Kathryn Mitchell Inaugural Lecture video transcript

Tonight is just my journey. It's going to be a personal journey and an academic journey. But I have been very privileged on this journey because I had funding. I had support. And actually I had great colleagues. So the journey isn't just mine, it epitomizes the people I worked with. So what I want to say to you is, I'm not some sort of genius or I was born with some great academic capability. But what I did realize that was important, and I still believe is important, is endeavour and perseverance.

I want to go to this quote, which is great works for not by strength, but by perseverance. And actually, the whole of research for me is about perseverance because many people give up I want to say that for me the gift of being able to research and the opportunity to research, something that we should never ever lose as academics. But my journey started in my first year at the University of York. And I was a bog-standard graduate who really enjoyed much of university life, which was socializing, and turning up to lectures when I could manage it.

But I applied, I wasn't a well-travelled student, and I applied for a travel grant from the University of York and they said well, you can't just apply for the grant, you have to actually do something. So I said, Okay, I will go and do some work in a hospital called Tumu Tumu in North Kenya in a place called Karatina. And I met somebody that changed my view of what I should be doing. And I met somebody called Ingrid Halfyard. And she was the anaesthetist at the hospital. And she came from Taunton. And she decided that she also wanted to change her life. She was very, very bright. And what she taught me was, it's really important to think about the care of patients, and not just actually, let's just do something today to really consider how we can impact lives for the future.

Now, it was also very interesting that she never mentioned until we decided to climb Mount Kenya, that she said, my husband's going to come over with a couple of friends. So I thought that's nice. So Ingrid Halfyard who's Dutch and very interesting, and her husband arrived and she introduced him and he said, Nigel Popplewell, well, I wasn't a great cricketer at the time. So I didn't know that Nigel Popplewell was a cricketer at Somerset, but I did half recognize Viv Richards and Ian Botham and so it was a very interesting experience, it probably gave me different outlooks on life, I climbed Mount Kenya, I wasn't a great climber but actually, I managed to get up and down because I was inspired by other people that were interesting on that journey. But what I did go back to is to do my degree. And actually, the one thing that I then became very interested in was the neuron. And that is the simple, the most functional unit of the brain.

What I was really interested in is how does it work? How does that connect? How important is that in our behaviours? How does it function? How does it make things good? How does it make things worse? And I really became quite involved in what would one cell and those connections of cells do. So I did well, in the end in my degree, and in my last term, my tutor came and said, Welcome Trust has announced that they're going give 10 scholarships, and we would like to put you forward for one of these 10 scholarships. And I'm going to say I didn't quite know what that meant.

I sort of said, Oh, that's very nice. And so it was a PhD funded. And if I look at the struggles of today, I was awarded a £10,000 tax-free stipend for three years. But I totally had to go and find what I wanted to do. I thought, oh, people introduced me and said, you're going to get this with the Iverson's at Oxford. And then there was Jeffrey Gray in London. And this is sort of the components that, you know, it wasn't all very focused.

I wasn't knowing exactly what I wanted to do. So, many of you in the room because I think there are many of us are of a certain age but there might be a few that don't remember this. You know, we had payphones. So I had ten pence, I don't know what I thought I was going to do with ten pence but I was quite nervous. And I rang Jeffrey Gray at the Institute of psychiatry. And I said, Hello, I've been asked to talk to you, I want to go for one of these Wellcome Trust scholarships, and I said I've got 10p, I'm really sorry, if you could ring me back that would be helpful. And he rang me back and he asked what I was interested in.

I became very nervous at this point, and I said alcohol. And I don't know why I said alcohol, but probably, you know, I did like alcohol at the time. But strangely, he did have quite a few projects. So he's going to come down and we'll have this meeting. So we went down, and clearly enough, I wasn't particularly interested in alcohol. But I ended up at the end of about a 5-hour meeting, and that's probably when I first met Steve Mitchell here at the front, who didn't think I looked like a Scientist because I didn't. But actually, what I ended up with is a project that was about neurons.

I ended up working on a project that was, in a way world-leading because what we were trying to do was to look at chronic disorders and the one I was working on was Alzheimer's. And it was why do those brain cells die? And can we replace them? And how do we replace them? So the main project that I worked for Jeffrey, who I think probably shaped me to who I am, you have to deliver, you couldn't not deliver. And in fact, but he was a genius. And you would walk in his office and think I'll just try and talk about something and you'd come out thinking, really I need to go and learn quite a lot more.

