Spotlight on ECRs: Dr. Thomas McDonnell

Interview by Dr George Robinson, Inflammation, UCL

Research Questions

1. We will start at the beginning of your research journey. What led you to pursue a research career in immunology?

It’s a 2-step thing, I wanted to do research because when I was about 6, I lost my nan to non-Hodgkins’s lymphoma, and I said to my mum at the time that’s what I wanted to do. So I started trying to speak to people when I was like a teenager about doing research. Immunology itself became more apparent when my mum ended up with antiphospholipid syndrome. I was about 15 and I started doing some genetics research over at Great Ormond Street and the PhD came up for making a new drug for APS and I figured, you know, why not? It’s so relevant but don’t worry, not all my answers will be about various illnesses that my family have had. There is some more depth to it, but it was the case of the opportunity came up and it was something I knew that would motivate me because I know, when you do a PhD, you need to really have motivation and love your project. So I thought I’d do that and I’ve kind of stuck around ever since.

2. You were awarded a Versus Arthritis Senior Fellowship for your innovative investigations into identification of novel autoantigens in Rheumatoid Arthritis between UCL Biochemical Engineering and the UCL Division of Medicine. Can you tell us a more about this award and the project you are working on?

Sure. I think it was the last of the senior fellowships from VA, which has quite a prestigious run of people that have been awarded this fellowship. If you go back through their records, there are plenty of fantastic scientists and they’ve got a really good community of research fellows. We meet up once a year for the Fellows Day and exchange ideas. It’s really nice and I’m glad I got this particular fellowship because everyone really wants to work together in this community, and the project itself is quite interesting. So about 30% of our patients don’t have the classical autoantibodies for diagnosis, and so that means they get delayed diagnosis. Treatment in RA is better in the first 12 months, so they missed that 12-month window, so they’re more likely to fail treatments and miss remission, so they have a generally worse outcome, and it’s a really fixable problem because you just need to pick them up earlier. What my project is doing is taking patients who have lacked these classical antibodies and using a number of cell lines and biophysical techniques that I’ve cobbled together from my experience to identify new diagnostic autoantigens. We are a year in and we’ve got three or four good biological targets that we’ve identified that we’re currently going into validation within January, so we are very hopeful about where it will go forward, but the aim is to identify these patients so that they can respond to the treatment earlier as it’s such a fixable problem.

3. You recently became a Group Leader at UCL through various fellowships and secured funding to work on your ideas for investigating autoantibodies in autoimmunity. Can you tell us more about the process you went through, and what is different now that you are a PI?

Regarding the process it took to get here, UCL has an unwritten law, that if you have two fellowships in the division of medicine, they generally want to keep you around because it’s quite difficult to get to fellowships. I was lucky that mine were consecutive, so when I got the second one, I had a couple of months at the first one left, which is always good. The process itself has been the idea of movement to be honest, but not necessarily geographical, but intellectual. I started out doing drug discovery in my PhD, and then I moved through the immunological phase and biophysics but still studying the protein that was interested in, so that’s an intellectual move. From there I have moved back to do antigen discovery, but in truth, I’ve never been more than about 15 minutes away from any of the labs I’ve worked in. My whole career has been in Zone 2 to zone 1 basically, but there’s a lot of people that put a lot of emphasis on movement.

The other thing is collaboration. There are a whole wide range of people you collaborate with. At UCL I currently have collaborations running with biophysics, with archaeology, and I’ve got a group in Germany that are regularly go and visit and that was very important to getting fellowships. If I was to give people advice early on, it would be a case of, you know, look for opportunities, be open to going to other fields and thinking outside the box, and develop your networks whenever you can. My German collaboration has come from someone emailing us saying ‘are you interested in this protein?’, Yes, and then it’s been four years of the most productive collaboration I’ve ever had.

My journey was quite straightforward at that phase, which was lucky, but to get to that phase from my undergraduate degree, I’ve worked in the NHS industry, government, research, academia, genetics, all over the place. The thing you need to realize when you move through these things is techniques are transferable. You are picking up methods and moving them to fields, and that’s where you get instant wins. For example, one of the things I’m doing now is trying to implement more mass spectrometry in the division of medicine. It’s a technique as old as time, but there are so many opportunities when you take it to a new field that doesn’t really do much of it.

The thing I would say that’s changed most when I’ve become a PI is the lack of time. I’m very much a lab scientist. I like to have my hands on the puppets and do it myself and now I am learning to be more hands off, and to that respect I’m just about to send an offer today for my first official employee. I’m going to have to give a piece of my research to him to do, and that that’s the thing I think I struggle with the most.

4. Do you have any staff/students working with you on this project, and if so, what kind of relationship do you have with them? Do you think you would keep this interaction when you become more senior, or do you think you will follow up with the pass of being less approachable?

