Hope Is A Verb - Sonia Vallabh - A Scientist's Quest to Cure Her Own Disease

Episode Date: October 21, 2024

Meet Sonia Vallabh, a lawyer turned scientist with one of the most compelling stories we have ever heard. In 2011, Sonia was diagnosed with prion disease, a rare and fatal genetic illness with no viable treatment. Against all odds, Sonia and her husband retrained as a patient–scientists and set out to cure the disease before Sonia misses her window. Thirteen years later, they've found a way to shut off enough genetic signals to halt the disease - and save hundreds of thousands of lives around the world. Find out more: https://www.ted.com/talks/sonia_vallabh_my_quest_to_cure_prion_disease_before_it_s_too_late?subtitle=en https://www.broadinstitute.org/bios/sonia-vallabh This podcast is hosted by Angus Hervey and Amy Davoren-Rose from ⁠⁠⁠⁠Fix The News⁠⁠⁠⁠. Audio sweeting by Anthony Badolato at Ai3 – audio and voice.

Hope is a reminder. It's the fuel of your soul. It's so much more infused with action. Ability to see a much better future. You really have to earn it to have it. Hope is happiness. Welcome to Hope is a Verb, a podcast about what it takes to change the world through conversations with the people who are making it happen.

I'm Amy. I'm Amy. I'm Gus. And in each episode, we shine a spotlight on the ordinary heroes who are stitching our social fabric together, mending our planet and creating solutions to some of today's biggest global challenges. In this episode, how one woman's fight against a rare genetic disease led to a scientific mission that could save hundreds of thousands of lives. I don't think I appreciated nearly enough until I was in this is just how hard this is. Real R&D, where you're trying to take a problem that has never before been solved on Earth and come up with a molecule that is going to solve that problem,

is it's so hard. It's so impressive. I think it is miraculous that we have any drugs that work at all. We've spoken with a lot of incredible people on this podcast, but I feel like the story of how we found today's guest wins the award for the most interesting way we've tracked someone down. Gus, can you tell us how you met Sonia? I met Sonia on a bus in April this year, and the two of us were at a conference in Vancouver and it was the opening night and we had all been shipped up to a cocktail party in the hills at a fancy mansion. It was one of those events where the furniture is fabulous, the food's incredible, and the conversation is terrible. After an hour or so of standing around and trying to be interesting,

we were all shepherded back onto the bus. And I sat down randomly next to this person. And the two of us got chatting. And over the course of the next half an hour between the hills of Vancouver and downtown, her story unfolded. And it was just one of the most compelling things I've ever heard. It made a huge impression and is something that I'm still thinking about today. Sonia was diagnosed with a genetic disease called prion disease and it's something that affects hundreds of thousands

of people worldwide. She was diagnosed back in 2011 And her response to that disease was to retrain as a biomedical scientist to see if she could form a team to actually try and solve that disease and find a cure. And her husband has come along for the ride with her. It really is an incredible story. So when I got back to Melbourne, I called you straight away and I said, Amy, we have to get her on the podcast. And I'm so thrilled that we finally are able to share our conversation with her. Sonia, it's so great to see your face again. The last time we saw each other was in Vancouver at

the TED conference and your TED video has come out since then. So congratulations. It's great to have you on the show. It's great to be here. That was certainly a memorable few days in Vancouver. Sonia, what is giving you hope right now? Oof, a lot of things. Right at this exact moment, I've been riding a real wave of energy around the intersection of what is possible in the sort of biomedical research space and what is possible among the tools that we might apply to our problem, which is trying to develop a therapy for prion disease, but also sort of across the board, the tools that are coming online. We've been on this sort of constantly accelerating technological journey, which is amazing. But I feel that there's an intersection in my life

right now between the tools and the people. We are so lucky to be running a lab of fantastic people, to be collaborating with people who are as in it as we are. That's a really special thing, right? Like biomedical research, very particular, whatever, but whatever it is that you do, to be in it with people who are as in it as you are, I think that is like hope incarnate to me. When you say that the technology, the power of those tools has been improving, does it feel different to the way it did, let's say, five years ago or even a year ago? Oh, I think so. Eric and I left our old careers and started retraining as scientists 12 years ago. Genetically targeted therapies was a very new area. The idea that you could

know the gene that causes a disease, this had been around for decades, and yet it had not been leverageable into therapies that went after exactly that gene. And we're living in that era now. It's all kind of happening in real time. The number of tools that can go after, whether you're going after the DNA or you're going after the RNA, but in this very targeted and sequence-specific way, is exploding. We live in this world that traverses many domains. I think there's sort of the technology developers who, you know, they have engineering minds and they are always coming up with the next great thing. And then there's a whole spectrum between those folks and the neurologists who are actually seeing patients.

