Titans of Science: Julie Williams
Julie Williams has dedicated much of her career to uncovering the genetic signposts for the most common cause of dementia: Alzheimer's disease. Chris Smith caught up with her to hear about influences she had growing up, how a revolution in genetics means we could be on the verge of key breakthroughs in fighting neurodegenerative conditions, and speaks about her time as Chief Scientific Advisor for Wales...
In this episode
00:52 - Julie Williams: Inspired by TV science
Julie Williams: Inspired by TV science
Julie Williams was born on the 11th of September, 1957, in Merthyr Tydfil in Wales and grew up in the small village community of Cefn Coed.
Julie attended Ysgol Y Graig Primary School and Vaynor and Penderyn Comprehensive School before studying psychology at Cardiff University.
Professor Williams is a leading authority on Neuropsychological Genetics and her research aims to study the risk of developing psychological and neurodegenerative disorders such as Alzheimer's disease.
Julie also served as the chief scientific advisor to the Welsh Government between 2013 and 2017. She was just the second person to hold the post.
Julie is currently the centre director at the UK Dementia Research Institute in Cardiff. In her spare time, she enjoys relaxing with her family and watching rugby.
Chris - Alzheimer's has dominated your professional career, but what actually is that? When we say that word, what do we mean?
Julie - Well, I think most people are familiar with memory problems that occur, usually late in life, and those develop into a full blown degenerative disorder that is terminal. But, actually, Alzheimer's begins probably about 20 years before that. So it's asymptomatic in its early stages.
Chris - And why did you end up going down that path?
Julie - I was interested initially in how the brain worked and that got me into psychology, but I was a little frustrated with not being able to understand it at a level that I wanted to. So, when the opportunity arose to go into something more biological, and specifically genetics, I took it, and that has opened up a greater understanding of the minute processes that go to underlie diseases such as Alzheimer's disease.
Chris - So when back in history did you actually start working on the disorder?
Julie - Gosh, it was probably about 25-30 years ago I would say. I joined a team headed by Peter McGuffin and really just went from there. It's an amazing area, genetics. It seemed to develop new ideas, new methodologies almost every year. We were able to do a lot more. So it was a very exciting area, but it opened up our understanding of the biology underlying these diseases.
Chris - Let's go back a bit further than the start of your career because Alzheimer's disease is named after Alois Alzheimer who was a French neurologist/pathologist. He recognised this disorder in its first instance. What would he have been looking at?
Julie - He would be looking at individuals that presented. The first individual that presented with degenerative dementia, he took that through to after the death of this individual to look at the neuropathology and he described the neuropathology in great detail, drawing out what he saw in the brain of this individual and subsequently others'. You saw clumps of amyloid plaques, these plaques that were found outside the neurons, the brain cells. There were sub tangles within neurons and there was a lot of immune activity that the glial cells were also in his drawings, actually. There were more drawings of glial cells than neurons. So he was trying to describe and understand what the picture was and identifying this as a genuine disease, not really a natural way of ageing.
Chris - And how had that picture changed about a hundred years later when you embarked on your work?
Julie - At the time, we knew through twin studies that genes were playing a significant role in Alzheimer's disease. We knew that those with very early onset disease had more of a genetic contribution. With early onset Alzheimer's, before the age of 65, you have about a 90% heritability based on these studies. We knew that there were certain families that had a very strong risk of getting Alzheimer's. We knew if you had some of these mutations in the genes at the initial stages and then that grew to three, you would get the disease. And we could always predict within five years when you would develop the disease, but these were extremely rare, these families, in the population. So we knew genes were there to play a role, but we didn't know what they were for the majority of cases.
Chris - So that was to become the major target for your life's work, as it were. Let's wind back before we talk about that a bit and consider how you got to the stage where you could even take that on. I mentioned where you went to school, but were you from a science-y family?
Julie - No, not really. My father was a businessman, and my mother did a lot of charity work. But my father was always curious. We would routinely sit down to watch Tomorrow's World and he'd always encourage us to do new things and try out new activities or new experiences. So we had an upbringing that allowed us to think more and become curious. My sister is also a pharmacist and she went into science in a different way. So it affected us.
Chris - So you had that, I suppose, springboard into the area of interest, but having the interest and then translating into being a professional, that takes a bit more, doesn't it? So what was it that made you say, 'I'm actually going to do this?'
