The Bioinformatics CRO Podcast

Episode 20 with Matthew Holt

Matthew Holt, neuroscience professor at VIB-KU Leuven, explains the role of glial cells in neurodegenerative diseases and discusses boxing and motorbike racing.

On The Bioinformatics CRO Podcast, we sit down with scientists to discuss interesting topics across biomedical research and to explore what made them who they are today.

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Matthew is a group leader at VIB-KU Leuven Center for Brain & Disease Research, where his lab studies the molecular mechanisms that control development and function of astrocytes in vivo, and how they interact with neurons.

Transcript of Episode 20: Matthew Holt

Grant: Welcome to The Bioinformatics CRO podcast. I’m Grant Belgard and joining me today is Matthew Holt. Matthew is a professor at VIB-KU Leuven in Belgium, in the Department of Neuroscience. He is also a big fan of the Liverpool football club. Welcome Matthew. 

Matthew: Hi, Grant. How are you doing? 

Grant: Doing well. It’s good to have you on.

Matthew: Good to be here. 

Grant: So can you tell us about what you do? Yeah. So I, as you quite rightly said, am a scientist, but unlike the vast majority of neuroscientists who work on neurons in the brain, we’re very interested in the non-neuronal cell types, in particular the astrocytes. And we’re very interested in these cells because they’re the main support cells for neurons in the brain.

They influence how they work and during disease, they go wrong. And it seems increasingly likely that it’s alterations in these glial cells that actually initiate disease. So what we want to understand is the basic biology of the cells, so we can try and correct them when they go wrong. And hopefully we can keep people’s neurons alive in diseases, such as Alzheimer’s and Parkinson’s.

Grant: What have been some of the biggest discoveries in the glial biology space during your career?

Matthew: The big initial discovery for me was the discovery that astrocytes can actually sense activity in local neurons, but then can actually respond to it and respond to it by releasing neuroactive substances, which modulate neurotransmission. And then I think just recently a very, very interesting finding was the fact that astrocytes are responsible for the elimination of neurons, both during development and also in adults, which implies that they could also basically eat neurons during neurodegenerative disease. And I think that that’s a huge finding, which will alter the way people look at this type of condition. 

Grant: How has the field responded to these discoveries? Are neuron-centric people still as strongly neuron-centric as they once were or has the field as a whole been moving in this direction? 

Matthew: You know, I think there’s an increasing realization amongst neuroscientists that glia in general, so microglia and oligodendrocytes, are essential. I think one of the big issues of course though, is people are drawn to fields where they can actually do experiments. I think part of the problem with the glia field for years has actually been the lack of tools. And whenever you write a grant to work on glia, it can seem like it’s 20 years behind the people who are working on neurons.

And I think that that is a very, very difficult mindset to overcome. Having said that, I think with the type of technologies we’ve got now from single cell sequencing, viral vectors, genetically encoded calcium sensors, cAMP sensors, so on and so forth. It is becoming much easier to do those experiments. And I think as you see that, of course, it’s going to draw more people in. 

Grant: So as our listeners can probably infer from your accent, you’re not Flemish. Can you tell us a bit about what it’s like to work as a scientist in a foreign system? 

Matthew: Oh yeah. I’d be happy to, I mean, I think there are advantages and disadvantages of course. I think one of the advantages is personal growth. You get different perspectives on science. Of course different experiences of how organizations are run and you can sort of cherry pick the styles that suit you best. Of course, there are also disadvantages. I think being a foreign scientist coming into any system, you need to understand that system.

And I think the higher up you go, the more important that becomes. Especially. I think actually now the tendency is to get large consortium grants, and you need to have a preexisting network, you need to have established people who value your work, can vouch for you in a way and are willing to promote you.

And of course, that all takes time to develop. And I think one of the problems for early career stage scientists is very much that you have this five-year period where you are supposed to be hyper-productive. You’re supposed to pull in grants, publish songs and so forth. And if you’re having to fight your way into a system, it just makes things much harder. For me, I think I was quite lucky because I moved to Flanders with a very large European Research Council grant, which was one and a half million. So, for five years I could run quite a nice little group on that while we were finding our feet. But if you don’t have that type of resource, I can imagine it’s very, very difficult.

Grant: Other than getting a large grant, what steps can early career scientists take to mitigate that? 

