Faces of UCL

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Michael Spence: Welcome to Faces of UCL, where we uncover many stories from around University College London. I'm Michael Spence, UCL's President and Provost. I'm excited to bring you conversations with some of the remarkable people who contribute to our vibrant university community. This podcast is a window into the people and the stories that make UCL the special place it is. This week, I'm talking to John Hardy about neuroscience, dementia, and his career in the sciences. John, how did it all start? You're not a doctor, right?

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John Hardy: No, I'm a PhD so [OVERLAPPING].

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Michael Spence: Not a real doctor. He says rather controversially.

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John Hardy: I'm not a real doctor. [OVERLAPPING].

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Michael Spence: No, I think that is a real doctor.

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John Hardy: Yeah, of course... [OVERLAPPING].

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Michael Spence: But not of use in a plane.

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John Hardy: Yes, exactly. I always wanted to do neuroscience. I went to university wanting to do neuroscience. I went to Leeds University, and I had a great time there, I have to say. Then I did a PhD at Imperial in neuroscience. I have to say in those days and still, everybody looked up to UCL as the centre for neuroscience. I started to. And when I then went to Newcastle, I really was inspired to start doing genetics. Actually, UCL is the right place to do genetics of neuroscience, because it's the tertiary referral centre. All the people with unusual diseases come here. I always wanted to come to UCL, to Queen Square. It was my ambition to come to Queen Square. Right from then.

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Michael Spence: When did you arrive in Queen Square?

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John Hardy: 2007. I should say I was turned down for the job I currently have in 1992.

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Michael Spence: Wow [OVERLAPPING].

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John Hardy: I waited 15 years [LAUGHTER] to get the job that I had applied for in 1992, but I'm really glad I got it.

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Michael Spence: Was it always dementia? Was it always the degenerative conditions, or did you look at other things on the way through?

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John Hardy: No it wasn't. It was neuro-diseases, in general. I was interested in schizophrenia earlier in my career, too, but no, it was neurodegenerative diseases, which became my passion, if you like.

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Michael Spence: Did that happen through a kind of hunt for the mechanisms for particular pathologies, or did it happen because you wanted to understand how the brain worked better? How did that shift happen?

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John Hardy: In 1983, there was a great paper from Jim Gusella in Boston, showing that the gene for Huntington's disease was on Chromosome 4. I thought how cool it was to be able to understand how a disease started. That was the paper which really changed my career. I was working at the time in Newcastle, where they were interested in Alzheimer's disease. Some of the early work on Alzheimer's disease happened there. So, we started to look for families to, if you like, emulate Gusella's Huntington's work in Alzheimer's disease, and that's when I switched, really.

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Michael Spence: There's lots of theories about the origins of dementia, of Alzheimer's disease. How does it all work? For a pig-ignorant layman like me, how do you lay out the topography of this disease?

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John Hardy: The pathology of the disease is protein depositions in the brain. One protein deposition is amyloid, another protein inside the cells, is of a tau protein, and then you've got cell loss. There was lots of different theories about the disease. Some people thought it was amyloid. Some people thought it was tau. Some people thought they were merely the gravestones, if you like, of dying neurons. That was the field that we came into. We started to collect families with Martin Rossor, who is actually still my colleague at Queen Square. When we started to work on those families, we found mutations in amyloid. That allowed me to write a very influential paper saying that amyloid in that family was how the disease started. More generally, it allowed us to postulate that that was where the disease always started – with this amyloid deposition.

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Michael Spence: Where does the amyloid come from?

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John Hardy: It's a protein that we all make. We don't know the function of the protein even now 30 years later. But, we make it. It's metabolised in the brain and starts to deposit. That's what happens. I have to say we don't know yet what the protein does. Quite remarkably.

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Michael Spence: And as it deposits, it kills cells? [OVERLAPPING] It stops cells talking to one another?

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John Hardy: Yes exactly. [OVERLAPPING]

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Michael Spence: What does it do?

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John Hardy: It starts to kill the cells. It kills neurons, either directly or indirectly. I think it starts to kill cells because it overloads their capacity to degrade all the other proteins they need to be degrading. That's my own view, but others would differ with me about it.

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Michael Spence: It happens in particular parts of the brain rather than other parts of the brain?

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John Hardy: Sure, so the part of the brain it starts with is called the hippocampus, which is just behind your ear. It's a small part of the brain – rather like a crooked little finger. That's the shape. That's the part of the brain where it starts. That part of the brain helps you make new memories. So, the first symptoms are often the inability to make new memories. People can remember what happened to them years ago, but they can't remember, for example, where they put their keys is a trivial example. But I mean, I forgot that this morning. But people more pathologically, so to speak, might go to the shop twice to buy milk in the same day because they've not remembered that they've done that before. So that's the type of early pathological symptom, if you like.

