to foods, it just naturally is produced. It’s mainly found in foods when those goods are cooked at high temperatures and for particularly long periods of time so it’s usually when foods are baked, or fried, or roasted or toasted.
If we’re looking at the foods that acrylamide is found in most commonly, it’s in things like crisps, chips, biscuits, bread, and cake. These foods that I’ve mentioned contain the building blocks for this acrylamide to form basically. There’s a special reaction, it’s got quite a long name, it’s called the malide reaction, so basically that’s a chemical reaction that occurs between sugars and amino acids that are in the foods. When these two things, the sugars and amino acids, react and also with water, that produces this reaction and it creates acrylamide. That’s what give the brown colour to food and it can also change the taste of food as well, so it gives it that roasted, charred taste that you might know.
Tom - So we’re thinking roast potatoes or brown toast?
Jasmine - Yes, that’s right. That the malide reaction.
Tom - Why is acrylamide bad? What’s the potential issue here?
Jasmine - The concern has basically come from a number of animal studies that have found that acrylamide has the potential to damage our DNA inside ourselves and, basically, DNA damage can lead to cancer. It’s really important though that people remember that the same process hasn’t been established in humans. So we don’t have the data, we don’t have the evidence to say that’s there’s also a link between acrylamide and cancer risk at the moment, so we need more research in that area.
Tom - How significant is the actual risk?
Jasmine - The risk is basically been described as a ‘probable risk.’ It is in no way a definite risk and by that I’m talking about cancer specifically. If we compare the risk of acrylamide with things like smoking, obesity, basically I can’t do that. We can’t say that if you have X amount of acrylamide your risk is going to be Y. We just don’t have the data or the evidence to be able to put a figure on how high your risk of cancer would be based on your acrylamide intake.
Tom - It sounds to me from what you were saying earlier about it occurs in the largest amounts in biscuits, crisp. They’re generally unhealthy so we want to be avoiding these foods if possible anyway?
Jasmine - Yes, that’s exactly right. And that’s our message from Cancer Research UK that we don't want to tell people not to eat specific foods. We don’t want to say avoid having a roast potato now and then or try and avoid eating burnt toast. Our main message is that people should be maintaining a healthy, balanced diet in the first place, and a healthy balanced diet is one that’s going to be low in these sorts of food anyway. So yes, as you mentioned, crisps, chips and biscuits. They’re not everyday foods, they’re things that shouldn’t be eaten regularly to begin with.
Tom - Are there any other ways we can reduce the risk?
Jasmine - The FSA has also recommended, for example, if you are going to be cooking chips, just follow the cooking recommendations on the packet. They’ve also made some recommendations such as avoid storing your potatoes in the fridge, which increased the potential for the potatoes to develop acrylamide when you cook them.
Tom - Storing potatoes in the fridge seems quite crazy to me.
Jasmine - Yes. I personally don’t store them there.
Tom - No, me neither.
Jasmine - If you do - don’t! The other thing is that Cancer Research UK really want to get across the point that there are other things that will have a much bigger impact on your cancer risk. So, if you’re a smoker, stopping smoking. If you drink a lot of alcohol, try and cut down. Keeping a healthy weight. They’re all things that are going to have a much bigger impact on reducing your cancer risk. The odd crispy potato isn’t going to do you any harm at all.
12:30 - Inter-species transplant reverses diabetes
Inter-species transplant reverses diabetes
with Qiao Zhou, Harvard University
A replacement pancreas that cures diabetic mice has been grown successfully in an animal of a different species by scientists in Japan. Tomoyuki Yamaguchi and his colleagues injected mouse stem cells into developing rat embryos. Once the rat had developed they were able to transplant the pancreas tissue into a group of diabetic mice, fixing their blood sugar levels for more than a year. Qiao Zhou, a stem cell biologist at Harvard University but who wasn't involved in the research, took Chris Smith through what the Tokyo-based team have achieved…
Zhou - What it did essentially is we managed to grow a mouse pancreas in a rat. Then we subsequently harvested this mouse pancreas from the rat and transplant it into a diabetic mouse and was able to show that this can reverse the diabetes of the recipient mouse.
Chris - Now why is that a breakthrough?
Zhou - First of all this has never been done before. This whole process, I think, points to a potential way to grow organs for future clinical use in human organ transplantation. I think that’s the exciting part of it. It’s a proof of concept.
Chris - How did they do it?
