The Life Scientific: Sonia Gandhi

0:00Sonia Gandhi:This BBC podcast is supported by ads outside the UK.

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1:03Sonia Gandhi:Hello, today we're talking about the fastest growing neurological condition in the world. Parkinson's disease is a progressive neurodegenerative disorder that causes tremors, stiffness, slowness of movement, leading on to serious cognitive problems. There are treatments that can help manage the symptoms, but no cure yet. Already around 11.8 million people are affected by the condition worldwide, and that number is forecast to double by 2030. Although not if today's guest has anything to do with it. Sonia Gandhi is a clinician-scientist specialising in neurodegenerative diseases, specifically Parkinson's.

1:43Sonia Gandhi:As Professor of Neurology at University College London and Assistant Research Director at the Francis Crick Institute, she uses stem cells to build models of the human brain, helping to drive the development of drugs and other therapies for Parkinson's patients. Crucially, Sonia's work also explores how and why this disease comes about, so that by better understanding it, finally we might find a way to stop it. Professor Sonia Gandhi, welcome to The Life Scientific. Thank you for having me. Can you give us a picture of what exactly is going on in the Parkinson's brain and the range your symptoms?

2:19So you explained it very well, but at the time that I might see a patient with Parkinson's, they would have presented with a movement disorder. As you said, tremor, stiffness and slowing of movements. And what's happened in their brain is that there is a circuitry that consists of neurons and those neurons control movement by secreting a chemical called dopamine. and those dopamine neurons start to first become dysfunctional and eventually die. Now it's also worth highlighting that before the movement disorder sets in, in the 10 or 20 years prior to that, people will also have other symptoms, losing their sense of smell, constipation, depression and a sleep disorder.

3:05And in those years we know that the process of Parkinson's is just beginning but it hasn't yet caused those dopamine neurons to degenerate or die.

3:14Sonia Gandhi:But those are really sort of general symptoms that could be symptoms of all sorts of other problems or conditions. That's true, they are common symptoms. And there's something very specific about the combination of them that can lead at some point to Parkinson's disease. And whilst that can raise alarm bells and anxiety, it means that that phase of the disease, we call it as clinicians, the prodrome is an opportunity where we could intervene early before those dopamine neurons have died. Because at the time that someone presents, nearly 60 to 70 % of that part of the brain has degenerated and we can't bring that back.

3:51Sonia Gandhi:And then what happens once the disease sets in? So Parkinson's is a progressive condition. And as well as that prodromal early phase, there's then the motor phase where an individual will suffer from the movement problems. And then over the next 10 to 20 years, they will develop non-motor symptoms. And they include cognitive decline, difficulties with memory. They can also include some psychiatric features with the onset of hallucinations and difficulty with controlling the sort of automatic functions of the body. So control of bladder and bowel and blood pressure. I also mentioned in the introduction that it's the fastest growing neurological disease in the world.

4:29Sonia Gandhi:Why is that? We are really struggling to understand the exact reasons for this. But the strongest belief is that we're an ageing population and Parkinson's disease increases with age and age is a major risk factor. And also our environment is changing all the time. And we know that part of the risk to Parkinson's is mediated by our environment. So there are risk factors in the environment that are constantly changing. And we think also that may account for why it's rising. Do we know what fraction is inherited genetic and what fraction is environmental conditions? So there are a small proportion between 5 % or 10 % that we call familial Parkinson's, and that is where a single mutation in a single gene that can run through families is the driver of the condition.

5:13Much more commonly is what we call sporadic Parkinson's disease, where there's no one single genetic factor. Now, of the sporadic Parkinson's, there's also a genetic risk to having the condition.

5:24Sonia Gandhi:A predisposition. A predisposition, just as the risk for many common diseases high blood pressure, asthma. And that, we think at the moment, accounts for around 30 % of the risk. It's what we call the heritability of Parkinson's. And then we have this large other number, something like 70%, which is thought to be either the environment or the way that our genes, our genetic makeup interacts with the environment that then contributes to the rest of the risk. So basically, it's not just because we're living longer. It's not just because we're living longer. So right now, how do we treat Parkinson's?

