Spotlight On: Tara Spires-Jones

We are back with our 'Spotlight On' interview series, shedding light on inspiring women working in the field of neuroscience and reflecting on their distinct backgrounds and career journeys. The questions posed to these individuals explore the themes of job perks and challenges, developing new skills, their inspirations in the neuroscience field, and goals for the future. Stay tuned to see new interviews every few weeks from women in a range of neuroscience-related professions!

Professor Tara Spires-Jones, President of the BNA, Professor of Neurodegeneration at the University of Edinburgh, Editor-in-Chief of Brain Communications and winner of the WiNUK 2024 Leading Researcher of the Year: Neuropathology & Ageing.

We interviewed Professor Tara Spires-Jones, President of the British Neuroscience Association (BNA), Professor of Neurodegeneration at the University of Edinburgh, Editor-in-Chief of Brain Communications and winner of the WiNUK 2024 Leading Researcher of the Year: Neuropathology & Ageing. Tara discussed her academic experience in the US and the UK, the use of birth cohorts in advancing research and how to put a positive spin on projects falling apart! 

Can you tell us a bit about your background in science, your current area of study and what interested you about neuroscience initially?

As an undergraduate, I went to the University of Texas and Austin, and I studied Biochemistry and French. My scholarship was in Chemistry, but I realised that I was more interested in the biological aspects of chemistry. Towards the end of my undergraduate degree I decided that, although I loved studying Chemistry and Biochemistry, it wasn’t that exciting on the research front, so I started thinking about research topics with a more emerging field and lots of open questions. I decided I wanted to pursue Neuroscience but didn’t have any formal training in it. I wanted to come to Oxford, firstly because it’s Oxford, but also because my fiancé was living there. I talked to Colin Blakemore for advice, who I had heard of because he was a famous neuroscientist, and asked if I could study with him as a graduate student. I wanted to do a Master’s because I didn’t know anything about neuroscience. He taught me one of my first scientific lessons, “of course, if you can find funding, I would love to have you as a grad student”, so I went back to the States and applied for funding and ended up getting funding through the Marshall Scholarship and the National Science Foundation to do my PhD (DPhil) and Master’s (MSc). One of my MSc rotations was in Colin’s lab and the other was in Paul Matthew’s lab, working on human fMRI and thinking about language.

I began my DPhil work studying postnatal synaptic plasticity - how synapses change in the barrel cortex (a region in the somatosensory cortex) in mice in response to activity - but that project fell apart, and my supervisor went to be the Head of the MRC at the same time. We decided that I would pivot and so I worked with a senior postdoc in the lab on Huntington’s disease (HD) mice, again looking at synaptic plasticity, but instead of during neurodevelopment, in a neurodegenerative disease model – the R6/1 model that Gill Bates made for HD.

And then I went to Boston for a postdoc, because I met a fantastic scientist called Brad Hyman who had an amazing microscope for studying synapses in Alzheimer’s disease mouse models. I thought I would be there for two years, and I ended up staying there for nine years – the first two years as a postdoc and then as a junior faculty member for seven more years. Then I moved back to Edinburgh. 

How did you deal with your project falling apart, and other challenges? It must have been difficult not knowing what direction your work was moving in, especially early on in your scientific career.

Yeah, and I had been really excited about that project. I was using electron microscopy (EM), which is still one of my favourite techniques – I was actually on an EM this morning. Within that project, we were looking for an organelle that had been discovered in these mice that had a knockout, but I only saw one in the couple of years I was looking. It's just so rare that it wasn't a phenomenon that was worth studying. It was challenging to have to drop that project because it's what I had been reading about, thinking about and preparing for. But at the same time, I had also been becoming more interested in translational work, and I thought, “oh, it'd be kind of fun to be in the Huntington's mice field” because that's a little bit more translational, a little more disease-oriented. So, it was fun to reorient - I just looked at the bright side. 