Zhou - The way they did is they took a mouse pluripotent stem cells, also called embryonic stem cells that are capable of giving rise to all tissue and body parts, and injected them into a very early stage rat embryo. At this point the embryo is just a ball of cells. The mouse injected stem cells intermingled with the resident rat stem cells and together they gave rise to a rat. But in this rat, which is called a chimeric rat, every tissue and body part has both rat cells and mouse cells. This is true for pancreas normally, you will have a normal mixture of rat cells and mouse cells, except in this case, the scientist used a method to suppress the growth of the rat pancreas so that the pancreas itself is entirely, or almost entirely made up of mouse cells.
Chris - And it was from that mouse pancreas tissue that they then extract this mouse pancreas and put that back into other mice to show that it works as pancreatic tissue capable of controlling their blood sugar?
Zhou - Yes, exactly. They didn’t use the entire pancreas, but groups of cells, so-called endocrine cells. These are the hormone secreting component of the pancreas that secrete insulin to regulate blood glucose levels to cure diabetes
Chris - Now the pancreas that grew in the donor rat, was the tissue exclusively mouse tissue or were there other rat tissues in there? Because the thing is that although they stopped the pancreas forming they didn’t stop things like important structures like blood vessels from forming. So did they end up with mouse pancreas tissue with rat blood vessels in it?
Zhou - That is indeed the case. You are exactly right, the majority of the cells in the pancreas are derived from the donor mouse, but a minor fraction of the cells came from the rat host including blood vessels.
Chris - Is that not a consideration that when you transplant that tissue, were you to use a similar technique in a person say way in the future, you would potentially be transplanting animal blood vessel tissue with that organ, you might get a fairly vicious immune response against that foreign tissue which could destroy your donor tissue?
Zhou - Absolutely. That is a major concern. But what is surprising in this study is they have shown that if you use a relatively mild immunosuppressant to treat the recipient mouse for just a few days, that seems to be sufficient to suppress rejection.
Chris - What are the dangers of doing this kind of thing? If we are to see this come to fruition and we were to start using this as a source of spare parts for people, what could go wrong?
Zhou - The clear danger would be in the creation of the chimeric human animal. You don’t want a contribution of human cells into an animal’s system or even morphological features.
Chris - Are there risks from things like infection? Is there not a chance we could bring some additional infective cargo with it which could unleash some kind of problem for everybody afterwards?
Zhou - Yes. There has been a concern voiced for a long time and, for example, in the pig there are xenogeneic viruses that can move around. But there are new technologies that are being applied, for example, by a group in Boston where they have been able to eliminate all all the xenogeneic viruses from the pig genome. So I think the technology is at the point where we can get a super clean animal that doesn’t have any viruses that could, potentially, be transmitted. I think that can be done technically and people have taken important steps in that direction.
18:11 - Mythconception - Does brain training actually work?
Mythconception - Does brain training actually work?
with Ginny Smith
In our regular ‘mythconception’ Ginny Smith did some brain training…
Ginny - If you could improve your memory, attention and reaction time just by playing a few simple games for 15 minutes a day, wouldn’t you want to? Well that’s what the huge number of “brain training” games on the market for your phone or tablet computer are offering… but it seems their claims might be too good to be true.
Indeed, since the time brain-training games first went mainstream, the scientific community has been divided over whether these activities really can streamline your mind.
The premise seems to make sense. Connections between brain cells can be strengthened the more we use them, and we also know that the brain can change visibly in response to the way we use it: take the study of taxi drivers learning the layout of London for instance. The region of the brain called the hippocampus, which mentally maps out the world for us, was much bigger in the cabbies after they learned the London roadmap than before they began their taxi training.
So it doesn’t seem surprising that there are lots of studies that claim to show that brain training games have mind-sharpening benefits too. But, a more recent review suggests that in fact the evidence for any benefit is far too weak to back up the claims companies make. So you might want to save your cash and buy a book of crosswords instead!
Because writing in the journal Psychological Science in the Public Interest, a group of psychologists, led by Daniel Simons at the University of Illinois, and including researchers from Cambridge, Florida and Michigan, scrutinised the 374 studies cited by the leading brain training companies in support of their products.
The analysis showed that the majority of the studies didn’t measure up to the ‘best practice’ they had defined: they just weren’t good science! The sample sizes were small, or the studies lacked a control group or proper baseline, making the results at best dubious and more likely meaningless.
Many studies also failed to account for the placebo effect: if you are told that playing a game will make you better at something, you may get better at it just because you expect to, with no help from the game at all.
That said, there were a few solid studies amongst those the team reviewed. But, damningly, these didn’t show any substantial benefits for brain function across the board. Instead, people only tended to get better at the task being trained.
