Neuroscientists at University College London have developed a method of manipulating star-shaped cells situated within the brain using microscopic magnets. We spoke to researchers Dr Yichao Yu and Prof Mark Lythgoe to find out more.
Your technique is focused on brain cells called astrocytes. What exactly are they?
Yichao: They're a type of glial cells [non-neuronal cells that are found in the brain and spinal cord]. They're very abundant, they outnumber neurons manyfold. Traditionally they're viewed as support cells, they recycle the neurotransmitters neurons release.
They do many logistical maintenance-type of jobs in the brain. But in recent years, as we’ve learnt more about these cells, we’ve found they have many other functions, such as regulating cognitive behaviour.
Mark: For the last hundred years they’ve been the second-class citizen in the brain in terms of cells, neurons have taken the limelight – they’re electrically active and supposedly control all our functions. But these cells, although not electrically active in the same way, can communicate and sense and process and control bodily functions.
What are the micromagnets that you use made from?
Yichao: They're very simple magnetic particles. They have a core which is made of iron oxide and a polymer shell, which enables us to attach various things to their surface.
What happens once they’re in the brain?
Mark: Astrocytes have all these finger-like projections that come off them, a bit like a Christmas tree. You decorate a Christmas tree with baubles, but in our case we use magnetic particles.
They're bound to the Christmas tree by little hooks - antibodies that are specific to the branches of the astrocytes. When you put force on the baubles and move the star-like processes [by applying an external magnetic field], they can sense this touch. The astrocytes are constantly feeling and sensing their environment.
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What effect does this have on the brain?
Yichao: We are trying to activate very specific signalling pathways. One is the release of a single molecule called ATP, adenosine triphosphate. When we stretch the membrane of the astrocytes [using the magnet], these signalling molecules are released. The ATP released by the astrocytes can then go on to affect neighbouring cells.
Mark: When the astrocytes get stretched they release this signalling molecule, ATP. And then that comes in close contact with the neurons and then the neurons become activated and control the different functions - everything from memory to heart rate to blood pressure.
Yichao: Our collaborator Alex Gourine previously discovered a very small region within the brainstem that acts like a master regulator of sympathetic neural activity - the part of the autonomous nervous system that controls your fight and flight responses.
He found that if you stimulate astrocytes in this region you release ATP and the ATP acts on the neurons in that in that area. This then directly stimulate the sympathetic nervous system and cause heart rate to increase, breathing rate to increase blood pressure to rise. All those kind of responses. So what we showed in this study is that if we target those specific astrocytes with attached micro magnets we saw the same response he saw with optogenetics.
What are the advantages of this technique?
Mark: Deep brain stimulation is used remarkably widely and with great success for treating Parkinson's, epilepsy and, more recently, depression. But this involves inserting two long electrodes deep into very specific regions of the brain and requires a complex and lengthy neurosurgical procedure.
The simple notion of just being able to have an external magnet that you can bring in contact with the particles to get the same effect as the electrical stimulation is really appealing because it doesn't have the invasive complexities of this full-on neurosurgical procedure. The other thing is that with deep brain stimulation it will activate anything that it comes into contact with.
Whereas we're trying to be very specific and selective, just targeting the astrocytes. So we’re increasing the specificity of the technique, but importantly, reducing what would be called off-target or side effects associated with those techniques as well.
Yichao: The idea is we want to be able to stimulate these cells without inserting anything into the brain itself. That's why we went along with this magnetic approach. One of the advantages of our technique is this remote control.
The other advantage is that to implement our technique the target cells don't have to be genetically modified. Currently some of the most widely used cell control technologies, such as optogenetics and chemo genetics, require a protein to be inserted into the cell membrane of the target cells, usually with the help of a virus.
This has been a slight obstacle to clinical translation and led us to develop our technology, which doesn't require genetic modification, so that we'd have a more promising future as a neuromodulation therapy. And also maybe an easier path towards the clinic.
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What conditions could this technique be used to treat?
Yichao: One is depression. We are very interested in that because there has been some very robust evidence in animal models to show that ATP from astrocytes has very strong anti-depressant effects.
And as we have shown that we can cause the astrocytes to release ATP in whichever brain region we target, our technique will be a very good candidate for the development of a therapy for major depression. The kind of very severe depression that's resistant to common antidepressant drugs.
That's one of the most promising applications in terms of the clinical development in the near future. But there are other things as well, because astrocytes do all sorts of things in every area of the brain.
Mark: It could be used post-stroke. The release of the ATP would hopefully mop up some of the toxic molecules that lead to inflammation and therefore reduce the overall size of the stroke damage. This could be the same for epilepsy as well. Epilepsy is also [currently] treated by deep brain stimulation, and we could see this as a replacement.
What's coming up next for this technique?
Yichao: In its current form we still need to drill a hole in the skull and insert a needle to inject the particles into the target brain region. Our next step would be to employ some kind of more advanced particle delivery approach so that we don't have to do brain surgery at all. This will further reduce the invasiveness of the technique and make it even more appealing.
Mark: What we're looking for is a trap door into the brain or a back door into the brain. We can do that with ultrasound. We can decide exactly what parts of the brain we want to target and fire focussed ultrasound in.
This creates a slight weakness in the brain lining, which is like a little trapdoor that opens for a short period of time, then the particles can rush in and because they've got the antibodies on them can bind to the astrocytes. Then the trap door closes and then we can do the magnetic activation, all with a single intravenous injection.
About our experts, Dr Yichao Yu and Prof Mark Lythgoe
Dr Yichao Yu is a research associate at the UCL Centre for Advanced Biomedical Imaging.
Prof Mark Lythgoe is the Founder and Director of the UCL Centre for Advanced Biomedical Imaging.