I did have to go learn a lot more because I had done a psychology degree and I ended up having to do neurobiology. And it's also interesting if we look at the times again now, I went to Queens square, which is the neurology centre for the country, world-famous. And I sat in on the master's programs every Tuesday and Thursday evening so that I could learn to what I was doing in the daytime on my PhD. I never sat an exam, I never paid anything. I just sat and learned all the stuff. I'm not sure we let people into universities, but it's interesting how it transformed who I was. But this slide might look quite boring. But actually, for me, this is probably one of the most important things I ever did.

So we took cancer cells, human cancer cells, and we had to differentiate them, we had to make them so that they wouldn't keep proliferating. And nobody at that time and we look at everything that's out there had actually injected so we had fluorescent cells. We were the first group that have hooked this fluorescent dye in human cells. And we worked on lesion models with animals. And so we had the hippocampus that was the area that is part of the memory process. So we actually transplanted the cells into
these mammals to see what was happening. And the two things that happened. One they survived, which we weren't sure would they be rejected, because actually, we were putting human cells into animals.

So we wanted to know would they survive? Would that be a model that we could look for to see what happened? But the second thing was, we wanted to know would they express anything like a neurotransmitter so, in a neuron, the three constituent parts are it has pathways coming in called dendrites, it is has a cell body in the middle and they have an axon. And at the end of that axon is a synapse where the neurotransmitters release. We needed to know could these cells in vivo in the animal release any transmissions. And they did. They did. And what we can see is that we could get behavioural changes, positive memory changes by actually testing in animal models and animal models were probably the most important thing at a time, probably not at all now, because actually we've moved way forward.

That really took three years of my life to get that right, getting the cells differentiated, getting them stopping from being cancerous in any way. But at the end of that, we were really in competition with three of the larger organizations Cambridge, Professor, Steve Dudek who ran all of the big centres in Cambridge was examined me for my PhD, a big group in Sweden and our group with Jeffrey Gray. My only regret is at the same time there was another group at the Institute of psychiatry working on mental health disorders, and they got a Nature paper. So that was irritating and I didn't publish to get a Nature paper at the time.

But that was really quite mind-blowing. I then finished my PhD. And I was very fortunate that I was funded by the Wellcome Trust again, to be a research fellow for them in this area. So that was fantastic. But I didn't read the letter very carefully, because the letter actually said you can't do it in the UK. They said that the best place for you to go to is America. Bit of a hiccup I literally had submitted my thesis the week before I was getting married, I was a very calm bride. And then I did actually ask them to defer my movement to America for two months. So I got married in October and I went in January.

And I went to work for an amazingly bright man. He worked at UCL for quite a long time. And I went to Bruce Wainer. Bruce Wainer was reasonably bright. But what I did learn at Bruce Wainer is that the genius was somebody called Eva Eves and Eva Eves was world-famous for looking at these cells and actually making them totally immortalized so you didn't have to keep differentiating cells. What she created was a cell line so that every time you just wanted to be working with it, they immortalize those cells, and you did it by actually transfusing or with a, what was called a heat-sensitive oncogene.

I won't go into details if there are any molecular biologists I'm doing it in a very simple term, but it was another gene that actually made those cells not proliferate, but actually they keep repeating themselves. So that was pretty impressive. We had a whole supply all of the time to look at, can we manipulate those cells even more? Can we get more different types of transmitter releasing from those cells? The most important one was the cholinergic cells, and we use the cholinergic cells in this group called NS20Y that cell line then was manipulated and put into an animal model again, what we could see was that we actually got even better results.

At that time worldwide was probably five groups by now all looking at what was going on in Alzheimer's. The bit that we got wrong, and we still got wrong was the cholinergic, the neurotransmitter did die. Wasn't released and didn't allow people to have their memory. But it wasn't the trigger. It wasn't the trigger why people were getting Alzheimer's. We knew if we gave some more cholinergic drugs or whatever, we probably can improve memory. But it is not the cause of Alzheimer's. It was a bit of a blow. But anyway, we still went on, and I then went to work with probably the scariest man in the world. And It was quite amazing.