5:57Well, we understand that the motor problem is related to a lack of dopamine in the brain. So we treat Parkinson's by giving back dopamine. And that certainly does improve the motor symptoms early in the condition. So when we're not using a drug that restores dopamine, we might use something called deep brain stimulation, which is where we can implant electrodes into the deep nuclei of the brain and stimulate that same circuitry.

6:21Sonia Gandhi:Many people will have seen this footage of the patient whose brain is being electrically stimulated. and seems to instantly stop the tremors. You know, the hand that's shaking hand becomes stable. But that's not the broader fix, is it? No, because as the condition progresses, many of these interventions become less effective because they're now working on circuitry that's really deconstructed. And of course, the other thing it doesn't do is prevent the spread through the brain of the condition. None of the treatments that we have at the moment can slow down the condition, let alone stop it or reverse it.

6:56Sonia Gandhi:It's obviously an extremely complicated condition. And we're going to hear more about your research into it shortly, Sonia. But I wonder, what is it that drew you to working on neurodegenerative diseases in general and Parkinson's in particular? Well, I'd always known that I wanted to study the brain. And within that, there's a sort of plethora of possibility. So I think from a clinical perspective, I wanted to do something that was addressing a really large unmet need. and then on the scientific side, you know, I like the challenge, the challenge of a very complex set of conditions that we really knew very little about 20, 30 years ago and really be part of that process, being able to understand the condition using good neuroscience and then actually make an impact to patients' lives.

7:41Sonia Gandhi:Well, as you say, you do clearly love a challenge as well as the research itself and I know your parents have been a big influence on you. So let's hear a bit more about them. First of all, how they met, which I gather was a bit of a whirlwind story. So back in India in the 1960s, my father was travelling through the region Varanasi where my mother lived, was introduced to my mother. She had just completed her studies and they were engaged, I think, within a few days, married, honeymooned and then in the UK within 12 days. Wow, within 12 days of actually meeting for the first time. Absolutely, yeah.

8:20Sonia Gandhi:And they're both scientifically minded. Your mum's a biochemist, your father's a recently retired GP. Yeah, they're both the first in their families to pursue university studies. And my father studied medicine in India. And my mum was very keen scientist, but also she's a very strong willed and determined person. And when she wasn't allowed to travel for her studies, she went on a hunger strike until she was allowed to take on a PhD. By her parents. By her parents. So she eventually took on a PhD and studied bichemistry. And I think it was very much her curiosity that I remember growing up and her clarity of understanding, I think, shaped me as a child.

9:05And I think my father, because he just worked so hard. And he worked also for social causes. He was really interested in setting up healthcare for the homeless population. He won an award for that. And he worked until 83. So his work ethos, combined with my mother's quick thinking and intelligence, were both big influences on my grown-up.

9:25Sonia Gandhi:Not surprising then that you've ended up with a successful career. Well, Sonia, you were born in Cardiff in 1975 and grew up there with your parents and two older siblings. How do you remember your childhood? It was a happy childhood. I was very well looked after. From quite a young age. I was put up several years at school. So I ended up being very young for my peer group, two years younger. At what age? At five. Oh, okay. Amongst kids two years older than you, that's a big difference. And I think that meant that I was stretched intellectually, which was great. But I think I realised early on, I thought quite differently to people.

10:04And then I certainly looked different to everybody. And so I definitely felt different. And I mean, I think differences weren't celebrated in the same way as they are now. And so I certainly became a bit shy and just kept my head down really and went through those years enjoying learning, but really kept my thoughts to myself.

10:24Sonia Gandhi:You've described yourself as quite a geeky child. Did you enjoy your school years? I did. I particularly enjoyed, there was three years during which I was catching up these years that I'd skipped and I went and joined my brother's school. And actually, in those years, I had a lot of fun and I really settled into being me. Well, Sonia, in 1992, you went to study medicine at the University of Cambridge and went on to do your clinical studies at the University of Oxford. From there, you moved to London to study neurodegeneration at UCL's Institute of Neurology. We're going to get into some of the science now, Sonia.