The biggest challenge I found was during my postdoc, when I got pregnant with my first kid. The difficulty in the US, especially, is that you only get 8 to 12 weeks of maternity leave. I found that a huge challenge to try to come back to work after that. But my mentor was amazing because I said to him, “I'll go and be an electron microscopy technician because the work hours are better, and I can balance that better with family”. And he said, “You’re brilliant, why don't you just come back part time and see how it goes?”

Oh, that's great – very supportive! 

You've spent time in academia in the US and the UK. Other than the issues with maternity leave in the US, how did you find academia compared? 

There are differences, but it depends a lot on the institution. The only broad generalisations would be that there was, generally, more funding in the US, so you had access to equipment more often and that made things a little bit easier. But there was also an expectation of long hours, so there was very little annual leave. I was working at a hospital, but maybe universities have more leave than hospitals. 

 In the UK, I would say it depends on the field, but there's a little bit less funding. If you look at the numbers nationally, I think we fund a smaller percentage of our GDP to research, than the US. But also, it’s much more relaxed in terms of there being more leave and more of a focus on work-life balance. I would say there is something special about the two institutions that I spent a long time at in the UK. There's something nicely academic about them and nicely thoughtful about the way that neuroscientists, and scientists in general here, strip things back to key questions and really pursue those - partly because of there being less funding. So, it's just a bit of a different approach and there were very different approaches to grant writing for the national system, so I had to relearn to write grants. It is a big adjustment, but it's not as big as if you went to a country that doesn't speak English.

Of course! I’m sure that will be useful to people considering a postdoc in the US. 

You've worked with post-mortem human tissue, animal models and cell models. Can you tell us about how you found working with each - the advantages and disadvantages - and whether they work very well, hand in hand? 

We have a balanced portfolio of human post-mortem tissue, mouse models and cell models in my lab. I think it's really important to get the right model system to answer the right question. I work mainly in Alzheimer's disease and other neurodegenerative diseases now. Our animal models are far from perfect. They don't recapitulate all the disease phenotypes, but post-mortem tissue is only a snapshot at the end of the disease and the living model systems that we've tried to use, like iPSC (induced pluripotent stem cell) neurons, also have their limitations. There's a colleague in the department, Claire Durrant, who collaborates and has living human tissue that we can challenge with dementia-relevant stimuli. I think it's important to come at questions from multiple angles to be sure that what you find is more likely to be right. I think they complement each other nicely and, depending on the question, you need a different tool.

I've read about your discovery of tau and amyloid beta accumulation at the synapses. Could you tell us a little bit more about that?

When I joined the Alzheimer's field, which was 21 years ago now, there was a bit of a debate still going on about the pathologies that have been known about in the brain for well over 100 years: how they damage the brain and how they actually cause neurodegeneration. The two pathologies are plaques and tangles. The plaques are made of amyloid, the tangles are made of tau protein, and they make these big clumps in the brain. We all thought that those big clumps in the brain were toxic to cells, that they were killing neurons. 

The other thing that was known when I joined the field was that the loss of synapses correlates closely with the cognitive symptoms of Alzheimer's disease. I joined the field to try and bridge that gap, to ask how synapses are dying. I thought that the big clumps were probably toxic. We did a lot of work in mouse models and now in human post-mortem tissue - it turns out that the actual big clumps themselves aren't really toxic. They're inert because they're so big, but the soluble forms of  amyloid and tau, the oligomeric forms, are very toxic to synapses, in particular. So, we started studying that and it was a real challenge at first. We started in mouse models, where we have mice that have amyloid plaques, and we have mice that have tau tangles. They don’t get every facet of the disease. But we looked at both of those and in the mice with plaques, we could see synapses were lost in vivo; by looking through a window in the skull, we could watch dendritic spines die over time. And that happened around plaques, but we couldn't visualise the oligomers themselves. We just knew that it was near plaques that it was happening. The same in mice that had the tangle formation - we could see that tangles would form, and actually the cells didn't die. They lived, but there was some synapse loss. I started thinking about how we could look inside individual synapses, and that's a challenge because synapses are smaller than the resolution of the microscope, so even with our fancy two photons, you can't really look inside very accurately. 