Julie - Well, I suppose there were other influences. One other thing that really influenced me was this series called The Ascent of Man by Bronowski. I've started to re-watch it actually because it's come back on. This is about somebody who is curious about a variety of things, but it was the science and the biology that really intrigued me and, as I then went on to do my degree trying to understand how the brain worked, people like Broadbent influenced me because he was trying to understand the brain in a very conceptual way, but it was limited. I remember reading something he wrote about the frustration that he would probably never see in his lifetime this biological basis to cognition. But I thought, well, it would be rather nice to see some of that in my lifetime.
07:31 - Julie Williams: Using genetics to understand Alzheimer's
Julie Williams: Using genetics to understand Alzheimer's
Chris Smith asked Julie Williams how she has leveraged genetics to help us understand more about Alzheimer's disease...
Chris - The problem is that, the situation you arrived at where you wanted to grapple with the genetics of this very important and very common condition, but there weren't the tools there when you started that we really very much take for granted today to do genetic work. When we want to find genes today, it's very easy in comparison to the situation in which you would have found yourself 30-40 years ago.
Julie - That is true. I've never been in an area where we were learning new methods, technologies, perspectives, almost on an annual basis. So yes, when we started, we would spend perhaps nine months trying to understand a bit of a gene to try and describe its variation and compare it between people who had Alzheimer's and people who didn't. Now we can do whole genomes in a very short period of time and really interrogate those differences between those with a disease and those without. And what we also needed was to have very powerful samples - that was another thing that allowed us to find these things out because there's a lot of variation in there, and you could be finding things by chance a lot of the time. You need to build a lot of power and that's what took a lot of time in collecting enough people with Alzheimer's, comparing them to people without.
Chris - How did you go about that then? So you recruit families who have a premature onset of Alzheimer's? Or just lots of people who get it? What were you selecting and then how were you trying to find out what genes might be involved? Because in a genome of 20,000 genes, which we now know there are in a human, that's a huge number of moving parts.
Julie - My interest was in understanding the common forms of Alzheimer's disease. That was the initial focus: to collect hundreds of people so that we could just sample their DNA through a blood test or a saliva test and describe their disorder. That took a lot of time, but we spent about 20 years collecting, throughout the UK, Northern Ireland, these samples. More lately, collecting rarer samples of people with very early onset disease, which is more severe and probably more genetic in its basis. But there's going to be hundreds of genes, thousands possibly, that could influence the disease.
Chris - And how does one connect a gene that someone carries to a disease? How do you then square that circle so you can understand what its contribution is?
Julie - So we would take an individual's DNA, and the DNA has markers throughout it that can tell you whether there is a variant that is actually that variant or something very close to that variant that is associated with the disease. So we would compare DNA from individuals with Alzheimer's and without Alzheimer's, and we would look at simple changes that can occur in one or two forms, these snips or single nucleotide polymorphisms and if, for example, people with Alzheimer's had more of the first sort of that than those without, we could say with some confidence that there was something in that region that was associated with Alzheimer's disease. It may not be that particular snip, but it may be something close to that.
Chris - So it's like a signpost that says, in this region of the genome, there is something linked to this disease. And if you have that particular marker, then probably in that bit of the genome you have something that's going to increase or decrease your chance of getting that particular condition. So look at enough people enough times with enough outcomes and you will begin to hone in on what those areas are, even though you don't have to know exactly what the gene is yet?
Julie - That's true. So what we were seeing were patterns actually that were quite surprising when we first did our initial very large, what we called genome-wide association studies - these are these big studies of all the variants that tag most of the genome - we were seeing patterns that implicated our immune system. We knew from Alzheimer's first drawings that glial cells, immune cells, were there around the damage in the brains, but we'd always thought that this was just a normal reaction to something going wrong in the brain. But what the genetics was telling us is, no, these changes in the immune system are actually part of the pathway to disease.
Chris - If you look at people who have down syndrome, who have an extra copy of chromosome 21, they also get an Alzheimer's like change in their brain, don't they? So is the same thing going on or is that a red herring?
Julie - That's a very good question. I think there are a number of components to this complex disease and the component that is probably implicated there is more to do with the amyloid pathway, if you like. And that's maybe what is common, but it's not exactly the same as common Alzheimer's disease which is contributed to by a number of different components going wrong at the same time. It's the accumulation of risk in those various areas that pushes you into a disease process.
13:11 - Julie Williams: Developing Alzheimer's tests
Julie Williams: Developing Alzheimer's tests
Chris Smith spoke with Julie Williams about promising developments in spotting the signs of Alzheimer's disease...
Chris - So there are lots of different factors happening at once. It's not just that there's one cause, although there might be in some people, I suppose, but you've got lots of different factors all playing a relative contribution. So how can you unpick, then, which ones really matter?