I arrived at Rockefeller and Paul Greengard said, Hello, very glad to have come from England. And then he said, What shift do you want to work? I've no idea which shift I want to work. So, and I sort of laughed, actually. And he said, No, I'm serious. What shift do you want to work? We have three shifts a day. And then on Friday, we all see each of the results and then we'll see who's done best. And then after that, if you've not done very well, you're on the worst shift. So he gave me the nicest shift, but I will say, I did have the most beautiful flat in Manhattan. I could never afford that again when I got a free phone.

But Paul Greengard is a Nobel Prize winner He died last year, and probably made the biggest, the most significant impact on understanding how the cell works through different proteins. But at the time, what we were working on was okay, we've got immortalized cells that we've been able to differentiate. And I might use those words, it might sound a bit complex, but my god, it was really hard to do. It was really hard to do, and we had to do a lot of work on it. But what Paul Greengard was interested in is how do we get the connections, right? And he believed that actually, the lack of connectivity, particularly in these neurodegenerative diseases, was quite problematic. And if we could make the connections better, by better release, by the better connectivity, then we'd be able to better understand these degenerative diseases way better.

So we went with my NS20Y cells to Paul Greengard's lab and we manipulated them with this substance, protein called Synapsin 2. We put Synapsin 2 into the cells. And it's really interesting these pictures probably would look so much better in 2019 than they did in 1996. But actually what we can see here is that is the Synapsin and that is showing that by enhancing Synapsin, what we did see was better release of the neurotransmitters.

So we put these products in and we got more release with the neurotransmitter. So it wasn't again going to cure it but what we could do is get more of that neurotransmitter released through the synapses so that actually in the pathways or in the brain, you will be able to actually get better behaviour outcomes. And that was really hard work. I don't think I went to bed much of the time. What you realized is that actually, everybody was on the same shift because no one wanted to go home at all.

And so we were all fighting around the lab but probably, again, working with somebody that challenged you, that asked you questions every minute of every day that stood over your shoulder when you were doing some of your work. It made you become two things. You had to believe in what you did. But you had to be resilient and had to really, really understand that someone like Paul Greengard his whole life was just in his lab, his whole life is just about making a difference through research.

So then we took a sojourn to Switzerland, probably not of my choice, but my husband got a job over there. And this is when I decided I knew I no longer liked molecular biology. So I went to Switzerland, and again, very well funded, Wellcome Trust funded me and I went to work at the Friedrich Miescher Institute. And I sort of had to, I still love my neurons. And I was still very passionate about the way forward with cell transplantation models, but there were none of those in Switzerland. So I went to work for a guy called Andrew Matus who believed he did have the cure for Alzheimer's, and he believed that it was in a protein called microtubule-associated protein 2. And he believed that if we could get understand that that would be a massive cure for Alzheimer's.

But actually, as most of you have never heard of MAP2 we didn't have a cure. I came back from Switzerland and I went back to the Institute of Psychiatry. And the whole landscape had changed in three years. It'd changed because actually, we'd moved from just total foetal transplantations and into stem cell transplantation. And that is now mind-blowing. The opportunity for me with stem cell transplantation is really, really exciting. We've seen it in how people may be able to move their arms better through stem cell transplantation. What it hasn't really worked effectively yet on is in neural transplantation. We've not seen as great outcomes.

They did think there was a model for Huntington's disease, but it hasn't quite worked. But actually the concept, which I sort of feel quite part of that understanding of how we got to stem cell transplantation. But my other belief was, and I did find it really hard was when I came back before we moved straight into stem cell, as I was the person that had to go to the abortion clinic to pick up the foetal material. And I had just had two children. And so not only did I feel I was no longer wanting to be a molecular biologist, I didn't feel well, I don't know... if that's me anymore. So I didn't continue. I sometimes regret that because I look at the advances in stem cell now I look at some of our friends running companies with multi-million pounds that we were working with.

But it was probably a decision that actually took me some way back into what am I really about. And what I did feel was that I had moved too far away from the clinic and moved too far away from the people I was impacting. So this is mind-blowingly fantastic for me, it has had a huge impact on the science that happens today. Probably if I'd been in a different place at a different time, I might have moved in different ways with my research. But I probably now say that the last part of the story changed the impact dramatically in that this was always very viable when you're in a world-class leading lab with the Nobel Prize winners because you could see the clinic every day. But when you were just in a little lab, I didn't find it as close to that clinic.