People often liken the brain to a muscle. And they say that, just as a weights session at the gym can boost your upper body strength and make it easier to carry your shopping home, gymnastics for the mind helps keep the brain in tip top condition too.
Unfortunately, the brain is not like a muscle and this doesn’t seem to work with brain training games. People who use them do become better at the specific games they are practising, but, unfortunately, this doesn’t carry over into other aspects of your every-day life.
That said, there are some people who might benefit. Barbara Sahakian, at Cambridge University, has built some brain training apps for patients with schizophrenia to help them improve their memories, and they have seen these benefits carry over into the patient’s daily lives. But just because something works in one sub-group of people with a specific illness, that doesn't mean it will necessarily benefit the rest of us, or that all brain training games will have the same effect.
So if brain training games don’t help keep you sharp, is there anything you can do to ensure your brain stays healthy? Luckily, the answer is yes, and it’s free! There is a lot of evidence that physical exercise has benefits for the brain as well as the body, as does a healthy diet and an active social life. So if you want to stave off the ravages of time, put down the computer game controller and grab someone to accompany you on a nice walk instead...
21:32 - Climate change: fighting fake news
Climate change: fighting fake news
with Sander Van Der Linden, Cambridge University, and Doug Crawford Brown, Cambridge University
With 2016 being announced as the hottest year on record, lots of people are talking about Climate Change. But not everyone agrees that humans are in fact altering our climate. Donald Trump famously tweeted it was a hoax orchestrated by the Chinese. And there are plenty of websites arguing this too, which can cause confusion for the average person. Thankfully, scientists at Cambridge University have come up with a way to protect people against fake news, in the form of a vaccination. Georgia Mills went to get inoculated, but first checked in with climate specialist Doug Crawford Brown to find out whether scientists really do agree on the issue.
Doug - The large majority are. Typically you see numbers of 98% of relevant scientists agreeing with 2% being on the outside. And it’s about as certain as one needs to be at the moment to do the policy measures. But certainly there are some conflicting signals that we get so we would expect that perhaps continuously the temperature would be going up, but it’s not, it’s stabilised since about 2005/2006 and is only now again starting to go back up again. So that little bit of information provides a sort of counterweight against an overwhelming body of information suggesting that the climate is, in fact, changing at the moment and will change very dramatically in the next several decades.
Georgia - Why is there this stabilisation?
Doug - Well, it has a lot of different causes. Some of them have to do with the El Nino La Nina cycle. Some of them have to do with issues of heat being pushed down into the ocean until the ocean has equilibrated and then it comes back into the atmosphere again. So there are lots of causes of it but it does produce this escalator or step function in the temperature.
Georgia - So scientists, by enlarge, are agreed… but are they? There’s a petition on line signed by 30,000 scientists stating that climate change is a lie - sounds pretty convincing. It’s even been signed by Charles Darwin and the Spice Girls!. Wait a minute - this sounds like it might not be genuine. And as Sander Van Der Linden from Cambridge University found out, show someone a fake petition like this alongside a real article, and they effectively cancel each other out. So how do you fight this? Well, him and his team reasoned if fake news is the virus, perhaps you could vaccinate against it.
Sander - Is it possible to preemptively inoculate people against fake news. And the way we went about doing that is that in the brief inoculation we first warned people that there’s politically motivated groups out there with an agenda. In the detailed inoculation we went beyond that specifically debunk the misinformation that people were shown, so basically arm people with facts that counteract that information. Then we showed peopled the actual misinformation, and found that they were more resistant to the information after they were pre-exposed and inoculated to it. And this process of pre-exposing people preemptively to information (debunking it) that helps people build this kind of repertoire of counter arguments that they can use to resist this influence and misinformation.
Georgia - By showing people this warning or disclaimer, Sander and his team found you could effectively vaccinate people against the fake news stories so they had less of an effect on your overall opinion. Legitimate new sites like the BBC or social media services could implement this as a way of tackling the rise in this trend. But why does fake news seem to have such an attraction?
Sander - One of the things that I’m interested in is what I call the psychology of consensus. So we tend to pay attention to consensus in a lot of domains and one is the social domain. They way it works is that where there’s an implicit consensus or social proof that something is important, we tend to interact with it without deeply thinking about it. So if something has been shown a million times, and a video has been viewed two million times, people simply share it without thinking. So I think just because it’s attractive and it signals to people this must be important because everyone’s paying attention to it and that creates a sort of self-sustaining mechanism. Where something gets shared, much like a virus, it’s replicated at a very high rate and at that rate it might overturn the rate of actual news. And I think intervening in that process is a actually one of the most crucial elements to try to prevent people from sharing information before they’ve processed the facts hopefully science will win out.