11:00Sonia Gandhi:And I want to make sure we have it in perspective because we still know comparatively little about the brain. Why is it such a difficult area to study? We know very little about the human brain because the human brain is very, very unique. Its complexity is unparalleled. So we have around 80 billion neurons. Each one of those might have thousands of connections. and we're trying to understand that complexity using quite traditional techniques that struggle. The second problem is that we normally understand biological processes by building models or looking at model systems, but there's no very good model system for the human brain.

11:42So animal brains are very, very different and it's very difficult to build a model of the human brain because what do you build it from? And then I think the third big problem is one of scale. So we're not very good at visualising and seeing small events at the nanoscale.

11:58Sonia Gandhi:So things that are going on inside the cell. Exactly. Right. And these challenges form the backdrop for your PhD research, which asks the question why Parkinson's might occur in an individual's brain. Where we'd understood up to that point was from a very interesting observation made back in the 1970s where a group of young people, six or seven, developed Parkinson's. And an astute neurologist at the time had gone to look at why these young people had all presented with the same problem. And it turned out that they were substance abusers and they had used a designer form of heroin contaminated with a chemical.

12:39That chemical, it turns out, it's called MPTP, gets metabolised inside the dopamine cells of the brain and affects one single bit of the brain that we call the mitochondria.

12:51Sonia Gandhi:And mitochondria, these structures within the cell, are basically the energy source, the battery that powers things, if you like. That's right. So mitochondria produce energy and it allows an organism to increase in size, in complexity, become multicellular. It allows a neuron to be specialised in all of its functions. And the brain, being this immensely complex network, consumes about 20 % of the body's energy requirements. And so what was observed was that if you poison the mitochondria and stop it producing energy, then people could develop a condition that looked just like Parkinson's. From then, a whole area of research recognised that mitochondria might be one of the origins of Parkinson's disease.

13:36So what my PhD was focused on was a gene had been discovered that encoded a protein that also went to the mitochondria and therefore a defect in the way that mitochondria might work was now a genetic cause of Parkinson's.

13:51Sonia Gandhi:So a mutation in a gene means that it doesn't produce this protein and this protein then can cause problems in the mitochondria. That's exactly right. And my job was to figure out how. This is summer at its peak. Whole Foods Market Summer Fruit Fest is your invitation to eat the season. Fresh, organic and bursting with flavor. Start your day with peaches and organic blueberries and yogurt. Build a grazing board with fresh fruit, prosciutto and artisanal cheese. Then fire up the grill with no antibiotics ever proteins and fresh produce. Savor the season. Shop Summer Fruit Fest at Whole Foods Market.

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15:02Sonia Gandhi:Well, after finishing your PhD, Sonia, you continued your training to become a specialist in neurology. You also married your husband, Nick, and over the next five years, you had your three daughters. Now, one thing that family life and a medical career have in common is that they're both utterly relentless. How did you find those final years making it to a consultant alongside being a new mum? So it was a tough time because the mental load is very high as well as being kind of physically tiring. And I guess that's the time that I learned to stop worrying about failure and start building a lot of resilience.

15:38Sonia Gandhi:On the research front, you started running your own lab. Your group started taking cells from patients to generate stem cells and turning them into brain cells, neurons. How does that work? So this is based on a Nobel Prize winning technology where it was discovered that you could take a skin cell from a patient and give it a cocktail of factors that basically reprogram it. We wipe its skin cell programme and we turn it into a cell called a stem cell. Basically rewinding, turning the clock back so this specialist cell becomes non-specialist. Exactly. A specialist cell that can't be anything else becomes what we call a pluripotent cell.

16:19It's capable of being any cell in the human body. And then we also devised ways that once you have the stem cell, you could then give it various molecular cues, if you like, to tell it to become the type of cell that would go to the brain. And then within the brain, the type of cell that would go to the midbrain. And then within the midbrain, the type of cell that would become the dopamine neuron that is affected in Parkinson's disease. So it's a remarkable technology. it's allowed us for the first time to take an adult and make a model of their human brain cells in a dish that we can then go on to study.

