EP. 138: RACING THE CLOCK TO CURE PRION DISEASE

WITH SONIA VALLABH

Nov 17

WITH SONIA VALLABH, PHD

A biomedical researcher describes what it was like to watch her mother succumb to rapidly progressive dementia due to prion disease, and her race to discover a cure for this mysterious entity — before it begins to afflict herself as well.

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Episode Summary

One of the most mysterious and frightening entities in medicine are prion diseases — rare neurodegenerative disorders that are usually infectious in nature but involve not bacteria or viruses, but proteins. Prions are misfolded proteins that can induce normal proteins to become misfolded as well, resulting in a chain reaction that leads to irreversible brain damage and death. What makes prions alarming is that they are incurable, can incubate for decades in a person's brain without symptoms, and are usually associated with 100% mortality within months to a few years.

Sonia Vallabh, PhD was a recently-married lawyer in her early career when she witnessed her mother's baffling sudden health decline and death. Her mother was ferried from hospital to hospital, yet dozens of doctors could not figure out why she was seemingly succumbing to rapidly progressive dementia at the age of 52. It wasn't until after her death that Vallabh discovered the cause was a genetic prion disease. Subsequent testing revealed that Sonia Vallabh herself had inherited the same genetic abnormality. Determined to find a solution, Vallabh and her husband Eric, a transportation engineer, decided to retrain as biomedical scientists in a race to cure her before it grew too late. The couple now leads a prion research lab at the Broad Institute at MIT and Harvard. They are also the co-founders of the nonprofit Prion Alliance.

Over the course of our conversation, Vallabh opens up about what it was like to accompany her mother in her last months of life, the psychological toll of dealing with a fatal medical mystery, how she lives each day with an awareness of how ephemeral life is, what prion diseases are and what makes them so difficult to treat, what makes her optimistic about the future of her work, and more.

Sonia Vallabh, PhD co-leads the initiative to develop preventive drugs for prion disease at the Broad Institute. She comes to this work with a personal mission. In 2010, Vallabh watched her 52-year-old mother die of a rapid, mysterious, undiagnosed dementia. One year later, Vallabh learned that her mother’s disease had been genetic prion disease, and that she herself was at risk. Vallabh underwent predictive genetic testing and learned that she had inherited the causal mutation, placing her at very high risk of developing the same disease. There was no prevention, treatment, or cure available. Vallabh quit her previous career in law and consulting, and, together with her husband, Eric Minikel, re-trained as a scientist in order to devote her life to finding a way to stop her disease before it starts.
At the Broad, Vallabh is focused on developing preventive drugs for prion disease. Lowering of prion protein (PrP) is a genetically well-validated strategy for delaying the onset of prion disease, and it lends itself to measurement of PrP as a biomarker available before the disease process has begun. Vallabh is working on the discovery and preclinical development of PrP-lowering drugs, credentialing of PrP in cerebrospinal fluid as a pharmacodynamic biomarker for such drugs, and establishment of a clinical pathway for preventive drug development. She co-leads a natural history study at Massachusetts General Hospital devoted to the assessment of fluid biomarkers in individuals at risk for genetic prion disease, and helped to launch the Prion Registry to promote and enable research participation in her community.
Vallabh holds a B.A. from Swarthmore College, a J.D. from Harvard Law School, and a Ph.D. in Biological and Biomedical Sciences from Harvard University. She trained in Stuart Schreiber’s laboratory at the Broad. In 2016, she served as a patient representative in the White House Precision Medicine Initiative. Her story has been told in The New Yorker, NPR, and WIRED.
In this episode, you will hear about:
• 3:23 - Vallabh’s early memories of her mother and the devastating experience that overcame her at 52 years old
• 16:37 - The process of grieving the loss a parent
• 22:32 - What prion diseases are
• 25:35 - How Vallabh made the decision to undergo the genetic testing that confirmed she inherited a mutation thah causes prion disease
• 36:27 - Vallabh’s major career change to become biomedical researchers
• 45:50 - Where the quest for an effective therapy for prion disease currently stands
• 52:08 - Vallabh’s message to listeners on how to approach life
Henry Bair: [00:00:01] Hi, I'm Henry Bair.