I talked to Kristina Micheva and Stephen Smith from Stanford who had developed a technique called array tomography, where you take little tiny bits of tissue, post-mortem, and fix them and put them in a hard resin, and then you section them like for electron microscopy (again, my favourite technique!). But then you can use those ultra-thin sections with immunofluorescence and so we took advantage of that, first in mice, then in people post-mortem. We can't put windows on people's brains, but we can take tissue if people donate it. In both mice and humans we were able to look inside individual synapses and we found both oligomeric amyloid and soluble oligomeric forms of tau accumulating inside synapses and that correlated with the loss of synapses. We've shown that tau seems to be moving through the brain by jumping out of one side of the synapses into the other. And I think that's important for translation because we want to stop that progression of pathology.

That’s so impressive! Thinking about the amyloid beta hypothesis; how much do you feel that scientific dogma has prevented the progress in the field of Alzheimer's disease research? 

I think people who can't change - or scientists who are unwilling to change - their minds are difficult for the field. And if you're sticking too hard to an idea because you believe it strongly and not because that's where the data are going, I think that can be damaging. In my career, I didn't really find that. I've always been agnostic. My mentor Brad always used to say, “data are data”. Some of the most exciting findings I've had were actually things I hadn't predicted, sort of the opposite; we disproved our hypothesis, and that was more informative than if we'd proven ourselves.

I find it exciting when I'm wrong - I like that. Right now we're doing something which I think we might have been dead wrong about. 

There was a time when other scientists in the field spoke openly about how they felt their research was quashed because it wasn't in the amyloid hypothesis field. In the end, most people seem to have come to more of a consensus that the initiating factor of amyloid is essential for familial Alzheimer's disease, but we still think, most of us, that it's very important, even in sporadic forms. But the field has expanded so much from when I joined, like the idea of microglia and astrocytes driving the disease process, not just reacting, was revolutionary, and everybody had to work on microglia for about 10 years. It's fun.

I saw that you'd worked with some data from the Lothian birth cohorts. I wondered if you could summarise your findings and how useful you think long-term cohort studies are?

Yeah, that's such a cool study. We're following up on that now. The Lothian birth cohort is a group of people who were cognitively healthy when they were recruited. The remarkable thing about the cohort is these people all had an intelligence test at age 11 - the Scottish Government tested every single school child who was born in 1921. Then, again, every single school child who was born in 1936, when they were 11 years old, were given an IQ test called The Moray House test. 

Professor Ian Deary, who used to be a cognitive psychologist before he retired, found the records for all these tests in our School of Education at the university. He recruited a couple of thousand people in their 70s, from the cohort, to come back to the university and take cognitive tests. That cohort has been expanded since.

When I joined the university in 2013, I was talking to Colin Smith, the head of the Brain Bank, about how difficult it was in Boston for me to find ‘control’ samples from people who didn't have a neurodegenerative disease, but we also knew their cognitive status. He set me up a meeting with Ian who said, “We have around 175 people who have agreed to donate tissue, but we don't know what to do with it. Why don't you come and use the tissue?”. It's been super fun to be able to look at. 

The hypothesis that we had at the beginning was, in Alzheimer's disease, the more synapses you lose, the worse your cognition - that makes a huge amount of sense as a neuroscientist. We hypothesised that in cognitive ageing, even if it wasn't dementia, that we would see a similar pattern with the loss of synapses. There's been indication in the field that there's changes in synapses in healthy ageing and changes in vasculature - a pretty straightforward hypothesis.