Georgia - Science for the win. But why does climate change in particular seem to attract these fake news articles and conspiracy theories? Douglas Crawford Brown again…
Doug - Partially it’s simply because the science is still relatively new, despite the fact that we’ve been looking at it for 200 years. The science is relatively new and it’s really been in the last 15 years that we’ve started to get really strong information. So the public partially is simply lagging behind the development of the science. But the main issue is that if there isn’t in fact climate change going on, which I think there is, then we’re looking at some potentially dramatic changes in people’s lifestyles and people generally don’t want to have to change their lifestyle. They would rather have a policy that focuses on bad industry or something like that. They don’t like to think in terms of their own lives as causing the problem, and whenever you know that a policy is going to lead to you having to do something dramatic there’s a tendency to back away and say maybe there’s not a problem at all.
Georgia - I know there’s this issue on social media of people being in bubbles of things and which bubble would you rather be in - the bubble that tells you everyone’s going to have a real problem in a couple of years or the bubble that says we’re all going to be fine?
Doug - Yes. That’s actually been the problem associated with social media, particularly as people increasingly get their news from things like Facebook and so forth where you can get into a little bubble. You go into there because you like something that you’ve heard there, and then because you like it you tend to keep going back to that same place. If these sources of social media information were being complete and unbiased and giving you the full information, then I wouldn’t be so worried about it. But of course, they’re not, they’re attempting to be sensationalistic, they’re attempting to attract a lot of likes and so forth, and you tend to believe things that you like.
28:26 - The algae that started it all
The algae that started it all
with Otti Croze, Cambridge University, and Kyriacos Leptos, Cambridge University
It may seem like science fiction, but with optogenetics scientists can control the behaviour of animals by simply shining a light into their brains. And this technology began… in algae! These single-celled plants are powered by the sun and contain built-in light detectors to control their behaviour. This discovery, and the isolation of the light sensitive protein that is responsible, led to the birth of the science we now call optogenetics. Tom Crawford went to see Cambridge University’s Otti Croze and Kyriacos Leptos to try to catch some of these incredible life-forms and in these circumstances in extreme conditions...
Tom - It’s about minus 10. Well it’s not but it’s freezing and we are going to be catching some algae. But the first thing we’ve got to do here is actually break the ice - that is how cold it is… We have a cup of freezing cold water with I can see a few little bits of salt and silt and things floating around in there. So hopefully we have some algae in there.
Otti - We can hope.
Tom - So that was fun, Otti, scooping out some water from the freezing pond but what are we actually looking for here?
Otti - We are searching for microscopic algae which are about one hundredth of a millimeter or a tenth of the average human hair, so these algae are not visible to the naked eye. But algae are an extremely diverse type of organism and some algae are actually microscopic, such as the seaweed that you might eat in your sushi.
Tom - Is there a specific algae that we’re looking for that is used in the field of optogenetics?
Otti - Yes. We’re not guaranteed to find it in this pond. But optogenetics was born from the soil microalgae Chlamydomonas reinhardtii, so that’s ideally what we would want to to find.
Tom - As Otti mentioned, we’re trying to find the algae Chlamydomonas. This is a single cell marine plant which has arms called flagella which it uses to swim towards a light source so that it can photosynthesis and make food. It does this by using a protein called channelrhodopsin which is light sensitive. This triggers the flagella to move and propel the algae towards the light. But by taking the channelrhodopsin gene from the algae and introducing it to nerve cells in the brain, scientists can use it like a switch to turn these nerve cells on or off just by shining light onto them.
Now let's head back to the nice and warm lab…
I can see some samples on the bench and there’s a bottle of what looks like clear water. But then, if you look at the righthand side, the entire inside of the container is green, almost as though the algae are concentrated in one spot. Kyriacos - what’s going on there?
Kyriacos - That’s a phenomenon that’s called phototaxis. It’s basically a behaviour of the microalgae. Algae are the photosynthetic so they harvest light to produce their biomass. They need to be able to detect the light so that they can survive.
Tom - So here the algae have moved to the right of the container because there’s a window on the righthand side?
Kyriacos - Yes. Phototaxis is actually the directed motion towards the light. So they need to have a sensor to detect the light and that’s called an eyespot. What’s used in optogenetics is a particular part of the eyespot, which is the one that’s actually sensing the light.