That’s something I think about a lot, to be honest. To answer the first part, I’ve got my first PhD student working with me at the moment, student doctor Emily Cornish, who is doing an antigen detection project in a different disease and is having wild success. She’s a very successful person. Jurt today I’m writing the offer for a post doc as I mentioned before, and so we had interviews last week. I’ve taken on two BSc students, and I’ll be taking on 2 Masters students this year as well, so the group will and grow and then shrink as per the teams gone past.

As for interactions, it’s an odd one, because I’m still in the same institute, I don’t feel that senior. I still feel quite like a PhD student that only finished a couple of months ago and I have found that the interactions with people are affected when you go up in academia, not necessarily because you choose to be different, but because your time is less available. You can’t just go and sit and have a good hour chat with a teammate over lunch as you’ve got stuff to do. I think I can come across as more blunt sometimes. That said, I’m still very engaged with a post doc community and trying to mentor people wherever possible to help them get fellowships. I do think it’ll become slightly more formalised, and I think I will greatly miss these informal interactions and the camaraderie you have at that level, as I go up.

5. Can you tell us something amazing about autoantibodies that people may not know?

It’s not necessarily autoantibodies, but it’s the weirdest thing that antibodies do. So IgG4, one of the subclasses, recombines with itself, so you get two different Fab arms, so it basically splits in half in vitro and becomes one antibody that combines two different proteins into two different fab arms, but still has what FC region, so it has one activity. We’ve tried to make drugs that can do that for years, but the body has just been ticking away in the background making it. There is no rhyme or reason that is obvious straightaway as to why that happens, it’s just something we’ve developed.

6. Can you tell us about a setback that you might have encountered as a researcher and how you were able to overcome it?

Rejections are always a good example of this. I had any most brutal rejection of my career by the Wellcome Trust, and that’s not an unusual sentence to hear from researchers as the Wellcome Trust are a private company that do the most investment in the UK, so they don’t have to follow what the government thinks is important. I submitted a fellowship and then they turned around and said we love the idea, we just don’t think you can do it. I went down to have a 45-minute discussion with them about what they think is wrong. It was the most depressing 45 minutes of ‘you need more bigger papers’, and also ‘we don’t think you could do it because of XY and Z’, which is demoralising. One of my mentors when I was writing my first fellowship said to me the week before I submitted it, ‘I don’t think you’re going to get this fellowship, It won’t get funded’, which is demoralising when you’ve spent months on it. The important thing is to ask why. Although the Wellcome did you know effectively do a 45-minute character assassination on me, I knew the metrics they were looking for was papers. OK, I understand you want bigger papers. How can I do that? Then the mentor was saying to me it was because the project was too complicated. OK, how can I fix that? It’s about taking kind of the positive criticism from within. I took an unpleasant scenario and applied it back ruthlessly to pursue this goal. To get fellowships is tough at the best of times, so you need to be able to be positive about the criticism you receive.

7. Can you share some interesting work that you read about recently?

I’ll be very self-promotional and talk about the mammoth tooth project. There was a paper that we put out recently, which has since led to us appearing on TV next April in Royal Autopsies, so keep an eye out on Sky history. The project started as some skeletons were dug up from the 1300s, and the question was, did they have rheumatoid arthritis, APS, or lupus, and how can we diagnose skeletons with autoimmune disorders? What we did was we took the teeth from the skulls, ground them up and then managed to purify antibodies from them. The crazy thing was that the antibodies were fully functional, and they bound to the modern Epstein Barr virus, which tells us that the way we respond to it hasn’t changed in 700 years. They also had functional intact Fc regions, meaning that the antibodies would have generated an immune response. This has opened this world of immune-archaeology and now we’re trying to see if we can push that on and look at other diseases, which may or may not generate antibodies. This is essentially an ‘ancient proteomics’ as it were.

When you write your thesis up, I had a page of quotes on the inside cover of my thesis because I’m an old man. I’m terrible for that sort of traditional thing. One of them was ‘What isn’t measured isn’t managed’, which is something from my dad, which I think is very relevant. The other one was from an author called Douglas Adams, who wrote The Hitchhiker’s Guide to the Galaxy, which is ‘Time is an illusion, and lunchtime doubly so’. I think it’s wonderful, but yes, I like the silly little quotes like that, to be honest.

Personal / Opinion questions

1. What are you most proud of attaining or achieving in your research journey?

My current role is massive to me. The proportion of people who do PhD’s that actually end up in a permanent role is something terrible, less than 1%, so that’s obviously nice. On the personal level, I hold a patent for a therapeutic that I developed my PhD and that’s a really nice thing as well because it’s a bit unusual, but it also was a validation of a lot of long nights in various pharmaceutical company cupboards, you know, working away on my own.