Our first study only had eight people per group; those with cognitive decline and people who were, what we called, cognitive resilient. We compared their cognitive test at age 11 to tests in their 70s. If they stayed similar in IQ level, we called that resilient. If they had declined lower than predicted, we called that cognitive decline. 

We didn't see any change in the synaptic densities, but the numbers were small in the brain regions we looked at. We didn't see any change in the amount of amyloid or tau in the brain. There’s a hint that there is more inflammation, associated with microglia, in one of the brain regions, but you would also predict this with ageing. When we looked molecularly, we ‘squished up’ some frozen brain tissue and enriched the synaptic fraction to look at the molecular changes in synapses. And again, the hypothesis was that synaptic proteins would be highest in the young controls. We had a group of people who died in midlife. We thought synaptic proteins would be a little bit lower in these people, then a little bit lower in the people who were older and had cognitive decline and then the Alzheimer's people would be at the bottom. So we thought of a super straightforward hypothesis. However, this study wasn't the best powered: only eight. But what we saw was the mid-life and the AD did what we thought - they were very different. But when we looked within the ageing group, within that Lothian birth cohort, the people with cognitive decline had more synaptic protein and gene expression changes than the people without. So I was dead wrong about the hypothesis, which was really fascinating. We have 31 donors now, so we're adding to this study to see if it holds up, but at least initially it does. And we published it and were careful about the interpretation. Initially, it seems like maybe efficient synapses are actually better when you age, not synapses that are working really hard. So it might be that those people who had the cognitive decline had hyperactive synapses for some reason, like we see with amyloid deposition. So that's the nutshell for the first study with the Lothian birth cohort, we're using them for a lot more now because they have blood donations and brain scans. And so we're able to correlate a lot of things with their living cognition and blood and things like that. Super fun.

Yeah, that's amazing. I assume that it's quite rare to have access to a study performed over such a long period of time, especially for a progressive disease like Alzheimer’s.

At Women in Neuroscience UK, we've been working with the BNA! As President, what does your role involve and what experience did you have that made you right for it?

The BNA is a fantastic organisation - it's our membership organisation for neuroscientists in the UK. What we try to do is represent the interests of neuroscientists across the field, from fundamental bench scientists to clinicians; the people working in industry and academia etc.

I have been a member of the BNA since I was a PhD student – so, for a very long time, except for the few years I was in the US. When I came back from the US to the UK, I didn't know anyone in the field because I had been working on Huntington's when I left, and I came back to the Alzheimer's field. The BNA was a fantastic way for me to go to their meetings, meet people in the field and really reconnect with the community. So, I'd been a member, and then I was asked if I would consider being president-elect. I didn’t put my name forward. And I was shocked. I thought, “Why would they have asked me? I'm not a super famous neuroscientist”. I was really honoured. I talked to the Chief Executive and decided I would give it a go. The role of the President is a figurehead for the BNA in a way. I chair the Council meeting – the Council are the trustees of the BNA, so we run the charity. We're fiscally responsible for the charity, we ensure that we're in line with the Charity Commission rules and that we're aligning with our charity goals as a society. I had never chaired Council meetings before, or been a trustee of a charity before, so they were new experiences. Now I'm trustee of two charities because I'm also on the Guarantors of Brain and the Brain Comms Editor. So I've gained a lot more experience in the past few years. Helping to support the BNA and think about new directions for the society are some of the more fun aspects. 

When they asked me what my manifesto was, I was terrified. I was thinking, “I just don't want to break the BNA! Can I support what's already going on because there’s already so much good work”. The one thing I was able to bring to the role is that I've thought a lot about training in neuroscience over the years, especially because I've seen it like you say, from two different countries’ perspectives. I think that, in the UK, there are some real gaps in training, for example during PhDs - you're not trained to teach, you're not consistently trained in particular skills that become useful as a postdoc, or in your future career. I think that makes a lot of people who train in the UK less competitive for posts in other countries. So, I had a chat with the whole BNA Executive Team and with the Council and we decided to really ‘beef up’ what we do for training. Now the BNA provides accreditation for neuroscience undergraduate degrees in partnership with the Royal Society of Biology - we came up with a list of things that we thought undergraduates should know once they complete their neuroscience degree.