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Michael Spence: I forget things all the time. How do you tell the difference between having dementia and just being tired?

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John Hardy: No, you're right. It's a very difficult line to draw – that's a very difficult line to draw. What we need to do is to be able to diagnose the disease earlier. But the example you've just given is exactly why that is difficult to do, because we all forget to do things all the time.

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Michael Spence: You know, we forget what we were doing last week. [OVERLAPPING].

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John Hardy: Yes, exactly. No, now that's really the grey area between normal behaviour and the beginning of a dementing decline. It's a very difficult line to draw.

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Michael Spence: One of the moral problems that always seemed to me, in terms of where we are in relation to dementia care, is that we are actually getting better at earlier and earlier diagnosis, right? Both through imaging and through clinical tests and all the rest of it. But there hasn't been much that we could actually do. You're in the funny position of saying to people, well, there's going to be some process we don't quite understand over the next five or 10 years where you're steadily going to get less and less well, and sorry, there's not much we can do about that. Is that changing?

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John Hardy: It's changing both ways. It's changing, first of all, that there are now treatments. They're not ideal. There's treatments, the two drugs that are on the market now, lecanemab and donanemab. They both slow the disease. You're right about how really there was no effective outcome to treat a diagnosis before. Those treatments make an effective diagnosis really important. On the other side of the equation. Now we've got biomarkers, blood biomarkers, which are getting close to clinical practice. In fact, my colleagues, Amanda Heslegrave and Henrik Zetterberg at Queen Square, at the Institute of Neurology there, are the leaders in this. We are getting better at diagnosing early in the disease using blood biomarkers. So, there's been progress both in drug development and in early detection, which make that statement not true anymore.

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Michael Spence: You've had a role in the development of treatment, right?

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John Hardy: The treatments are based on our idea the amyloid was where it started. So, absolutely, the treatments are anti-amyloid antibodies. They remove amyloid from the brain, and that is why they are effective. You're right. Yes.

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Michael Spence: The tau thing, was that a red herring, or is that an alternative mechanism for the disease against which we don't yet have treatment?

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John Hardy: It's part of the disease process. I think that we are going to need tau based therapies. It's downstream of amyloid. It's downstream of amyloid. But, anybody with a complex disease, like, for example, diabetes, people with diabetes – and I have type 2 diabetes – people with diabetes take insulin, they take metformin. They nearly always take blood pressure meds, and they nearly always take anti-cholesterol meds. You have a disease like type 2 diabetes – you have multiple treatments. I think that's the way we're going with Alzheimer's disease. The first treatments are anti-amyloid therapies. I think that the next ones are very likely to be anti-tau therapies. They're going to be part of the armamentarium. And I have to say that, that is also being worked on at Queen Square. My colleague Rohan de Silva actually is developing an anti-tau therapy, which is under development now as part of the armamentarium.

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Michael Spence: Across what percentage of dementia conditions, do you think work through the amyloid pathogenic process?

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John Hardy: Probably about 60 to 70%.

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Michael Spence: Oh, wow.

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John Hardy: It's easily the giant among the dementias. But there are others as well, and it's important that we get the diagnoses right.

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Michael Spence: Are there other diseases that are much more specific in their scope, things like Huntington's disease, that, of course, Sarah Tabrizi works on at UCL, is there or are there other general sorts of dementias?

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John Hardy: Huntington's disease is nearly always diagnosed correctly. Sarah's group really, is extremely good, and there's a genetic test. That's for Huntington's disease. That is rarely – occasionally – but rarely mistaken for Alzheimer's disease. No, it's diseases like frontotemporal dementia. Diseases like dementia with Lewy bodies and so on. Actually, the other dementia, which is quite common is vascular dementia, too. Those are the ones which are confused with Alzheimer's disease. It's a bit more subtle than I'm giving the impression, in the sense that quite a lot of people have what one might call mixed pathology. They have a little bit of vascular problems and Alzheimer's pathology. It isn't always a clean separation. A lot of people have a mixture of both pathologies.

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Michael Spence: Do we understand why some people get dementia early and some people develop dementia in later life?

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John Hardy: Genetics is part of it. Genetics is part of the reason, but more generally, I would say we don't yet know why, what the variability in age of onset is. That is something that we're still working on.

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Michael Spence: So, we've talked about age of onset. Is there just also healthy brain ageing? Not particularly associated with the accumulation of any particular protein or whatever. But does our brain just degenerate in other ways as we get older?

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John Hardy: I think it's very likely there is a general loss of intellect by age. If you look at people who are over 100, then a very high proportion of them are not as cognitively well as they would have been when they were 50 or 60.