And we have to hold hands with the technology developers and walk all the way together through the many steps that lead you to that clinical person who's going to put a drug into a person for the very first time. What I am always trying to be mindful of is how much it takes to make that whole journey. The momentum can feel phenomenal at the front end, but you're going to need more than an awesome idea. And as important as it is to have those breakthroughs,

there's going to be a ton of stamina that you need to sustain the boring parts of that journey and the tedious parts and the bureaucratic parts and the slow parts. You have to slog across that desert if the thing you made is ever going to help a patient. Sonia, finding a therapy for prion disease is not just your day job and your professional work as a scientist. It is also very much a personal mission. Can you take us back to the beginning of this story and the events that led you into this work? Absolutely. Not that long ago in the real reckoning of time, I was on a totally different career path. I was training as a lawyer.

My husband, Eric, was training as a transportation engineer. And in 2010, my mom unexpectedly got ill, but she didn't get ill in the way I was used to thinking of people getting ill. Instead, she had this confusing, seemingly disparate set of things that were coming up. Like her eyesight was unexpectedly worse than usual. She was losing a lot of weight rapidly for no apparent reason. She was kind of like looking into these things, but nobody was panicking until she started to experience a confusion that I now identify as dementia. But I didn't have firsthand experience with dementia at this point. And so it just seemed like reality wasn't quite sinking. I would talk to her and she would begin a sentence and not be able to get to the end of it without sort of losing her train of thought. The first conversation I had

with her where I really noticed this, I turned to Eric after and said, something's really wrong. Then the wrongness just continued to compound at a rate that was really hard to believe. She lost so much muscle mass that she couldn't stand up, but she had also become so confused that she couldn't remember that she wasn't supposed to stand up. So someone literally had to be with her at every moment. It is so not a one-person job to care for one person who can no longer care for themselves. job to care for one person who can no longer care for themselves. It was a many-person job to bathe her, to feed her. It was June when she sort of went into hospitals, more or less back-to-back until the end of her life. She had a living will that said that she didn't want to be kept alive with a terminal diagnosis, but we still didn't have a diagnosis. And when I look back on those months, it was very difficult to

reach a sort of family consensus in the absence of any information. By fall of that year, I had started to feel really strongly that even though we didn't know what was killing her, she had walked so far out of life that it would not be a favor to her to seize upon a diagnosis or some sort of intervention and ask her to walk back in. That just seemed like too much of a mountain to scale. And it wasn't until December when we got a preliminary diagnosis of prion disease, which is universally fatal, that we were able to reach a consensus to take her off of life support. Prion disease is not something that we hear about a lot. For anybody who hasn't heard of it before, can you tell us what it is exactly? Prion disease is ultra, ultra rapid once it happens,

and it's neurodegenerative. So you're losing neurons, you're losing your connections and your literal brain cells that make you who you are. And from first symptom to death in this disease, the average is five months. And we talk to people all the time who say, oh my goodness, five months sounds long compared to what I experienced because that five months retrospectively counts back to a first symptom that probably at the time you did not think was the first symptom of a fatal disease. It's virtually a lightning strike. Basically, you have a disease where one of the body's own proteins is capable of going rogue and creating a domino effect where it grabs other copies of itself and converts those. And it could be, other copies of itself and converts those. And it could be, in most cases, we think it just spontaneously goes wrong, basically bad luck. But in some percentage of cases, you have these variants in the prion protein gene that predispose that misfolding to occur at some point in your