Tyler Johnson: [00:00:02] And I'm Tyler Johnson.
Henry Bair: [00:00:04] And you're listening to The Doctor's Art, a podcast that explores meaning in medicine. Throughout our medical training and career, we have pondered what makes medicine meaningful. Can a stronger understanding of this meaning create better doctors? How can we build healthcare institutions that nurture the doctor patient connection? What can we learn about the human condition from accompanying our patients in times of suffering?
Tyler Johnson: [00:00:27] In seeking answers to these questions, we meet with deep thinkers working across healthcare, from doctors and nurses to patients and healthcare executives those who have collected a career's worth of hard earned wisdom probing the moral heart that beats at the core of medicine. We will hear stories that are by turns heartbreaking, amusing, inspiring, challenging, and enlightening. We welcome anyone curious about why doctors do what they do. Join us as we think out loud about what illness and healing can teach us about some of life's biggest questions.
Tyler Johnson: [00:01:02] One of the most mysterious and frightening entities in medicine are prion diseases. These are a group of rare neurodegenerative disorders that are usually infectious in nature but involve not bacteria or viruses, but proteins. Prions are misfolded proteins that can induce normal proteins to become misfolded as well, resulting in a chain reaction that leads to irreversible brain damage and ultimately, death. What makes prions alarming is that they are incurable, resistant to usual disinfection methods, can incubate for decades in a person's brain without symptoms, and are usually associated with 100% mortality within months to a few years. Sonja Vala was a recently married lawyer in her early career, when she witnessed her mother's baffling sudden health. Decline and death. Her mother was ferried from hospital to hospital, yet dozens of doctors could not figure out why she was seemingly succumbing to rapidly progressive dementia at the age of 52.
Tyler Johnson: [00:02:03] It wasn't until after her death that viola discovered the cause was a genetic prion disease. Subsequent testing revealed that Sonia Vala herself had inherited the same genetic abnormality. Determined to find a solution, Vala and her husband Eric, a transportation engineer, decided to retrain as biomedical scientists in a race to cure her before it grew too late. Ten years later, the couple now leads a prion research lab at the Broad Institute at MIT and Harvard. They are also the co-founders of the nonprofit Prion Alliance. Over the course of our conversation, Vala opens up about what it was like to accompany her mother in her last months of life, the psychological toll of dealing with a fatal medical mystery, how she lives each day with an awareness of how ephemeral life is. What prion diseases are and what makes them so difficult to treat. What makes her optimistic about the future of her work and more. Their journey from personal tragedy to scientific pursuit is the epitome of resilience and hope, and is an inspiration to clinicians, scientists and patients alike.
Tyler Johnson: [00:03:17] Sonia, thank you for taking the time to join us and welcome to the show.
Sonia Vallabh: [00:03:22] My pleasure.
Tyler Johnson: [00:03:23] So we usually start by asking our guests to explain to us how they became a doctor or in your case, a research doctor. And I want you to tell us that story. But given that that story comprises a lot of what we're going to talk about today, I want to sort of take it step by step. And so to get us there, eventually we will talk about that in full. But to get us there eventually, I was hoping that you could start by talking to us about your mom and specifically, what do you remember about your mom from when you were little? What do you remember about the way that she was a presence in your life, about the person that she was, and sort of how she engaged with you in the world?
Sonia Vallabh: [00:04:04] Sure. She was a really devoted mom. I think being a mom had been a big dream of hers for a long time, and she had some really lovely sort of artistic talents that she was super generous with. We made a lot of art together, but also she drew really lovely portraits, and even when my friends came over for play dates, she would like find a moment to sit them down and do a charcoal sketch of them and send it home with them. She was a wonderful hostess and cook, and part of, you know, the sort of like magic of childhood as I remember it, is that the house was full of people all the time, and people like locally. This was neighbors and friends. This was the Indian American community, which I grew up in western Pennsylvania. So you had to kind of like draw from the wider surrounds, but also like, you know, extended relatives who would just come and stay in our home for a year or two. So it was sort of a home with porous boundaries, and she was the hub of that.