2. Do you have any advice for PhD students and/or early career researchers who are starting their PhD/research journey?

Yes. I think that universities have tried to make it as open as possible for people to get long term positions. The problem is that it’s not advertised how to use the resource available to you. In UCL, there’s a thing called the Academic Career Framework, and it literally states what you need to do to get to the next one. If you want to get a fellowship, look at career framework stage eight and start seeing what is missing, and then you need to start ruthlessly going after opportunities. The next committee that falls into your inbox, say yes to, and that sort of thing. The other thing you can do is there’s the MRC and fellowship template CV which puts everything in boxes so that you can see the box that’s missing for you. I did this before my first fellowship and went to the head of the division and I said ‘right, I’ve got holes in these four boxes, how do I fix that?’ Then he started showing me where there were opportunities and started to be involved in developing my network with me. So, ask for advice, ask for help, but also be practical with it. It’s not an obscure mercurial thing that just comes out of the ether. You can develop a pipeline for it. Ultimately, we are all scientists. We’re all method development people. This is no different. You can develop a method for the same thing and on a personal note. Otherwise, ask questions and develop networks. You know your supervisor network is yours, but also build these at conferences. Just speak to people as you work in the medical environment. The turnover of staff here at UCL is enormous because that’s the nature of the game, so keep in contact with people. I have several contacts in Europe that are just clinicians who used to work here, who are now doing their own research. I keep in contact with them, and we trade samples. One of them turned up the other week and said ‘I’ve got a box of 35 placentas, have you got any ideas’? That’s not the sort of thing that comes about unless you keep in contact with people, so that’s what I would say is go after the opportunities, ask for advice, and keep in contact.

3. What research skill are you most proud of as a researcher?

I am a methods guy, and so I would answer this as I I’m proud of this array of different methods that I’m capable of pulling on to any project. I’ve got molecular dynamics, small angle X-ray scattering, and I’m learning cryo-electron microscopy next year. I would say the skill set that I’ve developed is probably what I’m proud of more than anything as I think there’s not really a method that I can’t do or don’t know someone that does in this field.

4. Outside research, what interests and activities do you like to pursue?

I’m a big fan of woodwork. I make furniture for my own house. I make little bits of decorative woodwork and things as gifts for people. I also like to do things outside. I’ve recently bought myself a 3D printer, so now I’m going to go down that rabbit hole. Everything I do is developing methods. I mean, we work on antibodies and stuff that you can’t see, so it’s gratifying to watch something actually take place and be able to physically hold it for a change. So that’s what my interests really are. I am also a huge Spurs fan. When I got my PhD interview, a question given to me was ‘how do you handle disappointment’? I responded and said, ‘I’m a Tottenham fan’, and the interviewer just ticked the box.

5. In recent years, the importance of mental health at work is becoming more and more important. What do you find helpful to keep your mental health in the lab?

I don’t have a good mental health balance, to be honest. I think being aware of your mental health is extremely important. I’m someone that’s very prone to be extreme fits of depression, and definitely over COVID. It showed me that I put too much of my self-worth into what happens in the lab, and you know, I’ve got a wife and two kids, and my wife will tell me that she can tell when I walk through the door if I’ve had a bad day in the lab because she can just read it. The whole aura is there and so I’m not great for giving advice because I’m obviously I’m not brilliant at handling my own. What I would say helped me is knowing that you’re not going to have a struggle or a problem that no one else has had. My Dad likes to say, ‘it’s called research, not search’. If it worked first time, you’d just call it search. You have to expect failure and failure can teach you a lot in the lab. It’s not a reflection of yourself, and it’s not a reflection of your ability to do it. There are certain steps you have to go through and sometimes you feel that if it worked first time, I wouldn’t trust it. I think that’s important. The other thing is having a network around where you can just speak openly and honestly. I’ve made it very clear to everyone I work with that I’ve had depressive fits. I’ve had bouts of poor mental health, and you should say it because the problem with depression is it only has a power over you whilst you believe the stigma associated with it and if you give it the power by keeping it inside. There was somebody used to work here who used to see me as I walked in and she would say ‘how are you’? I once said that I was really depressed, and she said ‘oh that sucks’! You know, that’s all I needed was for someone to look across the table and go, ‘yeah, that does suck’, and then it’s lost its power over me. That’s the thing, you’ve got to be open about these things and you have to know what your mechanisms are to deal with it, and maybe you don’t know yet. Maybe you will develop this over time, but you need to. You need to be aware of where you are, and you need to be in an open environment where you could discuss strategies for dealing with it.

6. Do you have a favourite quotation or memo that you would like to share with our readers?

When you write your thesis up, I had a page of quotes on the inside cover of my thesis because I’m an old man. I’m terrible for that sort of traditional thing. One of them was ‘What isn’t measured isn’t managed’, which is something from my dad, which I think is very relevant. The other one was from an author called Douglas Adams, who wrote The Hitchhiker’s Guide to the Galaxy, which is ‘Time is an illusion, and lunchtime doubly so’. I think it’s wonderful, but yes, I like the silly little quotes like that, to be honest.