Matthew: I think the obvious one of course that I would say is network. Network as much as possible as early as possible. I mean, in general, I think most people usually end up going back to their country of origin because that’s where they have the biggest network available.

But that’s the first thing I would say, is get a very strong network. I would also say to most people looking at a postdoc, actually, that it’s very, very tempting to go to a big lab with lots of money, with star power almost. And assume it’s all about the science, but I think what you really, really want is a very good personal dynamic with your PI as well.

You want someone who’s going to pick up the phone in three or four years’ time and tell their friends. I have a really good postdoc. You should be picking this person up. And I’ve known one or two examples of that actually in my career. Erwin Neher, who was a director at Max Planck at the time, was like this. Let’s face it nowadays. There are lots of people with very good papers. It’s very attractive to assume it’s a metrics game, but I really do think personal connections count for an awful lot.

And I would actually even go so far as to say, if you don’t think that you’re going to get that level of support or develop that personal connection, you might want to get out as quickly as possible and find yourself a lab where you will have that support, if your ultimate goal is to stay in academia.

Do you think that’s also true at the level of where you do your PhD or does that really become a lot more important with where you do your postdoc? Is the PhD lab also critical in that respect because there’s often this decision people make: do I work with the young PI who can give me a lot more attention and who I’ll probably get more mentoring from, or the very senior PI who’s always on the road, but very well connected and well-resourced. 

Matthew: You know, I would say that I think is probably a bit more important at the postdoc level. Or at least when I was doing my PhD, the people that I interviewed with, so long as you’re coming from a good Institute, were much more interested in trainable potential at that time than papers on the board.

Now, of course, whether that’s altered slightly now is open to debate. I mean, I certainly know that for the students coming through our institute now, it’s a much, much more competitive world. I have to say that I think that the example of the LMB, the Lab of Molecular Biology in Cambridge is awesome.

I mean, there’s a reason why it’s produced so many Nobel Laureates. And I think that this idea of small dynamic groups where  students have a level of attention free to discuss with senior lab members, but also are given scope to try their own thing even when the PI is 90% sure it will fail.

I think it’s a wonderful model. Right. And it’s a very, very hard balance to get, of course. But in terms of young career developments, I think it is a fantastic model. For me personally, I think if I had been put in a lab of 50 people and I had been given a desk and told to sort it out, then I would have struggled. So I think it’s also person-dependent to some degree. 

Grant: And let’s talk a bit about that because you had a pretty unusual path into science starting in law and so on. Can you maybe take us back, way back to what attracted you to law in the first place? And then why did you end up going into science?

Matthew: Why law? I think probably because of the background that I came from. There was always an assumption that if you went on to university, it was to end up with a professional career. So you would be a medic, a dentist, a lawyer. And I think there were two things that drove me to all law.

The first one was that my elder brother had already got into medical school and I had spent maybe the best part of over 11 years, constantly being compared to my brother. So going into law seemed not a bad idea. Then the other thing that sort of appealed to me was the almost romantic notion of defending the innocent party against the odds with these courtroom flourishes of oratory, maybe. 

But I actually realized quite quickly that at least in the UK legal system, it’s all based on precedent. And if you actually have a science background, which is what I had all the way through school, it’s very, very difficult to accept that nowadays you should be bound by a ruling made 250 years ago.

Because up until recently, it was actually a central pillar of British law that basically, if I remember correctly, the judgments made in the House of Lords were absolutely binding from the time they were made onwards. And I find that whole concept actually quite absurd, with the way societies change, things that were regarded as perfectly acceptable for my parents’ generation and grandparents’, now, people would be appalled. 

That was it. I found it very, very hard to accept that. I also found the work incredibly dull, if you like. I think because of course it’s very, very book and library based and I’d been used to being quite active in practical classes and taking a chunk of sodium and throwing it in the pond and watching the explosion experiments in chemistry.

So I was actually quite frustrated. And then one of the core legal courses that you have to take in the UK is actually at most universities is property law, and we have a lecture on intellectual property. It was a case about an American university, who had taken a tumor from a patient and this tumor produced large amounts of GM-CSF, which at the time was being touted as a therapy for HIV.

And the question was who actually would benefit from that? Would it be the patient or would it be the university who basically made the product? And it was quite funny actually because I was the only one in the class who had any idea of what GM-CSF was or what immortalized cells were. And as I was going out of the tutorial, the lecturer actually said to me, if you have a science background, you should seriously consider going back because over the next 10 years, patent law will explode and it will be scientists who drive this. 