life. Thank you for giving us this context, which leads me into my next question, because I mean, the grief of your mum's passing was enough to carry. And I have no doubt that just that experience rearranged you in all the ways. And these things tend to split your life in half, you know, it's forever before and after that event. But for you, a year later, there came another turning point. I think in your TED Talk, you called it the letter from the future. Yes, exactly. You know, I naively imagined that this chapter, as confusing as it had been, was behind us. And then in 2011, the news came to me through my dad that my mom's autopsy had shown that her disease was not just prion disease, but genetic prion disease. And that I

was at 50-50 risk of having inherited the causal mutation in the prion protein gene. So yes, it really was a moment when your life splits in two. And I think for me, that split happened when my dad told me I was at risk, not at the moment when I got my genetic test result two months later. A certain door had been closed to me just in the moment of learning about my risk. And I'm sometimes asked, like, why get predictive genetic testing when a disease is untreatable and there's nothing you can do? Isn't ignorance bliss? But I think the ignorance is bliss chamber had already been closed off to me. So my options were live in limbo or find out. But the living in limbo, I think to this day, was the most excruciating part.

There was no place to rest in terms of your assumptions about the future. And therefore, it kept moving around on me, like 50-50 feels a little different every day. So to me, it was pretty instantaneous that I knew predictive genetic testing would be the right choice for me. So we sort of set about trying to figure out how to get this information

that had been in every cell of my body since I was conceived. It wasn't so easy. Actually, there are a lot of people who are positioned between you and that information, which was a bit mind-blowing in itself. It was December of 2011 that I got my predictive test report and learned that I had inherited my mom's mutation. A lot of people react to a diagnosis by going out and immersing themselves in research and getting more information. I understand that maybe you go out and you start learning more about the disease and then one thing leads to another, then you find out more and more and more, but not many people go and retrain as medical scientists. So why did you guys do that? Where did that come from? It's one of those areas in my life where I feel like I can't take a lot

of credit. In the immediate aftermath of getting the test report, there were a couple weeks that were shaky, for sure. I functioned in those first few weeks by drawing a bubble around the present day and saying, I'm no more likely to die in the next week than I was before I got this news. And that bubble could sort of slide with me as the days progressed. There's a lot of literature out there on this sort of adaptation, but it was super surprising to live it and to realize that I could adapt to the new configuration of the furniture in my mind so quickly because it was only maybe three weeks after my test report that a friend came over and he was a scientist friend.

He came over with a thumb drive with articles about research into prion disease. And there was a bit of like a pulling back of a veil between what we had experienced in the clinical landscape of my mom's illness, which was this is happening ultra fast. It looks incredibly dramatic. How could people not know what it is? And then realizing that in the research world, there were people who cared about this rare disease and thought about it every day. And totally unexpectedly to me, that became the locus of a certain positive energy that catalyzed a series of events that led to us changing jobs, retraining in science, and now running a lab to try to develop a therapy for prion disease. retraining in science and now running a lab to try to develop a therapy for prion disease. That's where my brain wanted to be. And I could feel that really clearly. I left my job and I thought, I'll take a sabbatical and I'll learn more. And I would just go to classes, some of which I signed up for properly and some of which I just walked into. I would introduce myself to the professor and explain why I was there. And God bless them.

Nobody ever said, you can't sit in this class and learn everything you want to learn. It was really not long after that, that I was chatting with a TA for my night class in molecular biology. And I was saying to him that I hadn't taken biology since college. And I think I asked him, do you know of a lab where I could volunteer? I don't think I knew I was going to ask that until we were in this conversation. And he said, this lab at Mass General Hospital is looking for a technician. Apply, tell them why you want the job and why you can do it. So I did. I got that job.

And I started going to work in a lab every day. And I loved it. Part of what happens, I think, in these moments where your life is completely disrupted is that you have a certain freedom to do things that don't make any sense. We don't usually give ourselves that freedom. So I was doing this. And then Eric says, I feel like I'm getting left behind. He decided to make a switch. He already had a sort of computational skill set and ported it over to a job in bioinformatics. So we both had these jobs in science and we did them for about two years. And along the way started a nonprofit and he was in a human genetics lab. I was in a Huntington's disease lab. These were relevant topics and skill sets, but they weren't pre-on disease. So we kept thinking

