In our second interview based in the MRC WIMM’s ‘An evening with’ events, we spoke to Professor Angela Vincent, Emeritus Professor of Neuroimmunology at the Nuffield Department of Clinical Neurosciences. Angela kindly spoke to us about her research on antibodies and their role in neuromuscular diseases, and shared her thoughts with the next generation of scientists.
Over the past 40 years you have had a tremendous impact in the research field of neuroimmunobiology. In your opinion, what are the most important discoveries in your field in recent years?
The discovery of Central Nervous System (CNS) diseases caused by antibodies is of course the most important development over the last 20 years – because they can be treated with immunotherapies with substantial recovery. There are now two main groups of diseases: those with antibodies to membrane proteins on neurons that cause various forms of encephalitis with memory loss, psychiatric disturbance, seizures and sometimes distinctive movement disorders; and those against membrane proteins on glia that cause forms of demyelination (loss of vision, paralysis, pain). Some occur in young children and adults, and others mainly in older people.
The recognition of these conditions, and the antibody tests that are required to diagnose them, has led to an explosion of clinical studies and raised many questions, few of which have been adequately answered! So lots of opportunities for more research. One of the current questions, which is attracting a lot of interest but not yet any compelling answers, is whether there is a role for any of these antibodies in patients with pure epilepsy, psychiatric disorders or dementia.
Back in the 1960s you qualified as a medical doctor. How did you eventually become a researcher in neuroimmunology?
I was interested in medicine, but wanted to know more about the science of disease, and most of my reading was in the growing field of biochemistry. So, after one year as a junior doctor, I decided to do a two-year MSc in Biochemistry at UCL. This was definitely the right thing – and at that time very exciting because of the weekly papers in Nature which described the mechanisms of DNA replication, RNA and mRNA. Having a baby at the end of the first year was a slight interruption and meant I had to take the end of year exams a month later on my kitchen table – probably a good thing as they passed me anyway and let me continue on the course.
Next, at UCL, I worked on a hopeless project trying to separate pre and postsynaptic membranes from rat brain synaptic preparations – the aim was to localise the enzyme responsible for making cyclic AMP. This was before there were any monoclonal antibodies or other markers to explore the structure of brain synapses. On the floor above, a world-renowned scientist, Ricardo Miledi FRS (d 2017), was working on acetylcholine receptors at the neuromuscular junction (synapse), which could be identified by binding of a radioactive snake toxin bungarotoxin. I asked him whether I could try the snake toxin on the brain synaptic preparations. The aim was to identify the postsynaptic membranes and see if I had managed to separate them from the presynaptic membranes. He agreed to take me on as a research assistant and I stayed for five years, during which I never touched a brain but learnt from Ricardo a lot about the neuromuscular junction and research in general and how to do it with humour, tolerance and creative approaches.
Ricardo initiated a collaboration with John Newsom-Davis (d 2008), a neurologist who looked after myasthenia gravis (MG) patients. Myasthenia gravis is a relatively rare chronic autoimmune neuromuscular disease with an incidence of 1-2 in 100,000 people in the UK. When we started working on MG, little was known about the molecular basis of the disease. This new collaboration aimed to measure the acetylcholine receptors at neuromuscular junctions of affected patients. I showed that the number of receptors was markedly reduced in patients, explaining their symptoms of muscle weakness and fatigue. That started my long association with John and myasthenia.
In 1977, I went to the Royal Free Hospital where John and I set up a research group working on myasthenia. We were joined over the next couple of years by Bethan Lang and Nick Willcox and then later by David Beeson. We moved to Oxford in 1988.
Could you give some background about your move to the MRC WIMM here in Oxford in 1988?
After ten years at the Royal Free Hospital, John Newsom-Davis was asked to accept the Action Research Chair of Clinical Neurology in Oxford. He agreed but only on condition that he could bring as many of the research group as wanted to come, and particularly Nick Willcox, myself, Bethan Lang and David Beeson. In fact, 16 of us came from London, so the group was very much established before we arrived – and we were the first, I believe, to hang up our pipettes in the then new ’Institute of Molecular Medicine’ (IMM). We hit the road very well supported by an on-going programme grant from the Medical Research Council (MRC) which continued to fund Nick, Beth and I until 1999. Until John retired in 1998, the enlarged research group was led by a triumvirate of John, Nick and I (PICTURE). It continued to flourish at the MRC WIMM and is now led by Prof David Beeson FMedSci.