Tom - The part of the eyespot that Kyriacos is referring to is the protein channelrhodopsin that I mentioned earlier. Now let's see if we managed to catch anything from the frozen pond.
Okay. I’m looking down the microscope now and I can see a little dancing circle alost. What type of algae have we found?
Kyriacos - From its morphology it might be the algae euglena but you can’t be sure just looking at it. To be absolutely sure you would have to sequence it and then their regions of the DNA of algae that act as barcodes which allow you to identify the species quite uniquely.
Tom - I’m just impressed we found anything really considering the pond was frozen!
with Isabel Christie, University College London
How do we get from algae that respond to light to controlling the brain? Kat Arney was joined by Isabel Christie from University College London to explain the what and how of optogenetics...
Isabel - Fortunately we can use very clever genetics to take those genes from the pond life and put those into viruses. Then we can inject the viruses into the brain of a living animal such as a mouse or a rat. The cells that we’ve chosen to target using the virus will start to express that light-sensitive protein.
Kat - So I guess like in the same way when you catch a cold, the virus is delivering virus genes into you making you go all snotty and that kind of thing? You’re actually taking theses light-sensitive genes into the brain cell of the animal you’re working with?
Isabel - Absolutely. Once the cells have become infected by the virus they start to produce that viral DNA and they start to produce those proteins.
Kat - So the proteins are in these brain cells and how do you make sure that it’s just certain types of brain cells or is it any brain cells the virus infects?
Isabel - Well, that’s the really clever bit - the genetics angles, that we can choose which cells in the brain we’d like to express the light-sensitive protein. And that’s what gives this tool such great power because we can use excitatory cells or inhibitory cells in the brain and we can target specifically which cells we would like to make light-sensitive.
Kat - What’s the benefit of making a certain clump of nerve cells, a little clump in the brain? You’re making them sensitive to light by putting this molecule in them. So you shine a light on them, they go whoo - what do you do then?
Isabel - It’s all about control. As neuroscientists we want to understand the neural circuits of the brain and one of the ways we can begin to understand is to try and control them - turning them on or turning them off at will. One of the big challenges for neuroscience was this inability to control only specific brain cells at once. The more traditional techniques, using things like drugs, tend to affect many brain cells at once. So when you put a drug directly into the brain it will spread out in the brain and it will affect all the cells in the region.
The really clever thing about optogenetics is if we make only some brain cells light-sensitive, when we shine light into that part of the brain only certain cells respond. And that give us an ability to control the brain in a very specific way, so we can test the hypotheses in a way that we just couldn’t before with drugs.
Kat - So you can say okay, if these cells go on, what’s happening?
Isabel - Exactly. Some of my research is about saying if we turn these cells on, what happens in an MRI scanner? What happens in the animal’s brains? Or if you’re researching a particular disease where you thought some particular cells were responsible for causing that something to happen in the brain, you can turn those cells on and really test that hypothesis in a very direct way.
Kat - So we’ve got the genes, they’re delivered into the nerve cells, they’re making this light sensitive protein, they’re switching on, but how do you actually get light inside the brain? Last time I looked the brain was quite dark inside.
Isabel - Yeah. It’s one of the awkward aspects, I guess, of optogenetics. Some of the first experiments that were ever done were done in a petri dish with a slice of living brain tissue. It was very easy, you could deliver light through your microscope objective or via an optic fibre, but most optogenetics these days is being done in living animals. So what we might do when we’re doing the viral injections directly into the brain we will implant an optic fibre into the brain. And then, on the day of the experiment, you can come and connect an optic fibre externally to the animal’s head.
Kat - So it’s kind of like almost plugging in a remote control?
Isabel - It really is. If you look at images of optogenetics on the internet you really will see freely behaving animals with optic fibres plugged into the back of their heads. So it can look quite shocking when you see these images.
Kat - But presumably they’re okay?
Isabel - It’s quite an invasive process optogenetics. You’re injecting viruses into the brain and then you’re implanting optic fibres into the brain. But some of the great power of this research is that you can do experiments in freely behaving animals, so if people have designed very clever techniques of connecting the animal’s head to the optic fibre so they can still move around their cage and explore and do natural behaviours.
Kat - Why is this tool so powerful?
Isabel - Being able to control the brain in such a temporal specific way. You can turn cells on exactly on and off when you want to. There are so many hypotheses. I feel like almost every neuroscientists is trying to use optogenetics because it gives you a level of control that we just never had before.
Kat - It feels like a very exciting new tool. My specialism is in genetics and I’m following crispr for gene editing, and then following optogenetics for really precisely activating cells and switching on nerve cells. Does it feel like we’ve finally got this tool?