Julie - The secret is to try and use genetics now as a sort of platform to then understand the biology. So we look at individuals that have some of the risk factors that are involved. We are now creating stem cells that reflect the risk in those individuals, we also look at particular cells that we know express a lot of the risk factors, and one of these cells is called a microglia. This is a cell that has housekeeping properties, it has its own little patch of brain that it monitors and keeps clear of toxins or bad tissue and what we know from the genetics is that a lot of the genes that we have found as risk factors are expressed in microglia, some solely in microglia. So that's a big clue that they're playing a significant role in part of the pathway to Alzheimer's disease.
Chris - So does this mean then that chiefly this is a genetic disease, Alzheimer's?
Julie - No. Genes play a role. We look at these on a population basis, on an individual basis. One individual may have a very strong genetic contribution, another individual may have a more environmental contribution. So now we need to get down to precision medicine, a focus where we can identify people that have certain risks, certain susceptibilities, and we may have different treatments or preventions that are focused on these individuals in the future, compared to others.
Chris - How many genes, then, do you now know that strongly influence your likelihood of developing Alzheimer's?
Julie - Well, we think we are about to publish our first genome wide association on early onset. When you add those into the mix, we probably have about a hundred genes that we now know are associated with Alzheimer's disease.
Chris - And so if you took a sample from somebody and you read those hundred genes, how accurate could you be with a test for whether or not a person, that person, is going to get Alzheimer's now?
Julie - Well, we are a bit cleverer than that. What we do is we take those hundred genes and we look at all the other genes that may make a contribution, and we've created an algorithm that probably has thousands of genes involved. From that we can predict, at the extremes, with 90% confidence, whether you will or you won't get Alzheimer's disease. However, the majority of people will be somewhere in between in terms of their risk. Now that's important because, when we do find treatments, we want to identify people at the highest risk so that we can prevent the damage. That's the main, the golden aim, is to get in there before the brain is damaged. I think we can do that now but, in future, the real value of that will come when we have treatments to help people and use that information in a positive way.
Chris - That presumably gives us the 'if' you're going to get it or not, but can you say anything about 'when' yet?
Julie - That's more difficult with a number of factors that influence the common form of Alzheimer's disease. If you have the very rare forms of mutations, yes you can. I think it's going to be more difficult to do that.
Chris - But David Cameron was recently interviewed when we saw some of these new immune modifying drugs were being trialled in people with Alzheimer's disease and he was saying, pretty soon, we're going to have a test which will tell whether a person is going to develop this within the next X number of years. Is that genetic or does that look mainly at the biochemistry of the brain?
Julie - I think that probably would've been a genetic test. We've worked with a company and there is a test out there now. We wanted them to use the best information, so we gave them all our data so that we could best predict those at the extremes. But the problem at the moment is we can't offer people much to prevent that development. But I think very soon we may have more drugs, or maybe even genetic therapies in 5 or 10 years time, that can influence your risk of developing the disease that you can take at an early stage. Things are moving quickly.
17:58 - Julie Williams: Science in the public sphere
Julie Williams: Science in the public sphere
Chris Smith and Julie Williams discuss science's growing role in politics...
Chris - The thing that strikes me is that, while all this was going on in your life, in the middle of it, you suddenly depart and go into politics and you become government Chief Scientific Advisor for Wales, second person to do that job. Wasn't that the wrong time to go into science policy? Or was it?
Julie - Well, I'd just got some funding to do a big collection of early onset dementia so I knew I couldn't do a lot of the science for about three or four years until we had the sample. I wondered why we weren't doing so well in Wales with science so I thought, yes, I'll have a go, see if I can make a difference. I was lucky enough to be appointed and the First Minister said to me, 'I want you to look at why we aren't actually creating as many good scientific successes and bringing in the funding for science as you would expect from our population. Go away and have a look at that.' That's what I did, and what I found is that we didn't have enough scientists. It wasn't that the scientists were not good, they were actually punching above their weight, but we didn't have enough of them. So what I did was get some European structural money, and we were able to put about 50 to 60 million into bringing in scientific fellows and groups of scientists to come and address some of the major issues. A lot of them are still there in Wales I'm pleased to say.
Chris - How did you identify, though, that the problem was you just didn't have enough scientists? It's easy to say that, but how did you attack the problem of why Wales is lagging a bit and where the actual problem lay?