17:00Sonia Gandhi:So how were researchers studying Parkinson's before you came up with this way to generate lab-grown models of the human brain? They were largely using animal models and where we were using human cell models, they've come mainly from the cancer field. So they grow very rapidly, they divide very rapidly, you can use them easily in culture. They were human, but they were more indicative of cancer processes. Now, bear in mind, a human neuron never divides. We're born with a set that have to last 80 or 90 years. So that is very different to model in a dish. So our models were really unsatisfactory.

17:38Sonia Gandhi:And once you've created these brain cells, you wanted to find out more about the origins of Parkinson's by studying the protein buildups in the brain that cause the disorder? That's right. So what we do know is that regardless of whether somebody has a genetic form of Parkinson's or a sporadic form of Parkinson's, everybody develops these abnormal protein inclusions in the brain. And what that means is that we can have a protein, in this case called alpha-synuclein, and it can adopt lots and lots of structural conformations in solution. By which you mean it can sort of fold itself up in different shapes?

18:15In different ways, or be unfolded. And it can develop structures when it binds with membranes. But in disease, what happens is it begins to self-assemble and join other alpha-synuclein molecules. And then eventually what they do is convert into structures that are insoluble. And they are what we call the protein clumps that are then deposited inside neurons. And what we hadn't been able to do was ask why and where do they first form in the decades before somebody comes to a doctor with Parkinson's disease.

18:47Sonia Gandhi:Right. Before the clumping. Before the clumping. So you develop techniques to actually see these tiny proteins in the brain from the moment they start to go wrong. How does that work? So out of the whole population of protein that we have, only about 1 % is actually misfolding or clumping. So we have two problems, that the clumps are very small when they first form and that they're rare. So we've used two approaches. One is single molecule imaging and the other is super resolution imaging. So we pass the entire cell through a single molecule microscope and we study each protein one by one. Now doing this in the human brain, you have a lot of background noise from the rest of the brain tissue.

19:33do. It's a bit like trying to see the stars during the day. They're there, but of course you can't see them. So the first thing we had to do was try to reduce the contrast, make it night, for example. So we did that by using a set of methods to reduce the autofluorescence that was coming from the brain that was contaminating our signal. And then the second way was to amplify the signal itself. So the objects we're looking at, because they're so small, are dim. And so we had to capture as much light as we can. And so we use some very powerful microscopes to do that. And that combination then allowed to see these very small objects inside the human brain as well.

20:09Sonia Gandhi:So the idea is that you're shining laser light into the brain, and that light, that energy excites all these cells, and then they release that energy. And it's that released energy, that released light that you want to capture from those particular proteins that are malfunctioning. That's exactly right. And that was quite a big breakthrough. I mean, these new insights into where and why proteins malfunction started to help drive new treatments. Yeah. So we've had since that time a lot of interest on the industry sector, on people who are already trying to slow down the clumping of the protein in different ways.

20:46But now they were looking at it a little bit differently. And I think we helped in that journey show that that was going to be a relevant place to intervene.

20:56Sonia Gandhi:In 2017, you joined London's brand new biomedical research centre, the Francis Crick Institute, alongside your role at UCL. What did that mean for you? So what moving to the Francis Crick Institute and that opportunity gave me was coming into very close contact with many other different disciplines that would become very important for the biology we were studying. Immunologists, people who do metabolism, cancer biologists. And then the Crick ethos is very much about discovery without boundaries. And that's a really important backdrop to all of our work. And it also meant that when COVID-19 hit in 2020, the CRIC was ideally placed to offer support.

21:38Sonia Gandhi:In fact, you were asked to lead their pandemic response. Yes, I wasn't naturally, I think, a leader. But certainly the work we did in the pandemic sort of propelled me into taking large responsibilities and leadership positions. So together with the other clinician scientists who were based at the Crick, together, we essentially turned the Crick into a testing institute for especially the period of the first lockdown and began testing. And we had to develop a lot of those technologies to test at scale. We also had to interface with the NHS. So we were testing staff. And then shortly after that, we became a vaccine centre as well.