Tyler Johnson: [00:05:08] That's so lovely. Well, so in your Ted talk, you begin by referencing this sort of very brief, beautiful episode with your mom, I believe maybe at your wedding. But then very shortly thereafter, things begin to very dramatically and very painfully change. So can you talk to us a little bit about what was the change that you saw overcome your mom? What happened?
Sonia Vallabh: [00:05:37] Sure. So this was about six months after my wedding. So this was in 2010 that my mom went from being a healthy 51 year old and, you know, healthy with normal ups and downs and fluctuations, but, you know, high, high functioning to suddenly having a sort of raft of miscellaneous symptoms that didn't seem like a huge deal. Honestly, she was losing weight. It was weird. She was having blurry vision. But these were things that either didn't seem worth raising to a doctor or like, I think she saw an ophthalmologist because this seems like maybe an eye thing. And that sort of randomness persisted only for a few weeks, because it started to emerge that there was some larger coordinating thing that was going wrong. And the way that sort of announced itself to us is that she started getting very confused. It was remembering things, but also just getting communication out suddenly wasn't a natural thing. She would begin sentences and then trail off. She would forget what she'd been saying. There was like a sudden vagueness to everything. And this again was only the status quo for maybe, you know, a couple of weeks before she was so both confused and uncoordinated and had lost so much weight that even activities of daily living were an emergency.
Sonia Vallabh: [00:07:09] They were becoming impossible. She couldn't feed herself. She couldn't get around the house without assistance. And in this phase, a number of short term hospitalizations started happening just on the basis of acute things. She would fall and she'd hit her head, but she wouldn't be able to tell us, you know. Does it still hurt or are you seeing stars because she was too confused. So it would become, you know, we go in, we get a scan. She had aspirational pneumonia because she was having trouble eating properly. So that became a hospital stay. So all these like side things, you kind of end up going on these side quests that, you know, you have to resolve it in the moment and it draws your focus. But it's not the bigger thing. The bigger thing is like, well, what the hell is this? What's going wrong at the center of this?
Tyler Johnson: [00:07:56] I have to say that from an internist standpoint, who has spent many years working in hospitals taking care of patients, they're hearing you tell the story in some detail is so disconcerting to me for the follow. I mean, for many reasons, but one of the chief reasons is because when I hear you tell this story, this sounds actually really recognizable to me as a very common thing that happens when someone is about 87 years old, right? Yes. The whole kind of like, well, they're kind of in and out of the hospital and, and you can't really, like, put your finger on a particular like, yeah, there's these little things like, yeah, they fell or yeah, now they have an aspiration pneumonia or whatever. Like those things are sort of like little things that pop up here and there, but you can tell that they're not getting to the core thing. But for many people who are in their late 80s, then eventually it becomes clear that either this is just a function of sort of the normal winnowing process of aging, right? That their body is just sort of in a slow arc of deterioration.
Tyler Johnson: [00:09:00] Or sometimes it will be that there is an underlying, you know, they have Parkinson's disease or they have Alzheimer's disease or they have something, but those are things that generally, you know, maybe in someone's late 70s or maybe into their 80s. But the other thing about most of those diseases is that if you talk to a family member and you really get them down to where they can be transparent and think about things holistically, then they will say, oh, yeah, actually, now that you mention it, we've noticed that these changes have been ongoing for five years or whatever. Yeah, we just had sort of been like, you know, moving things around in such a way that we didn't have to bring them to anyone's attention. But now we're ending up in the hospital. But all of that is just to say that there's something very, almost sort of haunting about hearing this same story, except that it's compressed into the course of a couple. Of months in a person who's barely 50 and who was perfectly healthy six months before.