Grant: It’s incredible. How impactful those little comments can be

Matthew: Massively, massively. So I applied to go back and do biochemistry. And that’s why I ended up in Liverpool, hence the football connection. And the first two years were a really standard university experience. And in the third year, I actually did an industrial placement with Eli Lilly who at the time were arguably the world’s biggest pharma company in the neuroscience space. They had Prozac on the market at the time.

I was lucky enough to be there when they released Olanzapine, which was a huge hit for them as well. And this was really my first proper lab experience. I really enjoyed it. I got on fantastically well with the guy who was head of research at that time. He was coming from Bristol, David Lodge, who worked on excitatory amino acids. And David was just the most wonderful guy. And he used to take me to meetings, quite high-level meetings at Eli Lilly. Then he would take me off to meet collaborators at universities. Towards the end of my time at Lily, it was actually David, who said to me, I think you should do a PhD. Get back to me, if you want to do it.

And the funny thing was of course the arrogance of youth, it was almost like, Oh, I’ll find my own place to do PhD. And I applied to the LMB because I really wanted to go to the birthplace of DNA. I went for an interview with the guy that I eventually worked for. And the first thing he said to me was I see you know David lodge; he was my supervisor as an undergraduate. Which was my first first experience of how small science actually is.

And I had a great time as a PhD student. The LMB is a fantastic institution. There’s no doubt about that. I think at the time I’d probably have the best of it because there were still 5 Nobel laureates there. And it was fantastic. You could have coffee with these people, get to call them by their first names and they would know who you are and what you were doing. It was a fantastic environment. And then of course the question was, what do you do after you finish your PhD? Do you really want to put a suit on and go back to work in a bank or a law firm? 

At the time I was actually renting a room from a family in Cambridge. One of the members of the couple, he was a senior academic at the university and his wife was always telling me, go and work for a bank, go and work for a bank or go back to law. And I remember one night he just pulled me in the room and he actually said, look, Matthew, just look at you. You’re just never going to do anything but science. I can’t actually imagine you wearing a suit type thing.

So I think that was it. And then that’s what got me on the postdoc train. But coming back to what you said actually about just to conversations or moments really having a profound influence. When I was finishing my PhD, I actually had offers from Shelley Halpain at the Scripps in San Diego. 

Grant: You could have lived on a sailboat.

Matthew: Ah, yeah maybe. I also had an offer from Harvard Med and we actually went over, my supervisor and I to Erwin Neher’s 60th birthday party that was being held at the Max Planck Institute. And I just asked Erwin, can I go in and look around your lab please? Because I’m on the job market and it might be nice.

And I got in the lift and all the Max Plank directors have a floor to themselves, usually. And their name is on the lift button. 

Grant: It sounds very German. 

Matthew: Well organization is everything right? And I looked there and I actually saw the name, R. Jahn, and I’d seen Reinhard Jahn give a talk a year before at a FENS meeting. And it was a superb talk. And he had just been recruited back from Yale at the time. And I didn’t know this. And then you ended up with a single building with Reinhard Jahn, Herbert Jackle, who’s a fabulous developmental scientist, and Erwin Neher. I mean, it was just ridiculous. And that was it.

I wasn’t going to go to the US for a post-doc after that. And again, it’s just one of those really old moments. You walk into a lift and that’s it. It just changes the future in a way. 

Grant: You’ve of course been in Belgium for several years now. But you spent a number of years in Germany. Can you talk about what your culture shock was like in both places? What maybe didn’t surprise you and what surprises did you find? 

Matthew: The biggest shock was the expensive Belgium compared to Germany. I have to say Belgium, or at least where I am now  in Leuven, is very expensive compared to Gerstungen, where I was based before. Although I should qualify this. If you have to live in Munich, you probably need to own a bank.

I mean, Munich’s very expensive, but the first thing was the expense. And I think generally Belgium’s much more expensive, but I have to say in general, I think that moving from the UK to Germany, from Germany to Belgium, there’s not huge changes. I think European culture is quite standard.

Maybe, I think actually your culture shock when you moved from the US to Oxford would have been quite larger. Right? I think that there is this fallacy that because we speak a common language with the US somehow the cultures and the expectations are quite close. 

Grant: But what’s the expression? People divided by a common language?