Isabel - I think it is one of the most powerful research tools that we’ve ever had in neuroscience and I think it’s already revealing so much about the brain, Just very cutting edge and very exciting times for neuroscience.
Kat - do you reckon it’s going to be a Nobel Prize winner?
Isabel - Absolutely! I think it will be probably shared by Karl Desaro and Ed Boyden and probably Gero Miesenboeck.
Kat - And, like you say, so many different ideas to be tested out there.
Isabel - I mean it’s just so wide ranging. It doesn’t have to be all inside the brain. You can also look at the peripheral nerves and you could look at other parts of the body. It’s very powerful.
39:01 - Using lights to send flies to sleep
Using lights to send flies to sleep
with Gero Miesenboeck, University of Oxford
Now that we have this incredible neurological tool in optogenetics, what exactly can we do with it? Gero Miesenboeck is one of the pioneers of the field of optogenetics. He is using the technique in fruit flies, which can be put to sleep simply by flashing a red light in their direction. Tom Crawford went to Oxford University to meet Gero and find out why…
Gero - Neuroscience has for a long time just passively recorded the function of the brain and tried to draw conclusions from these observations. But, of course, in order to really understand how a system works, you have to be able to control it. We do this by hooking up the gene that encodes the light sensor to a gene that’s linked to a particular characteristic of the nerve cell.
Tom - In simple terms, what Gero is saying is that they first identify the neurons in the brain which they think are responsible for a particular behaviour. For example, the area of a fly’s brain that causes it to go to sleep. The DNA of these cells is then altered such that the neurons can be turned on by red light.
The theory is then tested in the lab where a red light is shone at the fly from above. The light penetrates the skull of the fly and activates these specific neurons that have been genetically altered. These neurons then switch and then, hopefully, will cause the fly to fall asleep. Of course, this is provided that the team have identified the correct circuitry in the brain that controls sleep…
I’m now outside the room where experiments on the flies are being conducted and we’re just about it enter. It’s going to be very dark. Yes, as I suspected the room is really dark. There’s a little patch of green light illuminating what I can see on the screen is a little fruit fly inside of some kind of very small (the size of one pence coin) little rubber walled area it seems. The fly’s just sitting in there not moving and has a green light shined on it from above.
So Gero, what is it I’m looking at?
Gero - You’re looking at a fly that is just having it’s afternoon siesta. It’s about 2.30 in the afternoon at the moment, which is when many flies are sleeping. So what you’re seeing here is not optogenetically induced sleep but just normal, natural sleep.
Tom - Okay. We’ve brought out a second fly now and this guy is definitely not having a nap. I can see him moving around on the screen and, if I look down really closely, I can see the tiny eye. It’s just fluttering his wings and seems to be grooming himself almost.
Now we’ve turned on this high 60 flashes per second red light and the fly’s stopped moving. He’s kind of sprawled his legs, almost like a starfish, if you can imagine, if you’re really tired and fall face down onto your bed with all your limbs spread out. Pretty much what the fly’s doing and he has completely stopped moving. Is it safe to assume the fly was asleep there?
Gero - By every behavioural criteria, yes. We know that the flies when they are in this optically induced state show the classical hallmarks of sleep. That is they don’t move, they don’t support their own bodyweight and they also have heightened arousal threshold. So, if you give them, for instance, a light or a tap meant to wake them up these stimuli need to be more intense to elicit the response.
Tom - The red light has now been switched off and, almost instantly, our fly has started moving again. Gone back to shaking his wings around and crawling around on the lid of the dish which he’s contained in. It’s really quite amazing to see how quickly - I mean I can’t wake up that quickly in the morning so I’m impressed the fly can.
43:19 - Could optogenetics cure epilepsy?
Could optogenetics cure epilepsy?
with Andrew Jackson, Newcastle University
Could optogenetics be implemented in humans? If we consider some of the major conditions that might well be treated using this technique - one of them is epilepsy. Andrew Jackson is leading a project called CANDO at Newcastle University, and he spoke to Chris Smith…
Andrew - What the CANDO project to do is it’s a combined therapy that involves a gene therapy to render neurons sensitive to light using optogenetic technology. And also a brain implant and that brain implant has the capability to both record electrical signals from the brain and send light into the brain to control neurons. The aim of this is to develop a therapy that will prevent seizures that arise from epileptic conditions.
Chris - Now when a person has epilepsy, what is actually going on in their brain to produce the manifestations that people are probably familiar with - fits and seizures.