Sonia Vallabh: [00:09:59] That's exactly it. It was eerie, and it felt a lot like watching a time lapse video of someone aging. Just the pace of change, like I think, you know, in general, we go about our lives not expecting that everything could completely change in a day or a week, but it can. It did for us. So that was just shocking, right? That was just an existential shock. But the other thing that was equally shocking, but then I was very naive, was that the presentation, what was happening could be so dramatic, so dramatic to look at and to experience day to day. And yet no one could tell us. No one could tell us what it was. And we, you know, rushed her around and we got a bunch of tests. I feel like she was getting blood drawn constantly. She got CSF drawn. She got scanned. We did all the things, but we did not get a diagnosis in her lifetime.
Tyler Johnson: [00:10:54] And can you just tell us a little bit? And I know you you sort of referenced this briefly before, but it will be important as part of our later discussion to just highlight and explore this a little bit. So, you know, as you describe, you first of all are used to this mom who is sort of the hub of the wheel, right? You have family members who are coming in and out of the home that you're, you know, sort of gathered in Indian American community coming in and out of the home, and you're having social events and you're having this and that. And then to go from that to a person who, over the course of a couple of months, enters into this state of, as you put it, vagueness, where she can't even, you know, finish a sentence or she's, you know, unsure of exactly who she is or who you are or sort of what you know, is even going on in the world. And this all as your, you know, I mean, I'm putting words in your mouth, I guess. But in one of what I have to imagine was one of the most exciting times of your life, right? You've just gotten married. You're starting a new life together. You're sort of, you know, whatever. What was it like psychologically and emotionally to have this? You know, from what I gather, this sort of anchor in your life who was just kind of rapidly it was like they were being erased in front of your eyes. Like, what was that like for you?
Sonia Vallabh: [00:12:14] Um, I mean, that's a perfect way to put it. It was like she was being erased. And I think it's not flattering to reflect on, but part of what went on for me psychologically was just a very, very strong feeling, like a voice in my head screaming, this can't be right, because I had had the good fortune up until that point in my life to live a pretty narratively cohesive life. Not everybody has that good fortune, but I, I had it, you know, and this was my first experience with a completely unexpected, unexplainable like, just like a shattering of, like what you thought you had. What I thought I had was this home base, right? This stable place. But suddenly it was being, um. Yeah. Erased.
Tyler Johnson: [00:13:09] Yeah. You know, it's such an interesting thing, I think, to reflect on, because I've become convinced that one of the overriding rules for our emotional well-being in life is that how happy you are is what you expected, minus what you got, right?
Sonia Vallabh: [00:13:25] Absolutely.
Tyler Johnson: [00:13:26] And so if you're in a place where you can, you know, and I think that's in a funny way, almost even more true, or it's somehow accentuated in a period like the period right after a wedding. Right. Because almost by definition, yes, there is a part of a wedding that is backwards looking in terms of appreciating your courtship and whatever. But for the most part, a wedding is inherently forward looking, right? Yes, it is like your community coming together in effect to celebrate the life that you are committing to make together, right? Which is just to say that I think, you know, most people on a day like that, it is about sort of imagining a narrative for the rest of your life. Right? And, and if you're thinking of having children, which I know you you later did, you know, then it's about, oh, thinking, you know, what is my mom going to be like as a grandma? And how like, what is it going to be, you know, like, am I going to be my own hub of activity the way she was and have her over to the parties at our house, the way that she had, you know, family members over to parties at our house. And it is almost by definition, this beautiful, hopeful act of future projection. Right?
Sonia Vallabh: [00:14:37] Absolutely. Yeah. I'm a big crier at weddings, even when I'm a very peripheral guest. I'm like the person who's crying the hardest. And I think it's exactly that. It's exactly what you just said, that it's this moment of coming together out of, like the hecticness of daily life and like taking a pause to look towards the future with hope. It's so beautiful to me. Right.
Tyler Johnson: [00:14:58] And actually, I just officiated a wedding at a wedding a couple of weeks ago, and I'm standing there, the couple standing in front of me, and then the audience is seated behind them. Right. And what is so beautiful to me is that, in effect, that's what the people who come are doing, right? It's like a it's like an act of community solidarity in projecting the future and sort of saying we, your loved ones, will be here with you to celebrate and protect all of these milestones that are to come right when you know, for whatever anniversaries and if you choose to have them, the birth of babies and all the rest of it. All of which is just to say that I can only imagine that when you're in that state of, you know, almost enchanted future projection to then just have this, you know, have it's like the cart is going off of the road and into this ditch. Had to just be truly devastating.
