“Migraine is not a holistic disease where all patients fit into the same box. That’s why we don’t have a single treatment that works in every patient. We need to offer patients options, because in some patients one part of the disease biology may be more important than the same part in another patient. Hence, it’s nice to find different ways we can modulate the disease.” – Anna Andreou
Anna Andreou, PhD, is Medical Research Foundation fellow and director of Headache Research at the Wolfson Sensory Pain and Regeneration Centre (SPaRC), King’s College London, and the Headache Centre at Guy’s and St Thomas’ NHS Foundation Trust, UK. Her research focuses on the neurobiology of headache disorders, and the investigation and development of new therapeutic approaches for migraine, other headache disorders, and facial pain.
In this Migraine Science Collaborative interview, she chats with Lincoln Tracy, PhD, a researcher and writer from Melbourne, Australia, to discuss her career path to becoming a headache disorder researcher, the projects she is working on, including her collaboration to develop non-paralytic botulinum toxins for migraine and pain, and much more. This interview has been edited for clarity and length.
What was your path to becoming a headache researcher?
My background is in biology and neurophysiology, and I had also studied clinical neuroscience before starting my PhD in London, which focused on migraine and neurological sciences. I finished my PhD at the University of California, San Francisco with Peter Goadsby, and then did my first postdoc in his lab as well. Although I trained as a neurophysiologist, I never worked in the field because I was so impressed with the headache research field, and when I started my PhD, being a migraine sufferer myself, I knew this was where I wanted to be.
It was a very smooth transition from training as a neurophysiologist to moving into headache and migraine research because I deliberately looked for PhD opportunities that involved some form of neurophysiology. My PhD involved a lot of electrophysiology, which was quite similar to the neurophysiology I had previously studied. The transition was also helped by my desire to undertake a headache-related PhD because my mother and I both suffer from migraine. I remember turning up at one of the first lectures during my master’s degree and being so excited to learn about what caused migraine. But the very first thing the professor said when he stood up was, “We don’t know what causes migraine.” It was disappointing to hear him say that, but the need to find out what causes migraine is a big part of why I’m interested in the field.
When I came back to London after finishing my time in San Francisco, it was challenging because no one across the entire UK was doing headache research, nor was there any funding for potential research. I ended up doing a postdoc on stroke, which was interesting – I had a fantastic time and met amazing people – but it wasn’t what I wanted to do. Luckily enough, two years later, The Migraine Trust announced a fellowship for a junior researcher. I applied, and was successful, and that’s how my journey began.
What are the main aims of your research?
My lab focuses on translational research, and we have three main aims. We use animal models to try to identify neurophysiological mechanisms involved in migraine. At the same time, we’re working with patients to find biomarkers for migraine as well as other headache and facial pain disorders. And then another big part of our work is identifying novel therapies for all of these conditions, as well as understanding the mechanisms of action of currently used therapies to improve them, or to help develop new, more effective therapies working via a similar mechanistic pathway.
Why did you decide to focus on both the mechanistic and translational side of things rather than picking one stream?
Well, I think you need to have patient contact and access to a lab to do basic science, because one fits with the other. You cannot do mechanistic science without talking to the patients to understand what the disease is. But at the same time, there are things you cannot do in humans, especially in conditions like migraine. It’s unethical to open the brain to understand what the neurophysiological mechanisms might be, so we need basic science to help on that front. Not to mention that any new therapeutics require toxicological studies in cellular and animal models, and we need good models to investigate their efficacy as well.
And why does your lab look at both pharmacological approaches and neuromodulation techniques to treat migraine and other headache disorders?
Migraine is not a holistic disease where all patients fit into the same box. That’s why we don’t have a single treatment that works in every patient. We need to offer patients options, because in some patients one part of the disease biology may be more important than the same part in another patient. Hence, it’s nice to find different ways we can modulate the disease. What has been interesting is that, in the past, migraine was mainly thought of as a brain disorder, so everything focused on the brain. But nowadays, we have treatments that work peripherally, but only in some patients. It’s nice to have treatments that can be combined to target different aspects of the underlying biological mechanisms.
Since I’ve been involved in the Headache Centre, we have introduced a transcranial magnetic stimulation (TMS) clinic where we use single-pulse TMS for migraine. And we see fascinating results in patients, which informs the basic science research we’re doing. But at the same time, it’s interesting to see how patients who may respond partially to newer treatments – the CGRP [calcitonin gene-related peptide] treatments, for example – may also benefit from a combined treatment involving TMS neuromodulation and drugs. It’s an interesting population of patients who respond very well to this combination of treatments. This tells us a lot about the biology of migraine.
What projects are you and your team currently working on?