Andrew - The particular type of epilepsy that we’re talking about here is focal epilepsy and that’s where a small part of the brain is behaving abnormally and the neurons become excessively synchronised and start firing in a very rhythmic manner. This abnormal activity then starts propagating through the brain network leading a seizure which is then associated with uncontrolled movements, loss of consciousness, and things like that.
Chris - How do we currently control epilepsy in patients who have this?
Andrew - Obviously, the frontline treatment would be drugs and there are a variety of drugs that can be offered but, in quite a large proportion of cases, those drugs are not effective without unacceptable side effects. So there’s actually quite a large population of people who have seizures that are not being controlled by the existing drugs.
Now the other solution then, in the case of focal epilepsy, is for a surgeon to go in effectively with a scalpel blade and remove the part of the brain that is abnormal and is generating these seizures. But obviously, when we’re talking about resecting part of the brain, that also has potential side effects and there are certainly some parts of the brain which can’t be removed like that without a really severe side effects.
Chris - So, if your project comes to fruition, how will it surmount those problems?
Andrew - The hope would be by using this implant and using the optogenetics technology, we could control that part of the brain but without destroying its function. So allowing that part of the brain to operate normally but preventing this abnormal activity from developing and causing a seizure.
Chris - Talk us through what would be involved then? How would you if you had a patient in front of you with epilepsy they can’t control with drugs and the drugs that they do take have horrible side effects, and they say right I’m desperate. I want some other alternative and I don’t want surgery - what would happen?
Andrew - What we would so is the first step, we would inject a viral vector. So this is derived from a virus but it’s a virus that can’t replicate so it’s safe. But that virus would be used to deliver the opsin gene to specific neurons in the region of the seizure focus.
The second step would be implanting the brain implant, which we’re envisaging is about the size of a drawing pin, that get’s put into the seizure focus. Now this drawing pin has the capability of listening to the electrical activity in the area of brain surrounding it. As these abnormal patterns start developing, this implant then delivers light to control specific cells in the vicinity in order to suppress the seizure activity and prevent it developing.
Chris - It’s rather like these automatic implantable cardiac defibrillators that people with heart problems have fitted. As soon as they tune into a heart signature that suggests you might be about to have a cardiac arrest it then kicks in with a shock and sorts the heart rhythm out, yours kicks in with a pulse of light which resets the nerve firing rhythm?
Andrew - That’s right. It’s worth pointing out that there are already quite a number of successful devices that are used quite widespread in clinical conditions that use electrical stimulation to activate the nervous system. Perhaps the best example of the would be deep brain stimulation which is a very good and established therapy for treating the symptoms of Parkinson’s disease.
Now there are also attempts to treat epilepsy with electrical stimulation but they only have partial success. Part of the reason for this is that electrical stimulation is rather like trying to play a musical instrument by hitting it with a sledgehammer, you sort of play all the notes at once. What optogenetics allows us to do is to use promotores to express the opsins (these light sensitive proteins) in only specific cell types and then we can activate particular cell types within the brain network.
The other thing I’ve got to say is because we’re stimulating with light we can also, at the same time, record the electrical systems from the brain. If you electrically stimulate, then those currents that you are using are much larger than the currents that the brain produces and so you can’t record at the same time. So, in principle, what this close loop optogenetics allows us to do is to listen to what’s going on in the brain and stimulate at the appropriate time. So that’s rather like playing your musical instrument, not only are you playing the right notes, but also being able to listen to what the instruments around you and the rest of the orchestra are playing, and play the appropriate thing at the right time.
Chris - What evidence have you got, so far, that were you to go down this path and put this into a person’s brain who has epilepsy, you have a good chance of controlling their disease for them?
Andrew - There’s been some promising studies in animal models that have this optogenetic technique to control epilepsies. We are also working with extensive computer simulations that allow us to simulate the effect of the optogenetic stimulation on the epileptic networks.
Then the other line of evidence which we’re working on, but is currently very encouraging, is that we can take… as you said to you one of the main treatments, at the moment, for some of these epilepsies is to resect that part of the brain from the patient. Here at Newcastle my colleague, Mark Cunningham, with the patient’s consent can take that tissue after it’s been resected and start studying it in the dish in the laboratory. So we’re beginning now to get data from actual human tissues having seizures and being able to look at the effect of optogenetics on that activity.
49:53 - Will optogenetics change medicine?
Will optogenetics change medicine?
with Isabel Christie, University College London
It’s not just epilepsy that could be cured using optogenetics, there are a whole host of other possible uses. Isabel Christie from UCL spoke to Kat Arney about whether it could have applications in eyes...