Sonia Vallabh: [00:15:54] Yeah. And I think in some ways, had I had a less fortunate childhood, I would have been better prepared for something to go so dramatically off track. But there was just a whole lot of like in addition to mourning my mom in this ambiguous and complex way, because was she still there? To what degree was she still there? Was there like a chance of her coming back? I didn't know enough about the brain at that time to conclude as early as one might that there wasn't a chance. And, you know, in the absence of information or diagnosis, it was like super divisive in my family. Is there hope? Is there not hope? But yeah.
Tyler Johnson: [00:16:37] Well, so then over the course of, you know, this very brief time, as we alluded to before, it is as if your mom is progressively erased and then eventually, in pretty short order, she dies. Yeah. So maybe talk us through a little bit. What was that like? And then once that happened. So then I'm sure that, you know, at least part of that was this desperate desire to know what in the heck was going on. Then what happened in the days and weeks after that? And where did that leave you?
Sonia Vallabh: [00:17:13] Yeah. So her whole illness unfolded over the course of maybe nine months, which half of that was life support. And I look back on that with a lot of regret because she very quickly in the course, it was not apparent that there was anything to her experience of the world except suffering anymore. And in that time that she spent in hospitals and long term care facilities, there were months and months where really her main reaction to the world was sort of flinching as people came over and over and over to needle stick her. She got to a physical state where she had, like, terrible myoclonus. She was like clenching her hands all the time. She was tensing all her muscles. She was writhing. She had to be restrained. This was like. It was like unbearable to look at. And I will say, and it took me a long time to be able to say it, but I now see this as important to share, because maybe other people can relate to it, that after that just total dark confusion and all of that suffering that we watched when she passed away, what I mostly felt was relief. I was so glad that she was no longer in that state. And we were, I think, under the shadow of that for a long time. I took years and years to grieve her illness. And like the trauma of the way she died and the trauma of the mistakes that we made, and I had to come out from the shadow of all of that in some ways, in order to begin grieving her like the person who she'd been.
Tyler Johnson: [00:19:02] Yeah, I know as a doctor who takes care of a lot of patients who end up dying. I know that one thing that can be really complicated for family members is a sense of relief at the end of suffering. But I think to your point, there is nothing unloving about being glad that a person you love is no longer suffering. Right. And obviously, we could get into complicated ethical questions that are sort of, you know, around some of those lines. But I think that those aside, I think it's just the case that it is enormously Emotionally, psychologically difficult to see a person that you love suffer. That is just that is always going to be true and exactly what that means and what you do with that. And obviously there's a lot of complicated questions about that. But I think that that is correctly affirmed from my point of view as a person who's seen a lot of families go through that. So then though, in addition and, and I should say also to that, to your point, you know, one of the things that had to have been so difficult about this was that it was almost like you lost her twice, both of them equally difficult and both of them equally unexpected. Right. Because you lost her first as you watched her be erased, and then lost her again when her body stopped functioning. And in both of those cases, it was shocking, inexplicable, bizarre. And I don't mean to overdramatize it, but it sounds like a horror movie, right? I mean, you could imagine why. 2000 years ago or whatever, people would have believed in a person becoming possessed. Because how else would you explain something like this? Right. Like, it's. So forgive the word, but it just sounds so. Not that she was, but the thing that happened to her was so grotesque. Yes. So demonic. Seems like an almost an apropos word because it's like this, you know, beautiful. As you use the word in your Ted talk, luminous person who is then overtaken by this sort of distorting, warping force that nobody can even explain to you. Right?
Sonia Vallabh: [00:21:09] Yes.
Tyler Johnson: [00:21:09] But so then you get postmortem testing done and autopsy and whatever other kind of testing that flows from that. And then what did you all learn?