So I did then have a little break from work. I had my lovely children. And then I decided that I would probably want to go back and do a little bit of teaching. And you'll see on the slide, you know I did go to one of the most barking institutions in the country called TVU and actually was renowned for being quite a hopeless place. Probably one of the most loved places of my life, because it did allow me to do several things. But I was allowed By TVU to continue my research and I was really privileged that Stan Newman said that he'd give me an honorary fellowship. So as is the way with academics, I did all my workload planning, it looked like I could have these two days, to do my research. It was absolutely fantastic. But then I was the programme leader and realized I didn't have anyone teaching on Tuesdays and Thursday afternoons.

So and this is where I am totally indebted to the lifestyle that we led because I had to then get the train from Slough at 5.30 in the morning, had to start work at seven o'clock at UCL, I met the Prof at eight o'clock, and then I had to leave at one o'clock get on the train to Ealing run through the streets of Ealing which I was probably getting known for. Almost like, open the way She's the madwoman running through the streets and then give my lectures. But what I do believe is being at a university is about creating new knowledge and I couldn't teach without creating that new knowledge. New knowledge is so important because we can't be regurgitating what we already know, to have that new knowledge is the power of our new curriculums of what we're delivering. So I did go and work for Stan Newman.

Again, it's just depressing that apart from Ingrid, I've only got men that were actually leading, but they were all very impressive. Stan was probably the most difficult. And if he was here, I would still say it, okay? Because he would never ever, ever finish a piece of research. He'd always say, let's just go back and find something. Let's go back and find what that means. But he did give me a huge opportunity because I wanted to do clinical, I wanted to go into the clinical environment. I've never been in that space. So he gave me a really, really interesting project. It's a self-monitoring project with patients with rheumatoid arthritis. And it was a really interesting project.

Patients on a drug called Methotrexate, which is actually quite a strong drug have to have their bloods taken very regularly. And what we'd found in the UCL clinic was that people missed their appointments. People were not always getting their bloods right. People were getting ill because basically, they just weren't monitoring bloods well. So what we decided was we'd set up a pilot to see if we could trust people to monitor their own bloods. They could just go locally to their local GP, or wherever or their nurse or wherever that was to have their bloods taken. But we would just send them the results and they make a decision did they need an appointment or not with the consultant And that would reduce consultants time, but it was also about patient safety.

However we invited everybody in, there were about 40 people in this project, about 40 people kept on the project. And the first thing they said is we've all paid our national insurance love. And actually I want to see the consultant. And so it was a really interesting project as I was thinking how exciting everybody wants to do their own thing. And there was another side to it. That quite a large portion of this population were probably over 60. And what I realized was it was actually their community. Coming to the clinic, the consultant, you know, we had one lady that she literally every month, booked her taxi, went to John Lewis had pancakes, met the consultant, and that was her absolute lifeline.

So it's really difficult when you're running these projects and you can't sort of see it always from that side of the monitoring because we needed to look at what was patient safety. So we did this blood monitoring with patients on all Methotrexate. And we clearly wanted to look at whether individual differences about how people also engage with the program. So we had all of these very high professionals that were always saying it was a nightmare I can't come and see a consultant, of course, I'll monitor my bloods well, everybody over 70 they really wanted to come in and trial it because and it was really interesting. They trialled it because they liked the consultant and didn't want to let him down. They didn't do it for themselves. They did it because they wanted to be supportive of their consultant.

So it was a two-hour training program. Everyone was trained really well and I did it with a really fun person who was a clinical psychologist. Often didn't turn up on time, but very reliable. And so we did a great project. What happened, and we did psychological measures, we wanted to know, in a way, how did people's belief about their medications, inform how they performed on the task. And also we wanted to assess whether any of the psychological measures such as their own timeline, their own belief, their own concept, their own concepts of the disease would influence how well they performed during this task.