Now we're moving on to starting our own training programmes for things that we see, or our members see, as gaps in training for UK neuroscientists, and we're running our own training sessions. I did one at last year's BNA members meeting about how you apply for fellowships. We're doing a dementia masterclass this year, so we've got a lot of training going on. Statistics is also a popular one. So, getting to help guide the strategy of a charity that's influential across the country is fun!

The lack of training can trickle up to more senior positions too -  for example, not being given training in how to manage people - and you go from being a postdoc, where you’re only managing yourself, to suddenly being in charge of a lab and you have to learn that on the job. How do you manage to juggle all of your roles? 

Yeah, that's something I struggled with at the beginning of running a lab. It can be overwhelming at times, but I remind myself that I do really love my job. I’ve got much more efficient at work after I had kids, to be honest, when I was constrained to daycare hours, and they were very short, and I had to learn to manage my time properly. So, a lot of it is time management and planning ahead. The hardest thing was learning to reserve time for the important things, not just the urgent things like I really want to work on a paper. So I was on an electron microscope this morning. I try to at least give myself half a day a week. It's usually all I can manage in a lab, either training a student or doing an experiment, or just cutting something or cleaning something just because it helps me remember why I like this job and why I did this in the first place . It was important for me to cope with the workload as I try and compartmentalise all my teaching stuff to one day a week, and I have office hours and if a student wants something they have to come to the office hours because I'm not going to respond to the 5,000 emails, it's just not going to happen. 

It sounds like boundaries are quite important - academics do receive a lot of emails from their students. 

How do you manage your PhD students? Do you tend to have lab meetings where everyone brings their updates and then have individual meetings as well? Regular one-to-one meetings can take up a lot of your working day!

I keep Thursdays and Fridays for lab members, and we have lab meetings every Thursday. Well, every Thursday I'm in town, which is not all Thursdays. And then each person has a weekly half hour slot. And again, I'm gone for a lot of weeks. I used to try and do it every other week, but then if you're gone one week, it becomes a month. I have the slot, but it's for them, so if people are too busy and don't want to come, it's fine. They just let me know or delete it in the shared lab calendar. It's just so that we have that dedicated time to talk one-on-one about data or career progression or whatever, just so we don't lose track of each other. That's the way I've been managing it. I think that works really well for us. 

My grants have been like buses, so I had nothing, nothing, nothing. And then I had three big grants. I had a team of around 20 people, and I couldn't meet everybody every week because that's then 10 hours already. So, I had to do it every other week and then it wasn't as good. If I can, I try to keep my group at about 10, because that's a much more hands-on, manageable size. The project students are supervised by a PhD student or a postdoc, so I don't worry as much about having five project students, as long as somebody has promised to look after them, so I don't meet them individually. Usually, I meet them in groups every week or every other week.

Yeah, and that's good experience for the PhD students to put on their CVs.

You mentioned potential biases in regard to peoples’ names or genders. Do you think that you've experienced any bias, either in the UK or in the US, in academia or publishing, or have you seen it happen to others?

So personally, not many overt issues that I've experienced. There have been smaller instances where I don't think people were trying to be directly mean. For example, I suggested something as the chair of a panel, and it didn't happen. It was just a rearranging of chairs and then the next morning one of my male colleagues walked in and suggested it and everybody picked up a chair and moved it and I was thinking, “well I said that, but fine. Maybe I didn't say it loudly or authoritatively enough” - little things like that, sure.