Sonia Vallabh: [00:21:20] We learned that she had died of a genetic prion disease, and the possibility that she had prion disease had come up a couple times in her illness. When she died, she had a preliminary diagnosis of prion disease, but the idea that it might be genetic was a total total shock. And partly, you know, prion disease isn't usually genetic. So that was just like numerical. But there also wasn't a family history. And I don't think after doing some digging that it was just sort of obscured and not talked about. Both of her parents lived long lives. They had a lot of siblings who lived long lives and died of other causes. Some of them, you know, stigmatized. And we've talked about that. But no one died of neurodegenerative disease. So, you know, my best working hypothesis at this point is that she was a de novo, and it has to start somewhere. And maybe it started with her, but at the time, it was just completely shocking to learn, as I did in Let Me See. October 2011, that she had died of a genetic disease that was autosomal dominant and I was 50 over 50.
Tyler Johnson: [00:22:32] So let's back up here for a second, because there's quite a bit of, you know, we have people who listen to our podcast who span everything from not being involved in medicine at all, all the way through to attendings. And they're probably, you know, some neurologists, which is to say, I'm sure there are many people who know a lot more about this than I do, but probably also a number of people who know less. So, you know, prion disease, even as a person who has been an internist for many years and has taken care of a lot of people with various forms of neurodegenerative disease, I think it is true that I have maybe once, I'm not sure once or never taken care of a patient with a prion disease, though I have invoked it in differential diagnoses sometimes and have read and thought and talked about it. I had a friend, actually, whose mother died of a prion disease, but and for those who may be listening, the most infamous form of this is mad cow disease, so-called mad cow disease. But let's just talk about, first of all, what is a prion and what is prion disease.
Sonia Vallabh: [00:23:32] Sure. So a prion. The terminology is so unfortunate, but it's what we're stuck with. So we all have a normal protein called the prion protein. That's not normally a problem. It hangs out in the body. We all have it actually all mammals have it. But it's got this unique ability that has actually like, you know, a bunch of Nobel Prizes to its name at this point, which is that that protein, which has a normal shape, can misfold into a different shape, and that is now a so-called prion. The misfolded form, in turn, is sort of self templating. So it can go around grabbing normal copies of normal prion protein and misfolding those. So you get a bit of a domino effect and it spreads across the brain and it kills neurons. So that's basically the phenomenon behind every case of prion disease, be it in humans. And there are different names for different subtypes or in in animals such as in the mad cow example.
Tyler Johnson: [00:24:34] Got it. So, you know, most people to the degree that they have heard about this at all. The reason that they have heard about it is because it pops up in the news every once in a while, right? And almost always, the way that it pops up in the news is that either. So, like, you know, people may know, for example, that when you go to give blood, there are special questions about when was the last time you were in the UK and how long did you spend there. And largely the reason for those questions is because that was the sort of the epicenter of this for a time. And so what will often happen is that you'll read about, oh, you know, there was a person in such and such a state or such and such a country who was there was concern about this. They were wondering if this is what happened, or there was a case that was confirmed. And then when there is a case that's confirmed, then they have to do this whole sort of like, you know, tracing and figure out where did the beef come from. And then there's like a recall. And anyway, it's a whole thing, right? It's taken enormously seriously. But all of that is to say that that's almost always the language around this has to do with that stuff, right? It has to do with, you know, agricultural policy and whatever.
Tyler Johnson: [00:25:35] And so I will say that I didn't even actually know until listening to your Ted talk that there is such a thing as a genetic form, a genetic predisposition or something. Sure. That I would have imagined. But a genetic form in and of itself I wasn't aware of, let alone an autosomal dominant one. So. Right. So the moment I can only imagine the moment that you find out, you know, that this is what your mom died from, you find out in that same moment that you have a 5050 chance of having that same genetic predisposition, and that if you have that genetic, you know, this is not like a thing where, oh, you might have a gene that will just hide out and never do anything. But you find out that if you have it, presumably the I mean, I don't know how definitive the information is about it, but that presumably you would have this sort of a like a ticking time bomb in your own brain waiting to go off at some point. So I'm curious, at the moment. And, you know, this is all happening, as we said at the beginning, in the first year or so of your marriage, at the moment that you find that out. What was it like to wrestle with the decision of whether to be tested yourself?