And lo and behold, all my 70-year-olds were the best performers. They got all their bloods right all the time. And all of my fantastic, high powered, forgot to do their bloods were all out of control and it was a bit of a disaster in the first component. However, we did work with them and we did a reference period. The accuracy overall was at 85 per cent. But what you can see is that most errors were in the first two months. The third and fourth month was 100% accuracy on people judging their bloods assessment. And then judgment of needing and outpatient performance was only at 80% accuracy. And that 80% accuracy was actually most of them would ring you up later on, they would ring you at all hours of the day, they'd ring you at one o'clock in the morning whenever it was, but what we found was that wasn't that they didn't know if they needed an outpatient appointment or not, it was they wanted one.

So it wasn't an error of judgment, but it was an error that actually, they didn't want to just not have their appointment. The other bit that this taught me was that actually, there were lots of stats on this project. And we proved it was significant at 54% that this project worked overall. But it also led me to think, Okay, what happens to the 40 odd per cent? Because if it doesn't go well, that 40% really, we're leaving them at risk in our community because they're not going to monitor themselves well. So it was a good outcome. Actually, this goes on now at UCL all the time. They only run clinics every six months when people on Methotrexate and it's had a great outcome.

What we did show was the people's belief in the importance of that medication to them then to how accurate they were in the study. But does it mean in the clinical environment, that 54% of satisfaction or acceptance in terms of the statistical model leads to the best clinical outcomes? I think that for me was quite a strong learning lesson. So I did that for quite some time. And after that, I had lots of different projects. I had amazing PhD students. I had somebody called Caroline Larfrage that worked on a huge project around acceptance of people that have actually had to have abortions with foetal abnormalities and what did that look like, really quite a scary project because there's not enough work done in the NHS for that.

I had...One of the biggest projects I've worked on is with one of my close friends now, who was probably quite a demanding PhD student, somebody called Maddie Ohl, and we ran a project which looked at students, young pupils that did not have opportunities at school. They're in the middle of the school band, they got missed they got forgotten. And we did a big project, which is now on the government listing for big projects called the pyramid project.

But the biggest opportunity for me to talk about is I came to Derby and I was a bit nervous as the vice-chancellor, was I ever going to be able to research again. And research for me is sort of in my blood. Research for me makes me who I am. Research for me is I would wake up every morning and listen to whatever is going on. And I'd want to know, particularly the areas that I'm most passionate about, such as stem cells, such as behaviours such as chronic disorders, and I was really fortunate that there was a project ongoing in the university and project was funded by a local philanthropist, Mel Morris looking at Acceptance. Well, they were looking at personalized models of dialysis and dialysis to these people that have kidney disease and it's not going well. Okay. And so they need to go regularly for their treatment.

The component in that project is we do very, very systematic approaches to how we deliver dialysis. It's all very regulated, so kept into metrics that are if the blood goes at this level, you wouldn't switch, you'd have to maintain everybody well. The personalized approach is everybody is different. And therefore in that personalized approach, what we want is that that actually, we might be out of the norms, we might be looking at people that actually their blood doesn't need to be within a normal range. So what that showed us was that's actually a bit scary. Nurses found that quite scary to go outside of the range. But actually what we wanted to look at was how to patients accept that. And we didn't just do it in that patient group. And I have the PhD student Carol Stalker here tonight who's just submitted dead-on three years.

It's brilliant. James Elander, who we've got loads of projects now working together and a team and Paul Stewart he's a professor here, but also Maarten Taal and Nick Selby from University Derby Hospitals. And this has been actually using Carol's work. But as the, one of the key supervisors, this is what we're doing, and this is what we're publishing on. And what we have really shown in this data is that we've done a longitudinal survey, it is with end-stage renal disease people because we really couldn't be manipulating bloods on people not at the end-stage, but actually what we're looking at is what factors lead to an acceptance both of the illness and therefore probably of their treatment.

So what we can see in this study, and you don't need to really look at all of the elements, but if you look at the first graph, what we can see here is the acceptance of illness was the measure that gave the biggest significant proportion in the physical quality of life. So if you've accepted your illness, you're more likely to do better, which is sort of common sense. But we have no idea why people were accepting their illness. We don't really know what acceptance quite means there yet. We don't fully understand what that might say.

In mental quality, the mental quality of life. What you can see in purple is depression plays a very key role in that as it does in kidney disease burden which again would expect as to be the norm. But what we need to really understand in this population is particularly the ones we've got a sub-group now that we're analysing that we haven't done a PhD, but we are analysing that we're in the personalized group here, not got probably enough data to give significance. But what we want to know is in that grouping, that having a very different style of treatment, do we see significant differences?