I don't feel like I've been discriminated against at all. In fact, I have won little fellowships and grants that were to help people coming back from maternity leave. And so, there's been positive action. If anything, I've probably benefited more than I've been directly hurt, but you never know how perceptions and context work in the background. To other people? Sure, I've also seen people who've struggled, probably at least to some extent, because of their gender or because of their background. It's tough to see. There is still a lot of work to be done in making neuroscience an equitable, diverse and inclusive place.

What advice would you give to other women that are at the early stages of their neuroscience careers?

There's not really a one-size-fits-all piece of advice. If you love what you're doing, I think scientific careers are the best because this is not as well paid as other careers maybe, but you get to have this new knowledge to help to generate and understand the world. It's just wonderful. It's worth it for me anyway; it was worth the downsides of the career. When I talk to people, it depends on the career stage. For example, when I talk to people choosing a PhD supervisor, there's very specific advice, and if you want an academic career, there's big advice, but generally it's just “if you love it, it's worth it. And if you don't, probably find something that pays better”.

Have there been any women in your life that inspire you, both in science and beyond? 

My mom is super inspiring. Her family was not well off, growing up in the middle of nowhere, Texas. She became a teacher; she went to university, and she got her PhD just before me because she was going to beat me in education! She always encouraged me to be a good student and study hard and work hard. And that was just transformational.

But in science, Anne Young, who was the head of neurology when I was at MGH in Boston. She was, I believe, the first woman to lead a neurology department. She spent so much time trying to help women in the department - she would come and give a talk and would say, “Look, ladies, every man has been in my office asking for more money and more space. And where are you? You should be in there”. She was upfront about the inequities and, that at times, some of it can be your fault. She was an inspiring woman to model after - very blunt.

And what aspects of the science and academic industry do you think need improving or addressing, particularly in terms of issues that minority groups may face?

It's a huge question. In the dementia fields, we have issues on both sides. We need to look at making sure that the people, the animals and the systems that we study are representative of broad genetic backgrounds and all sorts of diversity. Historically, we have more data on white, middle-class or upper-class men - and this is not just for dementia, it's in a lot of fields. I guess they have the time to participate, or the agency. We need to broaden that, but we also need to broaden the side of the people working in the field because we have these historic inequities, such as very few people of colour in high-level neuroscientist positions. Perspectives of people from different backgrounds is so important to make the field work better. There's a lot of work to be done. That's more than a 5-minute question.

What sort of goals do you have for your career and where do you see yourself in the next few years professionally?

My career goal was met in 2017 when I became a professor! I was like, “Yes, I've done it! I've hit the top”. I just love my job. I love being a Professor of Neuroscience – teaching, research, and then all the activity with the charities. I don't have huge plans to change. 

What I think is beautiful about this career is you can try new things. I'll rotate off the BNA in April and I'll rotate off being Editor in Chief of the Journal in the year after. And then I think I might write a book! You can just try new things. I tried the policy thing, and I found out that being on an Advisory Board for the government wasn't really for me. I think it was important, but I didn't love it. I don't know how impactful it was. You can drop things that aren’t great and try something else. I just look forward to trying new things and still enjoying being a scientist and a teacher.

Congratulations on your WiNUK award win in the Neuropathology & Ageing category. How did you feel to be nominated, and to win it, and how is it going to affect your career moving forward?

It was such an honour to be nominated, it was so kind. It was like when they asked me to be BNA president - I questioned it like, “Really? Do you mean that?”. It helps across the board, not just for me, but for everyone who wins these awards. It does help on your CV to say, “Look, I've been recognised as an expert in the field because I've been given a prize”. That helps build recognition of underrepresented groups. I think it's really important what WiNUK are doing. I think it does a lot for the imposter syndrome to say, “Well, I won an award, so it can't be that bad”.

WiNUK 2024 Leading Researcher of the Year: Neuropathology & Ageing was sponsored by Alzheimer's Research UK.

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This interview was conducted by Rebecca Pope and edited by Rachel Grasmeder Allen, with graphics produced by Lilly Green and Rebecca Pope. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.