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Michael Spence: As that happens, one of the things that is often associated, but not always, is particular kinds of mood swings. Some people as they get dementia, don't exactly enjoy their forgetfulness. I have an aunt who used to giggle every time she would forget something. My own mother, when she'd forget something, she'd get really irritated. Do we understand how this activity in the hippocampus then begins to affect other parts of the brain in different ways?

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John Hardy: What we think happens is we think the pathology spreads from brain area to brain area. We think that that's part of the process. One of the things, and this is not really, if you like a research view, but my personal view, is that what you see is that you start to see kind of an exaggeration of the person's earlier personality. [OVERLAPPING]

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Michael Spence: That's terrifying. [LAUGHTER]

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John Hardy: Yes, so you see that somebody who was grumpy earlier becomes angry.

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Michael Spence: Yes.

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John Hardy: With somebody who was cheerful earlier... [OVERLAPPING]

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Michael Spence: And yet, as it spreads to other parts of the brain, it doesn't seem to – or does it to seem to, spread to parts that affect mobility or perhaps speech or other functions. It only seems to spread to some parts. Do we understand why that is?

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John Hardy: To some extent we do. We think that eventually it will affect mobility and speech, eventually it will. It spreads slowly. That's rather later in the disease process, but it seems to spread inexorably along brain circuits to affect other aspects of personality.

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Michael Spence: Every 2 seconds in this conversation, you've said, and we have at Queen Square, somebody who works on X or Y or Z. It seems at Queen Square there are people looking at sort of the totality of the problem in all sorts of different ways. But what brought you to Queen Square originally?

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John Hardy: Queen Square, Institute of Neurology is really, I'm going to say, the only institution, in the world, which has a single mission, and that is to reduce the burden of neurological disease. The clinicians there, they all work on different neurological diseases, the pathologists, the psychologists, the surgeons, the basic scientists like myself. We all share a mission, and that makes it a really special institution. When you meet somebody – in other institutions, you might have nothing much in common with them. But when you meet somebody in the lift at Queen Square, you know that they're really on the same mission as you, and that gives the place a sense of purpose, which, I think is really powerful.

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Michael Spence: Now, John you're a bit of a rock star. Like, obviously, the work you did in explaining how amyloids work and their role in the disease and all the rest of it has really led to a revolution in Alzheimer's research. How do you handle that? At this point in your career, what do you really want to achieve?

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John Hardy: What do I want to achieve? I have such great young colleagues, really fantastic young colleagues. So, I want them to do well. It's lovely to see them doing well. Now I share a lab with my colleague, Henry Houlden. He was my undergraduate trainee 30 years ago, and now he really, I'm going to say he's my lab boss, in a way. I worked closely with him, and it's great to see his many successes. That's absolutely part of it. But, the thing about being a geneticist, It's a bit addictive, really. There's nothing like the thrill of finding a gene. That really is an exciting thing. You go from not understanding something one day and then the next day you find the gene, and then you understand a huge amount. That is a real dopamine hit. I'm kind of addicted to that. I always, when people say, do you want to, for example, do you want to retire? I just think, no, I want one more gene. One more gene. That's how it drives me on.

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Michael Spence: Yet individual genes, they work in combination and they work in your epigenetic contexts. How often do you have the experience of thinking, I know exactly what that does? How often has that happened to you in your career? [OVERLAPPNG] Often or sometimes?

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John Hardy: Four times.

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Michael Spence: Yeah.

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John Hardy: Four times.

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Michael Spence: Yeah.

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John Hardy: So, I mean, of course, we found many of the genes, but where I feel that it was, if you like, I don't want to say me but me who made the discovery, that that was my hit, for, I would say, four times.

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Michael Spence: Yeah, that's terrific. And one was amyloid... [OVERLAPPNG]

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John Hardy: Amyloid

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Michael Spence: The others?

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John Hardy: Tau.

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Michael Spence: Yes.

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John Hardy: Tau, as we've discussed. Then a synuclein mutation that we found, which causes Parkinson's disease. Then the most recent we found is a gene called TREM2, which is responsible for how the brain reacts to amyloid deposition. Those are the four, if you like – hits – that I look back on. Of course, we've done many other things, but those are the biggest, so to speak.

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Michael Spence: John it's been inspiring to hear you talk about your work. I really hope that between now and whenever you do decide that you're bored of genetics  – there's 5,6,7 and 8 more genes to discover.

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John Hardy: That would be nice.

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Michael Spence: Congratulations on your work, and thanks for being with us today.

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John Hardy: Thanks very much.

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Michael Spence: Next, we continue our journey through UCLs community with Dr Dan Honig professor of public policy, and he brings a fresh perspective to state and citizen relationships, mission driven bureaucracy, and what we can learn from all of that to apply here at UCL.