Sonia Vallabh: [00:26:43] You know, I've come to appreciate that I'm at an extreme end of a big spectrum, but for me, it wasn't a decision. I wanted to get tested as quickly as I could. And the main reason I think it's how I'm built, I would rather know than not know. And I think something that was very clear to me about my own brain at the beginning was that we had crossed the threshold already, where I knew about my risk, and that was going to be taking up a certain amount of my brain. Did I want that brain to be flipping the coin every day and thinking, well, do I have it, do I not? I might, I might not, or did I want to get the test and then see what the next phase holds in terms of what that part of my brain is doing. And a big part of feeling like it was it was the right thing. Was that my biggest concern? You know, after learning about my own risk, like instantaneously, my biggest concern was a my dad, who's the person who had been carrying this information since getting the autopsy report and needed to relay it to me and B Eric. And there was a 5050 chance that I could make a choice that would reveal to all of us that they didn't need to worry. So if there was a chance of sort of like, you know, cutting it off, that seemed worthy to pursue. And on the flip side, if this is a thing that I was going to be worrying about anyway, might as well worry, because there's a reason to worry and not because you're worried. There's a reason to worry. So anyway, to me, it was a no brainer. That doesn't mean that it was easy, actually. So we went through a whole circus of doing all the things to do all the things to do, all the things to get tested. But then at the end of that year, we got my results.
Tyler Johnson: [00:28:34] So I think that you are right, that it is. I don't mean to trivialize it at all, but it almost sounds like a like a made up scenario from a philosophy class, right? Right. Like, if you had this situation, what would you want to do and why? Right. It sounds like an essay for a final of a, like a college level philosophy class. And I think in a sense, it is. I mean, it largely rests upon your philosophy of life as much as anything, right? Like, it speaks in a very deep way to how you want to approach things. So, for example, it's very telling to me that such a large part of your motivation for making the decision that you did had to do with concerns for your husband and your father, right? And thinking about kind of how would the not knowing impact them, and how would the knowing impact them? Right. And and figuring that into your calculus. So you make the decision and then it sounds like it was not you know, it wasn't just like 23 and me spit in a tube and send it off to the mail. Right. It sounds like it was a relatively involved process, but between the time when you gave whatever the blood sample or spit sample or whatever it was, and when the result actually came back, what was that like?
Sonia Vallabh: [00:29:54] Completely surreal. But, you know, I think the surreality, if that's a word like kicked in, like as soon as I found out I was at risk and like actually giving the sample to get the testing was just part and parcel of a season that felt completely disconnected from everything around us and actually very like, consistent with that general feeling of like sort of being on a different plane and seeing everything sort of through glass or like down a long. Tunnel. We hadn't taken our honeymoon immediately after the wedding because. So many relatives had come from India and faraway places we just wanted to be with. Everybody. And we sort of postponed it, and it ended up falling in that window of time. We. Went to Japan, me and Eric. And there we were like quite literally in a place where we were. A completely separate little, you know, two person entity in a place where we didn't speak the language and didn't know anybody. And in some ways, it was a huge relief to not be faking full integration with our daily life and to just be living a literal version of our feeling of strange, you know, dream like isolation.
Tyler Johnson: [00:31:10] Yeah, I can only imagine. I mean, it is such a strange thing. I, you know, I remember Abraham Verghese in his novel cutting for Stone. So cutting for Stone is this story of these two brothers who both grow up to be physicians, and one of them is a surgeon and one of them is an internist. But in the novel, one of the brothers has the ability to smell death when it's coming. And I write, and when I first read that, I read it. I think as an intern, when I first read it, I remember thinking that that struck me as very strange and sort of unimaginable. But then as I have gone through my life as a doctor, it actually now is like, I get it, and I almost kind of feel like I have that ability a little bit. But the reason that I say that is because when I'm taking care of cancer patients, it is often the case that, you know, obviously we never know with any detail or precision or certainty, but it is often the case that we kind of know with some forewarning, right? Like, you know, we can sort of see the way that things are going on a scan or the way that the blood tests are looking or whatever the thing is. So the reason that I bring that up is just to say that it's one thing when you've already had to deal with the, you know, you were probably feeling sick for a while and you were probably looking for a diagnosis, and then you finally got one. And then that led to this, and this led to that. And like, there's this whole sort of train of events. Right. But the thing that is particularly bizarre and surreal about your scenario is that you're feeling totally fine. You just got married and your mom had been feeling totally fine, right? Like, yeah. And so to be waiting for that kind of a test result in a scenario where you are indistinguishably healthy from any other person on the street, had to just be almost like it feels almost psychologically impossible to imagine.