seriously about what it would mean if we can make a life in science. How could we take that next big leap and look to direct that life in science at exactly the problem we think needs to be solved? that life in science at exactly the problem we think needs to be solved. And this, I think, is a calculus that's different for every disease. We know a lot of super activated parent scientists, patient scientists, people who've come into their disease landscape in different ways and have found different things to be the critical piece that's missing. And for our disease landscape, actually for our rare disease, a surprising amount was known. There was already a patient advocacy group. There was already a

biobank. And it seemed that what was needed were people to sort of stand on that and say, maybe we have enough to stand on what we know and reach for a rational therapy. How to then put that into action was a whole different question. But after a bunch of like surveying the options, we decided to do this really immensely risky thing, which was enroll in a PhD program and just try to find people who would bet on this vision that we had. We were so lucky to find them right here at the Broad Institute where we still are. Some of the people who like made this place what it is were willing to bet on us as entering PhD students, a husband wife team with these super unconventional backgrounds and this super clear mission.

No one here had ever worked on pre-on disease before but they resonated with something about our vision and we've been here ever since. Everybody will have a health crisis at one point in their life. Both you and I have been through ours. So to listen to someone that is given a diagnosis like this and to have a response that is now going to potentially help so many people. You know how there is that saying that if you don't have your health, you've got nothing. And yet here is a person who uses it to do something extraordinary.

And I find so much hope in that one action in ways that I've never thought about having hope before. I find so much hope in that one action, in ways that I've never thought about having hope before. I think anyone who has ever come anywhere close to this field understands that you don't just wake up one day and try and cure a disease. This is an almost impossible task, and it is something where you're not just battling against biology, you're also battling against bureaucracy. The hurdles that you have to jump through to make

sure that everything that you're doing is safe, in addition to all the scientific challenges, just makes it something that most people might spend some of their lifetime contributing towards, but it's not something that you do in 10 or 15 years. And yet here, Sonia and her husband are leading a team of people that are getting pretty close to cracking the problem. And they've done it in such a short space of time with such clarity of purpose. I find it truly remarkable. It's been more than a decade since all these big events happened. But obviously in that subsequent decade, a lot of things have happened as well. And so your mission has shifted along with a wider shift in the field that you work in.

Can you please share with us maybe one, and this might be naive in understanding how science works, can you share like one eureka moment in like the last five years that you and your team have had? Sure. Many of the things that we have helped to move forward are things that we expected to work. And we've been very, very lucky to have that expectation come true. We have the orienting therapeutic hypothesis in the lab, which is that our goal is to lower the amount of normal prion protein before it goes wrong. So the formation of the first prion, the amplification of those prions as they multiply, and then the neurotoxicity that kills neurons, this one protein, PRP,

underpins each of those phases. So we had a vision that this was the thing we could make progress against in our lifetimes so we've now been collaborating with a company called ionis pharmaceuticals our first conversations were 10 years ago and it was in 2017 that they were sending us mouse versions of a drug type called antisense oligonucleotides, ASOs. And the mechanism behind these drugs is that you dial in a sequence and that sequence will go find the prion protein RNA and bind it, hybridize with it, and cause it to be cut up into pieces. And then you'll have less prion protein that ultimately gets made. So the fact that ASOs could work this way was known, but we took these molecules, we put them into the mice. And I remember the control animals died on schedule, the treated animals were still alive, and those survival curves were separating.

We would go for mentorship meetings with Eric Lander. And every time I would print out the survival curve and that line of surviving animals would be a little bit longer. And every time we would like rush to his office and put it on the table and say, look at this. It is simultaneously a eureka moment and scientists holding hands across disciplines and generations. Like it is so not our eureka moment exclusively. All of those things had to convene to make it possible for us to do this experiment and get this result and feel like we're on to something. But really this whole sort of invisible team is on to something. When I think of you in the lab, it's almost like seeing two people.