Anabel - Absolutely. As you mentioned, the cells in the retina are already light sensitive so one of the obvious ways of trying to cure blindness would be to replace those light-sensitive proteins in defective retinal cells. So channelrhodopsin was expressed in the retina of blind mice in 2006 and in 2015, the FDA actually approved retinal targeting of channelrhodopsin expression. I understand that the first transfer of opsins to humans occurred in 2016, so I think this is a really active area of research and something to be really excited about.
Kat - Are there other tissues in the body, other tissues that need to be excited, need to be turned on that this kind of technique could be applied to?
Anabel - Yes. There’s been a lot of excitement about the idea of targeting cardiac myocyte, the heart muscle cells. Often a pacemaker can be applied to the heart with people that have heart conditions and so cardiac myocytes can be stimulated in a similar way to nerve cells.
Kat - So you could do that really precisely though, rather than just having a battery pack?
Anabel - Absolutely. As your previous was just saying, the problem with electrical stimulation is it’s like a sledgehammer, you often hit many of the cells at once. Whereas with optogenetics, you can target specific cells in a more localised way so it would probably be much better than a pacemaker in the heart as well.
Kat - And also Andrew touched on the idea of deep brain stimulation. Particularly I’m thinking of Parkinson’s disease where certain cells that are not working properly and you want to kick them into action. Would this work and is this really a good idea to use optogenetics?
Anabel - I think it’s a brilliant idea because there are already patients undergoing invasive surgery where they’re having electrodes implanted into their brain, so they are already having a very invasive process. But if you were to use optogenetics you would have to implant optic fibres into that part of the brain and, in addition to that, you would have to genetically modify those brain cells. So one of the ethical issues that we would have to deal with if we were going to start doing this in people is genetic modification of human brain cells. I think there might be some reluctance to do that.
Kat - Although we have seen great advances in gene therapy lately. We’ve seen the tools that I’ve mentioned for gene editing - things like CRISPR, which enable these techniques to be done a bit more accurately. It feels like there is a world opening up… maybe?
Anabel - Yeah. I mean I personally think if we can overcome the ethical issues associated with genetically modifying human tissue then it will lead to many applications and many exciting things, but it’s just something to consider. With deep brain stimulation, you are just implanting electrodes into the brain. This would be a two step process. I think one of the challenges is can we do gene editing in a continuous way? Can we modify these brain cells long term, not just temporarily?
Kat - It seems like a lot of exciting techniques that need to happen?
Anabel - Yeah. It’s a very exciting time for neuroscience.
53:13 - Why is the Earth's magnetic field north-south?
Why is the Earth's magnetic field north-south?
Stuart - OK, first thing’s first, you might be interested to know that the earth has more than one north and south pole.
Graihagh - um, que?
Stuart - Yeah! It has geographic poles – these as the two points on the surface of the globe which the earth rotates around. But it also has magnetic poles. These are where the Earth’s magnetic field lines flow in and out of the earth’s surface.
But the magnetic and geographic poles aren’t the same – they’re a few hundred kilometres apart.
Graihagh - OK so where do the magnetic poles come from, and why are they different?
Stuart - Our current best theory is that the earth’s magnetic field is caused by its core. By studying vibrations from earthquakes as they pass through the earth, scientists estimate that the core is made of a solid metallic centre, surrounded by a layer of molten metal.
It’s the movement of this molten layer that’s thought to create the earth’s magnetic field.
So that’s why the magnetic north and south poles line up with the geographic north-south, rather than say east-west.
But as well as rotating, the layer also has convection currents, a swirling of the metal caused by intense heat.
It’s the combination of both rotation and convection that is responsible for the earth’s magnetic field – this is known as Dynamo Theory. This complicated movement, influenced by other factors, mean the magnetic and geographic poles don’t quite line up. And in fact, throughout the earth’s
history they’ve continually switched places!
Graihagh - Fortunately for us, this happens not very often – can you imagine the calamity and confusion if our compasses were all wrong? On average, the poles switch every 250 thousand years. And we know this...
Stuart - By looking at patterns in different rock layers, it’s possible to work out that the earth’s magnetic field has flipped direction many times in the past. Current researchers use supercomputers to try model and understand this still mysterious behaviour…
But what it does mean is that if the poles were to flip again, any compasses would be left pointing in completely the wrong direction…
Graihagh - Stuart Higgins turning our world upside down there. Next time, we’ll be tackling this: