The method, tested in rats, targets star-shaped brain cells called astrocytes. Neuroscientists Dr Yichao Yu and Prof Mark Lythgoe at University College London tell us more…
YOUR TECHNIQUE FOCUSED ON ASTROCYTES. WHAT EXACTLY ARE THEY?
Yichao Yu: They’re a type of glial cell [non-neuronal cells that are found in the brain and spinal cord]. They’re very abundant, they outnumber neurons [nerve cells] many times over. Traditionally they’re viewed as support cells, they recycle the neurotransmitters that neurons release. They do many logistical maintenance jobs in the brain. But in recent years, as we’ve learnt more about these cells, we’ve found that they have many other functions, such as regulating cognitive behaviour.
Mark Lythgoe: For the last hundred years they’ve been the second-class citizen in the brain in terms of cells. Neurons have taken the limelight because they’re electrically active [send electrical signals] and supposedly control all our functions. But astrocytes, although not electrically active in the same way, can communicate and sense and process and control bodily functions.
About 30 years ago, they were called the genius cell. This is because when Einstein died in 1955, his brain was taken out by the pathologist Thomas Harvey and it remained hidden for nearly 30 years. Harvey then started to release a couple of the sections to Marian Diamond, an amazing neuroscientist. She found that Einstein did not have more neurons in certain areas of his brain. He actually had more glial cells, and because of that they were known as the genius cell.
WHAT ARE THE MICROMAGNETS THAT YOU USE MADE FROM?
YY: They’re very simple magnetic particles. They have a core that is made of iron oxide and a polymer shell, which enables us to attach various things to their surface. For example, we attach the antibody to the surface of these magnetic particles so that they will be targeted to astrocytes specifically.
THE MICROMAGNETS ARE INJECTED INTO THE BRAIN THROUGH A HOLE IN THE SKULL. BUT WHAT HAPPENS ONCE THEY’RE IN THE BRAIN?
ML: Astrocytes have all these fingerlike 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 them [by applying an external magnetic field], they can sense this touch. The astrocytes are constantly feeling and sensing their environment.
WHAT EFFECT DOES THIS HAVE ON THE BRAIN?
YY: We are trying to activate very specific signalling pathways. One is the release of a single molecule called ATP, adenosine triphosphate. Our collaborator Prof Alex Gourine previously discovered a small region within the brainstem that acts like a master regulator of sympathetic neural activity, which is the part of the autonomous nervous system that controls your fight and flight responses. He found that if you stimulate astrocytes in this region of the brainstem, you release ATP. The ATP then acts on the neurons in that area, which then directly stimulate the sympathetic nervous system and cause heart rate and breathing rate to increase, and blood pressure to rise.
So what we found in this study is that if we target those specific astrocytes with micromagnets, we saw the same response he saw.
WHAT ARE THE ADVANTAGES OF THIS TECHNIQUE?
ML: Deep brain stimulation is used remarkably widely and with great success for treating Parkinson’s, epilepsy and depression. But this involves inserting two long electrodes deeply into specific regions of the brain and requires a complex and lengthy neurosurgical procedure.
And then you’re left with a second procedure where you have to implant the electrodes that come out of the back of the head under the skin into a powered box that lives underneath the collarbone. 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 with deep brain stimulation is that it will activate anything with which it comes into contact, whereas we’re trying to be very specific and selective, just targeting the astrocytes.
YY: 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 chemogenetics, require a protein to be inserted into the cell membrane of the target cells, usually with the help of virus. This has been a slight obstacle to clinical translation and led us to develop our technology.
WHAT CONDITIONS COULD THIS TECHNIQUE BE USED TO TREAT?
YY: One is depression. We are interested in that because there has been some very robust evidence in animal models to show that ATP from astrocytes has strong antidepressant effects. 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 therapies for major depression – the kind that’s resistant to common antidepressants. 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.
ML: 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?
YY: 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 a 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.
ML: What we’re looking for is a trapdoor into the brain. We can do that with ultrasound. We can decide exactly what parts of the brain we want to target, and then fire focused ultrasound at them. This creates a slight weakness in the brain lining 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 trapdoor closes and we can do the magnetic activation, all with a single intravenous injection.
DR YICHAO YU
Yichao is a research associate at the UCL Centre for Advanced Biomedical Imaging.
PROF MARK LYTHGOE
Mark is the founder and director of the UCL Centre for Advanced Biomedical Imaging.