There's the scientist that has all this drive to create something that is potentially going to save hundreds of thousands of people. And at the same time, there's a wife and a mother who is living with this jeopardy in a very real and personal way. And I'm interested how those two parts of you interact day to day. That's a great question. You know, I think I wear many hats, but I kind of wear them all on top of each other. When I think about what our drugs need to do,

not just for me, but for the other people in my position, what do these drugs need to do for these people on behalf of their kids, on behalf of their partners? Do we want to be waiting until we have no choice, but to stabilize these people in a state of dementia where the relationship that their family members have to them is one of intensive caregiving. You know, sometimes I say this and I'm like, this is just common sense. No one needs to hear this from me. And yet somehow the world does need to hear from me

that that is not our highest goal as makers of medicines. And I think we all know that. We all know that. What is one thing that you wish more people knew about what it takes to actually get a therapy into patients and actually start changing people's lives? One super basic thing that I don't think I appreciated nearly enough until I was in this, is just how hard this is. I have so much appreciation for everyone at every step in this process because it is just a nearly impossible job to make a drug. And sometimes it seems to me that people are quite angry

at drug companies across the board. But I think there's a lot of distinctions in there that get lost in the public dialogue. Real R&D, where you're trying to take a problem that has never before been solved on earth and come up with a molecule that is going to solve that problem, is it's so hard. It's so impressive. I think it is one of those areas in life for me where I find it to be a bit spring-loaded. The more I understand how difficult something is, and there is all of this weight around it where you could start to get bogged down and think, God, this is impossible, and I'm losing hope, and I'm becoming cynical. But the more of that there is, the more there is this countervailing force, which is feeling how

miraculous it is that anything ever works at all. I think it is miraculous that we have any drugs that work at all. But something else I think about a lot is we have a call to look around and say, what would be not just statistically significant result, but a result that we would be happy to come home to? And I think about my mom's illness. If a drug had been available to sustain her in that state, I don't think she would have wanted it. And I don't think I would have wanted it for her. Atul Gawande is one of my favorite thinkers on this subject. And I just recently reread Being Mortal. And I think he beautifully speaks to the need for all of us to think about what a good day looks like and what we are deploying medicine to preserve. We are having this conversation in middle to late 2024.

Where are things at right now and how are you feeling about whatever's coming next? right now and how are you feeling about whatever's coming next? So at the very, very end of 2023, the antisense oligonucleotide work went into human clinical trials for the first time to lower the amount of prion protein in prion disease patients. So there's 11 clinical trial sites live right now across the world and patients are receiving this drug. We won't know probably until next year at the earliest how it's going. And I have come to appreciate how much in that long schlep to the clinic compared to 10 years ago when we were having that first conversation with Ionis, so many more ideas out there of how to lower the levels of one disease-causing protein in the brain. The maneuver is to put a ton of energy and a sort of guarded optimism into this first drug,

where I am confident that we'll learn a lot. I cross all my fingers. And I also acknowledge all of the ways in which it is difficult for this drug type to reach all of the neurons in the adult human brain. You really do need to think about the different modalities that you could bring to bear, the different things that each one could teach you and the ways in which by putting many horses into the race, we can hope that something gets there. This is just a comment because I know Amy wants to ask you something, but I feel like this is kind of a metaphor for solving problems more generally, this idea of guarded optimism. You say, I have the solution.

I think it might do something. I'm not too sure. I know whatever happens, we're going to learn something. And all of this is about moving in one direction, but we're not hanging our hopes too much on one specific intervention. Anyway, I just need to get that out of my brain. Amy. Perfect segue into my question. Thanks, Gus. Sonia, what does hope mean to you? And has it changed over the last 13 years? Absolutely. I think there was actually kind of a pivotal role of false hope. In the early days,

when we were very naive and approaching the scientific literature with untrained eyes, it's easy to find reports in any disease that say X, Y, or Z is promising and deserves further study. And then you look at the date and you're like, oh shoot, that was 10 years ago. Like, where's the further study? A big part of those first couple years for us was developing the sort of sharpness of focus that could help us understand what really had legs and what was an experiment that someone had done in a lab that was not going to be a drug. And yet, the more I came to understand how many things don't work, the more amazing it became to me that some things do. There's so many ways in which we're lucky to

be fighting this fight at this moment. The world has shifted such that the very crisp genetic definition of our disease is an asset. And it means that we're a good match for some of these technologies that are themselves very crisp and precise. The thing that surprises me most about all of this is that we have real jeopardy. We happen to be at this moment where it is narrowly imaginable that we will solve this problem in time for people who are in my position, for like my cohort. And I just find that very narratively surprising, but here we are. I would say arguably the most hopeful thing someone can do is to start a family. And you started a family during this journey. This is something that you and I have spoken about before. What is behind that decision? And when you and I have spoken about before. What is behind

that decision? And when you and Eric were exploring that as a possibility, how did your condition come into it? We'd actually both had this thing in our heads that we wanted to have two kids. And I now think, God, you had no idea how hard it is to have two kids. How do people at an age where they don't know anything about anything have such specific visions? Anyway, one thing I remember, someone must have said it extremely early in our sort of like genetic testing journey was that it was possible to have kids through IVF with pre-implantation genetic testing so that you would actually create embryos in a dish, and then you could actually biopsy those embryos to test for a single gene mutation.