Matthew: I think so. Yeah, definitely. I think people forget actually, the reason we ended up with a United Kingdom was because we wanted a protestant monarch from Hanover rather than the catholic monarch from Scotland. In terms of culture shock, that wasn’t so much. I do miss Jim and Brad, I have to say.

And I miss German beer, but luckily, luckily the European train network is fantastic and you can zoom around quite easily.

Grant: That’s a big thing to say for someone currently living in Belgium, right? It’s not like you’re drinking bud light

Matthew: Well sure, sure. I don’t know. Maybe it’s the orderly nature of Germany, the fact that they have laws, which govern everything. So you basically know what’s in the beer, whereas in Belgium, if you go to the shops in brews where all the tourists are: cherry beer. I mean, it does seem a little bit bizarre, some of the beers that they come up with.

Grant: Yeah, it’s good though as a one-off. So do you also have some unusual hobbies? Do you want to talk about road races? 

Matthew: Yeah, so I was actually brought up in the Northwest of the UK and just off the coast is a little piece of rock known as the Isle of Man. And every year they close the roads on the Isle of Man and they just turn it into one huge race track. So it’s like 37 miles. It goes through Douglas, Ramsey goes over the mountain as well.

And it’s a big thing, actually, if you grow up there. It’s really quite spectacular, first of all, that there are still places that allow this and also that you actually have people that want to do it. I think it’s quite hard to explain, but basically you have people racing at speeds of 200 miles an hour, so 300 kilometers an hour. Basically on normal roads that on normal days have cars, tractors, buses, that type of thing. It’s in close proximity to stone walls, telegraph poles. And actually you’re so close that you could probably put your hand down and actually touch them as they go past. 

And it really is the most spectacular thing to see and to hear. And also the people that tend to go really are hardcore motorbike friends. And it has to be said from a very young age, I have had this real interest in motorbikes, which I think comes from my dad. And we used to spend hours on a Saturday afternoon going around the local bank shops and so on and so forth.

So we basically try to get to the races where we can. And in Ireland, they also run smaller race meets at the weekends during the summer. And that’s also great because I love Ireland. I think Ireland is a fantastic place. I think the Irish are great people: very warm, welcoming. And Guinness is great as well.

Grant: And what’s this, I hear about Olympic boxing trials. 

Matthew: Yeah. So it’s quite bizarre. My mom could never reconcile why a neuroscientist would like boxing? People have a preconception when you say boxing. I mean, obviously there’s the professional game, but the amateur level is a very, very different sport. but yeah, I do love amateur boxing because I think the guys are phenomenal athletes, to be honest with you. 

They’re great athletes. They are incredibly dedicated and yeah, this time last year, actually I did have tickets to the British Olympic boxing trials. And then of course COVID hit. And they closed them down and then there was talk of starting them up, but the boxes would have to wear masks until they got to the ring and so on and so forth, which I thought was quite ironic. Given the fact that when they got to the ring, they would spend nine minutes hitting each other, but…

Grant: Socking each other in the face and breathing on each other.

Matthew: Yes, of course. You know, the aim of the sport actually is to amass points basically. And you score points by striking your opponent. For me, I find fighters that can actually slip punches, work the ring well, avoid taking punishment, and to do that actually for nine minutes at a high level, it’s the longest nine minutes you’ll probably ever have in your life.

It’s not easy. They are very, very fit, mentally very focused. The professional games are different, of course there’s money involved. I think that people are badly used in the professional game, but for the amateurs I do like it very much. You can say what you want, but American football, whoever had the idea of basically using the head as a weapon. I’m not sure there’s a lot of difference.

Grant: Yeah. Fair enough. So when you’re talking about the skills of boxers, my mind for some deranged reason went to science. So what do you think are kind of the scientific equivalents of that? What makes you a good scientific ring fighter? 

Matthew: There’s a certain level of dedication. You have to love doing what you’re doing. I think there’s a certain amount of accepting pain. Whether that’s purely physical or just the sheer mind-numbing pain of things, not working. I think both are quite solitary events. I mean, basically your performance is dependent on yourself and I think there’s an awful lot of focus needed and many hours. To get to the top in either, I think you need good skills. 

And those come through hours and hours of practice and repetition. I remember talking to you about this, so-called, 10 thousand hours of practice. There’s a reason why people get good at Western blotting. Right. And that’s just because they make a lot of gels and they do a lot of blotts.