One project we’re working on is part of the mid-career fellowship award I received from the Medical Research Foundation, which is the charity associated with the Medical Research Council in the UK. We’re exploring the therapeutic benefits of novel botulinum toxin-like molecules. This work is in collaboration with Professor Bazbek Davletov from the University of Sheffield, who developed the molecules.
They’re interesting molecules because although they have a similar structure to the native botulinum toxin and the same neurobiological effects, they’ve been constructed in a way that means they’re too big to enter the neuromuscular junction. So they’re non-paralytic, but because they still have access to the free nerve endings of nociceptors, they can be used to treat pain.
In addition, the new molecules are not toxic, which means we can administer higher doses and get better efficacy without having to worry about the side effects. We’ve tested these molecules in animal models of migraine, and now we’re looking at inflammatory and neuropathic animal models of facial pain. We’re hoping to start a first-in-human trial within the next few years. I’m very thankful to the Migraine Research Foundation, from whom we received a small grant at the very beginning of this work back when Professor Davletov and I started collaborating. We couldn’t have done this without their support.
We’re also working on another project where we’re trying to understand the inflammation that occurs within the brain during the early stages of a migraine or a cluster headache. We’re focusing on the hypothalamus, which we have previously shown to be involved in the migraine process. We are investigating potential inflammatory pathways activated in the hypothalamus that initiate a cascade of events leading to the activation of nociceptive pathways.
You recently published a study that looked at the effects of switching from a monoclonal antibody against the CGRP receptor to an antibody against the CGRP ligand for treatment-refractory migraine. How are these approaches different?
That’s a good question. It’s hard to answer because there is still a lot of research that needs to be done in this space. In one sense, they’re different because the receptor may internalize at some point after being exposed on the cell surface, meaning it isn’t always there for CGRP to access it, or for the CGRP receptor antibody to block it. But when the ligand is released, it’s floating around, and the antibodies can block the peptide before it binds to the receptor. However, that’s just one possibility – there may be other biological differences that we don’t understand. We’re probably a few years away from understanding potential differences in efficacy between blocking the receptor versus blocking the ligand, as other receptors may also be involved.
An interesting point from that research is that it makes clinical sense to switch patients from a CGRP receptor antibody to a CGRP ligand antibody because there are patients who will still respond to it. What we don’t yet have is the opposite – will patients who failed the CGRP ligand treatment respond to a CGRP receptor treatment? This is an interesting question. My guess would be yes; we’ll still find a population of patients who didn’t respond to one part of the CGRP treatment but respond to the other. This may also show how diverse migraine treatments can be within the patient population.
You were previously the chair of the International Headache Society Trainees and Residents Special Interest Group. What was that experience like?
This was a great honor, because I’ve always been interested in promoting early career researchers in the headache field. This is an important area because it’s a waste of resources to train PhD students or postdocs only for them to leave and pursue research in other areas such as Alzheimer’s or multiple sclerosis. I don’t like losing trainees, so I want to keep being able to fund them to stay in my lab, or to be able to send them to another lab within the field to continue to gain experience. So during my time as chair, we introduced several short-stay scholarship awards, which I’m pleased to say are still being awarded today.
One of the other things I’m proud of is the introduction of the Trainees Excellence Tournament at the IHS International Headache Congress, which has since been adopted at other international congresses. It’s a competitive process where trainees submit their abstract, and a selection of applicants get to present to the whole congress audience, who vote on the best presentation. It’s not just about focusing on the science they’re presenting, but it also helps trainees develop their presentation and communication skills, which are very important in being able to disseminate our data and outcomes in a way people can understand.
But I can’t take all the credit for these initiatives – I must praise the fantastic team I had on the committee and the IHS board for their support. I’m very thankful for everyone that I worked with. I’ve gained some very good friends along the way, and I’m very grateful for that.
What are some challenges of working in your field?
One thing that comes to mind happened a few years ago, when a journalist interviewed me about the first CGRP monoclonal antibodies that had been released. One of the last questions I was asked was, “What will you research now that we have a cure for migraine?” It’s amazing that we have these new CGRP treatments when we didn’t have any new migraine treatments for such a long time. But it’s challenging to have to continue to emphasize that we don’t know how migraine attacks are triggered, and that these new treatments aren’t a cure. There are still some patients who don’t respond to the CGRP treatments, and there are others who may stop responding after initially showing some improvement.
There’s still a lot of research to be done in the field, and that’s not always understood. We often get comments from reviewers on grant applications along the lines of, “Oh, this project is no longer of interest because there are treatments for migraine out there.” But we still don’t have good enough treatments for all of our patients, and there are many, many questions we still have to answer.
A fun one to finish off with: If there was a movie made about your life, who would you want to play you and why?
God, I’ve never thought of that. It’s a hard one. I don’t think my life is interesting enough for anyone to make a movie about it – I don’t want to waste an actor’s career [laughs].
Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on Twitter @lincolntracy.
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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