I think both in our heads, almost right away, assumed that that was something we would at least try to do. I would never say that it was easy. Ultimately, we went through 12 cycles to have our two kids. In 2017, we had our daughter, Daruka, and then in 2020, we had our son, Kavari. Nothing is bulletproof. Like nothing in biology is completely 100% for sure, but we have as much reasonable confidence

as people could have that they don't carry my mutation. It has never been a secret from them what we do or why. What it means to them will keep shifting but I didn't want to build into our lives a sort of trapdoor moment where they would suddenly come to know like a terrifying secret. My dad had no choice. That was thrust upon him and he had to have a conversation with me,

which was the revelation of a terrifying secret. I like the fact that the kids know what we do and can appreciate in whatever ways they can appreciate sort of the seriousness that we bring to it. I have the two most humbling jobs in the world, which are science and parenting. And I just, I can't believe how hard it is every single day. I'm like, I just can't believe. They're good kids.

They're a lot of trouble. Which is exactly what all good kids should be. Yes. I will be walking away from this conversation with so many little gifts, which I really want to thank you for. I've got to say though, as I was doing the research for our conversation, there was this question that kept coming to my mind and it's a little left field. As a culture, especially in the West, we really struggle with finding the right things to say when somebody is going through a hard time, whether they have lost a parent, whether they

have just been given a diagnosis. Throughout your journey, are there any words or any language that you've learned that perhaps we can use when someone in our life is going through a tough time? Without grievance at this point, I do remember unhelpful things that were said. And I totally get it. People were very unsettled by these big changes. But what's been helpful all along is having people just ask, what's this been like? Or what is this like for you today? And just listen. I remember things that weren't direct structured conversations in the way we're used to them. People sending me poems or going for walks or just being present. Sometimes just sending me stories about their own days

to remind me that I hadn't been excommunicated from the regular world, that they didn't consider me untouchable because I was in such unique emotional territory. We were connected and daily life was also still happening and I still cared what was going on with them. When my mom died, I was 25. And I didn't have that many friends who had lost a parent. When I got my genetic test report, I didn't know anyone who had been through something similar. Although now, by virtue of the life we lead,

I know a lot of people who've been through something similar. One side of this coin is, I think more people become familiar with intimate loss as we go through life. I also think that we become more comfortable with all of these things being our unique, whatever, platter of experience, right? And just less self-conscious about the ways

in which our lives aren't shaping up into an expected shape. I read a lot of poetry. I read poetry every day. Part of that is looking at the edges of language for these experiences where our standard uses of language don't totally cover them. I don't know if that answered your question at all. It answered it beautifully and I love this idea of as a response it doesn't have to be linear. Yes. It just has to be inclusive. You know, I think it's common in this day and age for people to say that one person can't save the world.

But Sonia's story shows us that that's not actually true. One person who inspires people around them can solve a disease. And what is particularly special about this is that that solution comes from a moment of personal crisis. Someone who is facing the worst news of their life that would cause most people to shut down instead steps up to that challenge in a way that is going to change the lives of hundreds of thousands of

people going forward into the future. That is incredibly inspirational and a good reminder to my inner cynic that anything is possible when someone puts their mind to it. If you want to find out more about Sonia and watch her incredible TED Talk, click on the links in our podcast notes. We'd like to thank our paying subscribers for making projects like this podcast possible. If you're interested in finding out more about our work, check out fixthenews.com. There are a lot of podcasts out there. It means a lot to us that you chose this one. This podcast is recorded in Australia on the lands of the Gadigal

and the Wurundjeri and Woiwurrung people. If you enjoyed this conversation and would like to support Hope as a Verb, make sure you subscribe and leave a review. Thanks for listening.