And I think it’s sometimes really easy for people to overlook this because they regard it as a job or I’m at school. But rarely all those hours in the classroom and doing experiments, it’s all part of the 10 thousand hours. And that’s at least my view, if you like. 

Grant: Following a bit on that cause I don’t know if this would be a contender, but what are the biggest misconceptions you see among young scientists these days? And what are the biggest mistakes you think early career scientists make? 

Matthew: I think we all have this view of the heroic scientist, who’s on their own working all hours, day after day after day, trying to work through a problem. I think there are very, very few places in the world, unfortunately, where you are able to do that within the academic system. So I’m thinking of places like the LMB ,maybe Janelia Research Campus, but for most scientists, you are in a grant-based system and you are judged by productivity. 

And I think one of the things that people need to keep in mind is actually knowing when to give up. This again was a conversation. I actually remember having it at the sink with a colleague of mine when we were at the Max Planck. I had just come from the LMB. There were no problems with money. There really wasn’t pressure to publish and my colleague, who’s a very good friend, he’d come from a normal university environment. 

He actually said to me, this is not normal out in the real world. You are going to be asked at the end of three to five years, what have you got? And I think there’s a very, very fine line between persevering and giving something a really good shot, but also knowing basically when you just have to drop it or at least put it to one side for the time being. Because at the end of the day, you have to leave your PhD, you have to leave your post-doc with papers on the board. 

Now of course you can argue whether that actually is a good use of public money. Maybe you could argue that public money would be better spent by letting people go away, have ideas, and give them funding for 10 or 15 years. But that’s not the system that we’re in. 

To a certain degree. You have to play within the system you’re in, of course. And I think that for most people, it’s a fine line between pushing something that could give you your Nature Neuroscience, your Science paper, your Nature paper, or basically just putting your career into a grave after five years.

Grant: Well, what changes would you make to the current system? If Matthew Holt became the dictator of public science funding, what would we see? 

Matthew: One of the big things that carries a lot of weight on grant committees tends to be track record. And this may be a little bit contentious to say because I can see it from both sides. Right. You could argue that the best predictor of future performance is past performance, right? I mean, you can argue that. And to a degree there is some truth, people who published in the past are probably gonna publish well in the future. But at the end of the day, a good idea is a good idea.

I can never remember the name of the guy, but the guy that won the Nobel Prize for the Higgs Boson. 

Grant: Higgs

Matthew: Well, yeah, Higgs, but I can’t remember his first. 

Grant: Peter or something. 

Matthew: Yeah. Peter Higgs. But you know, he had like seven papers over quite a large period of time and he openly admits that he would never have survived in the current academic climate. But all of those papers from what I understand, because this is physics that is well above my level, are hugely influential. So if I had control of a large budget, I think I would be far more likely to give money for ideas to a person without necessarily a huge track record.

I think in a way also this is why established large groups suck up a lot of grant money, and why it’s difficult for young group leaders to get on the ladder. Because funding agencies want to see something for their money. And I also think as well, that track record sort of feeds into this feeling that I can’t have a gap in my CV. 

So you go from doing a PhD on LTP, and you do LTP as a postdoc, but it’s slightly different. And then you do it as our PI. But if you actually look at where big advances come, they usually come at the interface of subjects with people who have really broad expertise and can appreciate different techniques. 

I think a fantastic example was Roderick MacKinnon, who started life as a channel physiologist. And he used the tools that he came to know about doing physiology to check that the channels he was purifying were still functional. And he was also smart enough to realize that bacterial channels were easier to purify and then to crystallize, but this was someone who cross-fertilized their research across disciplines. 

I think that you want people like this. I think it was Seymour Benzer that actually said young people should be given a number of passes to do what they want when they’re a bit younger. Then when you run out of passes, you’ve got to decide what you want to do, but my concern is that people are being constrained far too early because of the comparative lack of funding, but also the number of people in the system as well.

Grant: Maybe one day, we’ll all have our own NFTs and go back to a Renaissance model of science funding. So for our closing question on what important question do you disagree most with your colleagues?

Matthew: Actually, I’d probably have to say the thing that I disagree most on is with my colleague Bassem Hassan about whether Liverpool or Bayern Munich are the better team 

Grant: Important questions. Well, great. Thank you so much for coming on. 

Matthew: Well, thanks for having me, Grant.