Julie - Well, we counted the number of scientists that were working in the various areas, mainly in universities. We don't have a lot of centres or institutes in Wales, and it was obvious that we were low, mainly in the more expensive areas of medical science, computing, engineering. That was the issue. That's what brings a lot of the funding into areas from those research councils and that was the problem. The way to solve it is to bring in some good scientists that could build on the strengths that we had, but produce the numbers.
Chris - Effectively be a nucleus then A nidus around which, once you've got momentum, there's embodied momentum there and money begets money.
Julie - Exactly, and strength begets strengths. This was built around the strengths that we had. We attracted some really fantastic fellows who wanted to come and work with individuals already in Wales. Also, we brought in whole groups of individuals working in certain areas and that is working. But, I must say, I would hope that that would continue on, but we need a bit more money put into Welsh science from the Welsh government, actually,
Chris - You did that for four years. Had you had enough by then or did you think, 'Right, I've done what I wanted to do.' Because as a good friend once said to me, you're best in the job in the first couple of years because after that the problem's become your friends. But what she was getting at is that you come in with a completely blank sheet, no biassed opinions, this is what I think I want to do. Is that what happened to you or did you think, 'No, I need to get back to Alzheimer's.'
Julie - Well, I think it was more the latter because, at that time, the medical research council and research charities got together and decided to put a lot more money into dementia research. I applied to host one of these centres and was lucky enough to get it. That's why I went back. So you need to invest in research to get the results and this was a great opportunity.
Chris - And your present role as the director of your institution, where does that put you? Does that put you at the lab bench or does that mainly put you in your strategic role where you can fall back on perhaps some of that politics and policy experience you had, to then guide?
Julie - I think more of the latter. I think they would ban me from the lab at the moment. That's my role, is to look at science in an overarching way, to bring people together to work more productively, to bring more funding in, but also to try and influence those that can make those decisions. That's probably what I'll do a little bit more of in the next few years.
Chris - Alzheimer's is a terrifying prospect, though, in terms of the risk to the world population. We're an ageing population, more people are making it to the sort of age where they may get Alzheimer's, so far we've dwelled really heavily on the genetics that underpin this, the mechanisms of the disease, and therefore the risk factors. We haven't talked about what the interventions might look like. Is that something that you have your eye on? Now, we're in a position where we can tell people what they're going to get wrong with them, but their next question is going to be, what do I do about it?
Julie - This is what the centre in Cardiff is focused on. So we work on Alzheimer's, Huntington's disease and Parkinson's disease. We are taking the genetic information on now to understand the disease mechanisms. One of those that I haven't mentioned is the complement system, which is about inflammation in the brain. And that is is implicated by a number of the genes that we have found. We're confident that maybe within the next five to seven years, if we can get these complement drugs into the brain, we will have some therapies there because these are already used for other diseases.
Chris - So that's Alzheimer's. What about the other diseases?
Julie - I think there are amazing things that Vincent Dion in my group is doing with Huntington's, using genetic therapies. You have biological scissors, this CRISPR technology, that can be put into each cell in the brain and reduce down this region of the Huntington gene. If you have repeats in this gene, if you have over 30 repeats, you get Huntington's disease. If you have less, you don't. What Vincent is doing is cutting that area down so that it becomes less than 30. And it's working, it's working in cells, it's working in in animal models. If that works, then that would cure Huntington's disease in a one-off treatment. So there are amazing things going on and I think genetic therapies in a different form can also be used for these more common diseases, and that's something that we are working on also.
Chris - So your hopes for the next five years?
Julie - I think we'll have a much greater understanding of the true complexity of this common disease and we will have some therapies that are, if not in the clinic, close to the clinic.
Chris - And how about a reflection on politics, policy, that kind of thing, having dabbled in that space. Any particular things you think, in retrospect, I wish I'd done that or I'm going to lobby for my successor to do?
Julie - It's a difficult thing. Getting science into politics, we need more of it. We also need to appreciate that many of the ministers and politicians that work in this area don't understand science and we need to make them feel comfortable about asking the stupid question because that's important. We need to support as well as advise I think, in the short term, until we can get more science understanding into government. Science covers every bit of progress probably that's going to come in the next 20 or 30 years. We really need to get to grips with it.
Chris - Tomorrow's World did a good job on you, didn't it?
Julie - Well, my father did probably as well.
Chris - I used to love that programme and I think nowadays we're deluged in science news, all news, but science news especially. Very accessible. But it was the go-to thing, wasn't it? It was a midweek thing that gave you a glimpse into the future, that programme.
Julie - It was and I think we need more science on television and radio and we need to try and understand it at a level that people can relate to because it's exciting. It's what the future will be about and I think people will be interested in it.
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