Because what we would like to be doing is understand what intervention would actually work with those people so they have a better quality of life just by the style of which they deliver dialysis. But there's no point in just saying that you might feel a bit better in terms of what your bloods tell you if you personally don't feel that treatment. So the components of the relationship between the medical model and putting it with our psychological approaches means that we do believe we'll be able to work on much more personalized approaches to medicine, which is probably what we will all be working on in the future. Each and every one of us probably in this room will expect a personalized model of medicine. As we grow older, I don't think we'll be expecting that if it works with the person next door, I think will be wanting to know, what does it mean for me?

So the model that we've been using, really shows that there are lots of factors that influence maybe particularly the mental quality of life, which is clearly how anxious you are when you go and have your treatment, how confident you are actually, self-efficacy plays a really significant role in actually how well you accept this treatment. And that also goes for the clinical environment, the support of the consultant, actually how you're supported. So this is the success really of James and Carol and the team at the hospital and Paul Stewart at the University. This to me is where I feel more at home. Now, I understand all of my medical approaches. I understand the medical models, I understand how chronic disorders all work. But none of the treatments are successful unless the patient or the person feels better.

And so, I don't think we can continue working on models that are just actually an answer that that that might work on you because data doesn't show us that just by giving you a medical approach leads to successful outcomes for all patients. What it does tell you is that there is a real necessity to understand how a person will react to that treatment, and how actually through looking at that personalized approach. We can get change and better outcomes. Although it might originally seem and sound an expensive approach, I don't believe it is because we have so many people returning into clinical environments.

We have so many people, actually in and out, we have so many people not feeling better after their treatment. And so for me, it's actually we do clearly and I'm not in any way deriding - without medicine we wouldn't be having this conversation. But what we do need to understand is, with with the collaborative approaches, between a very very world-leading clinical group at the University of Derby hospitals, and they are world-leading, Maarten Taal is world-leading, that working with him, we should be able to see how we can improve dialysis patients outcomes. And so, the team have won a grant.

It's not huge amounts of money. But actually, we've only been in this area in Derby for three years. And so we've got a 40k grant. There's a whole team of us working on it. But this is to look at a model around acceptance and commitment. And so what we're looking at is how do we tailor people's approaches to how an intervention model would enable people to, in a sense, accept and therefore for us to be able to understand and get them to feel better through their treatment?

It's a well-known model. James has worked on it before, but the component for me is, it's actually patient-centred. It's about how does the patient react and respond to how they're delivering their treatment. So I'm totally indebted to the team at Derby. I am totally indebted to lots of other people on this. I'm going to call out a few. You have got significantly other numbers of PhD students, and there are two people in the audience that probably don't even want eye contact with them, who are Dawn Forman and Chris Brannigan, both professors who every day come to my office and go we found two more people who are geniuses in the university would you like to supervise them.

What we do have at this university though, are lots and lots of people that are now working on chronic disorders. We've got an outstanding member of staff who works in hepatology and actually has just written NICE guidelines which have been accepted by the Royal College of Nursing for that treatment. I hadn't met her and actually, she's just stunning and is now going to do a PhD. Lots of publications. But we didn't know they were in Derby. And I've got David Robert Shaw, who's looking, which is a really interesting project, which was about Alzheimerís and dementia, but it was actually about how can we get information to people effectively through an online model.

Again, the collaboration between something that's been very innovative at Derby through UDOL. And actually using that platform to influence chronic disorders and engagement. So my journey is a little bit erratic at times. My passion and the importance for me of knowledge-creation is still the role of a Vice-Chancellor. But I think every day the important bit is, how do we make a difference through the way that we as academics deliver and engage is probably one of the most powerful things that universities deliver.

So I have lots of thank yous, thank you supporters influences academics, collaborators, students, but particularly the governing council here today. Thank you to them for allowing me still to be that person who wants to create new knowledge. Students and beyond: there are all my students, most of them, I'm really proud of our Professors or beyond, and we've got people that hopefully will be professors of the future, and other people, I've stayed in touch with. And they're all people that have influenced the journey that I went on tonight. Thank you very much.

Kathryn Mitchell Inaugural Lecture video

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