You have always been an advocate for the translation of basic science into the clinical setting. Could you give some background on how you set-up the Oxford Neuroimmunology testing service?
We started the service before we came to Oxford, but on a small scale. The first thing I did when we came to Oxford was to set up on my bench a test for myasthenia gravis. This test looked for antibodies against the acetylcholine receptor and was the only test we had initially. Over the next few years we began to develop two more assays for patients with related neuromuscular junction diseases, but it wasn’t until 1992 that I eventually became a University lecturer. Part of my remit was to establish a formal service for detection of autoimmune antibodies causing both peripheral and central neurological diseases using a wider variety of tests – though at first there were not many to establish. It was a gradual and rather slow process at first, but then much faster as the field of neuroimmunology grew. Most brain diseases cannot usually be treated very well, but the patients with these specific antibodies (eg. to the NMDA receptor or AQP4) really get better with immunotherapies. Neurologists are thrilled when they find out that their patient has an antibody that points to successful treatment.
Neurologists are thrilled when they find out that their patient has an antibody that points to successful treatment.
As further neurological diseases caused by antibodies were discovered, by us and others, NHS personnel came to gain experience in our lab and eventually took some of the assays back to the NHS Immunology lab at the Churchill Hospital. Many of the well-established tests are now done there. In 2007 we moved the Neuroimmunology group to the West Wing, closer to the newly-relocated neurology department; some of the most clinically-urgent tests continue to be done in the Autoimmune Neurology group there (led since my retirement by two of my previous team, Drs Irani and Waters).
You can look back at on outstanding career full of scientific achievements, alongside which you had a busy family life and four children to take care of. How did you manage to juggle your personal and work commitments?
I always describe my career while the children were growing up as treading water. It was of course not easy, and the childcare challenges are the only aspect of my life that I would prefer not to have to repeat! There were very few nurseries in those days – unless you were unmarried – and we could not afford to have a good nanny. So, I used child minders for much of the long childcare period – sometimes dropping off four children at different homes and schools in the morning and picking them up from childcare and friends in the evening.
Only once the youngest had become independent, did I feel able to really take off and, with my usual good fortune, this was the time that I eventually obtained an independent position.
Over the past decades, scientific techniques and methodologies have developed at an incredible speed. How has this change of technologies impacted your research over the years?
I am someone who, though marvelling at the amazing technologies that have been developed, only use them if I feel there is a good reason.
Very little, I am glad to say. I am someone who, though marvelling at the amazing technologies that have been developed, only use them if I feel there is a good reason. I despair at the current demands by good journals that mean, for example, being asked to use several knock-out mice and genetic techniques to prove something which is already shown by simple experiments. I do often think of genetic studies that might be interesting and worthwhile, and of course my colleague Prof David Beeson is doing many of these, but I usually have things that are simpler to do.
I suppose I would have to make an exception for the production of specific antibodies for pull-downs and microscopy, which has certainly impacted my work and makes the papers much prettier than they would otherwise have been! But as it happens, many of the commercial antibodies to membrane proteins that one tries are not very useful, probably since most are raised against recombinant peptide sequences rather than the native protein. The best antibodies are, intriguingly, those made by patients to their own proteins! The best monoclonal antibodies that we ever made were induced in mice against tirelessly-purified native human muscle acetylcholine receptors from amputated limbs – my first PhD student at the Royal Free Hospital (now Prof Paul Whiting at UCL) created the monoclonals and they are still used by us and others (available commercially).
What advice would you give early career researchers?
Make sure you work with people you like and get along with! There is something about people who work together well and are not too competitive with each other, which was very important in my career.
I always try to get [students] to appreciate their talents, discover what they are really good at and then find a way of doing it as well as they can.
Another advice is to find a way to make the most of your abilities. I have talked to many early researchers over the years, including those in my own group, and I always try to get them to appreciate their talents, discover what they are really good at and then find a way of doing it as well as they can. It is sad but inevitable that some hopefuls will not make the grade in the long-term, and helping them to appreciate the difficulties and find other ways of using their talents is something I feel is important. This notion of mentorship grew throughout my career and as my children grew up, I have seen what you need to do to try and support them in their choices. It just rubs off on what one does in other respects. For me, being a scientific mentor is a logical extension of motherhood!