Sonia Vallabh: [00:33:16] Yeah. And there was an irresistible pull during that time towards magical thinking. I think that like 50 over 50 is tough. That's like really tough for the brain. And one of the the tricks that the brain tries to do is to like, read little omens into everything. And I was like, I don't want to spend the rest of my life like trying to read the tea leaves of like, you know, all the little things that happen. I could just get this information. So like that. Also, that whole experience of limbo really, like solidified me behind the choice to get tested.
Tyler Johnson: [00:33:52] Well. And I have to imagine the other thing that my brain would do if I were in that scenario is come up with all sorts of bargains that I could make, right? If I am the nicest person on the planet for the next month until the test result comes out, then I can probably push it to like 6040 or something, right? There would be some I don't know. I don't know what the number would be, but I have to imagine there would be some idea that you could somehow like, you know, kind of tilt the balance or something. Yeah. Okay. So then what was the result? And then what did you do?
Sonia Vallabh: [00:34:25] So I inherited my mom's mutation. That's what we learned at the end of 2011. And I mean, what I, what I did right in that moment is, you know, we just sat in the geneticists office, and Eric cried and I held him. And then we went out to the waiting room, and we had asked two close friends to come with us, and they were waiting there, and we told them what we'd learned. And then I called my dad, and he got on the next flight, and he came to Boston, and the five of us just kind of spent the weekend together, you know, quietly. We went out for dinner. We just kind of spent time together in a low key way. And I would say it was that weekend that I sort of like stepped into a new mode, which was kind of coaching myself to remember that everything I knew about my like, bodies, you know, current status was all still true. Like this information, first of all, wasn't like it wasn't new to my cells. It was just new to my, like, conscious brain. Right? It had always been there. The answer just always had been what it had been. But also all the things that I felt, you know, around being healthy and young and, you know, very fortunate. Like that stuff was also still true. And I wasn't likely to die, you know, the next day. We can't predict age of onset and genetic prion disease with any confidence. But the distribution is spread, you know, widely, but it's sort of spread around maybe 50 for my mutation, give or take, a bunch of years. I was 26, 27. This wasn't likely to strike me dead the next day. And so I would draw a little bubble around, you know, the next week. And I'd say you say, you know what? Really, odds are I'm perfectly healthy for the next week. And then as that week advanced, I draw another little bubble, right. So that was the initial experience.
Tyler Johnson: [00:36:27] You know, it's so interesting. In the course of this podcast, we so we have many people who we talk to who, you know, not nearly all, but many of our guests are doctors because we're doctors. And so we always ask them, how did you become a doctor? And often, interestingly, some part of their answer is, well, when I was little, you know, either I was sick or my mom was sick or my sibling was sick or something. And, you know, there was something about that experience that catalyzed me to want to go into medicine. But I have to say that usually, you know, there's a lot of distance between the thing that happens and then a bunch of stuff, and then you kind of think about it for a while and then whatever. But in your case, so to be clear, you're a grown up at the time that this happens, right? You already had an established career as an attorney. And and your husband was, I think, some kind of an engineer. And and so you guys are well established in your careers and your and you, you know, have been now it's maybe been two years or whatever that you've been married. And so you're kind of like getting ready to or not getting ready to you are living your lives. And then what did you guys decide to do?
Sonia Vallabh: [00:37:31] Well, this for me is like a really humbling experience of not being able to predict what you will do around the next bend when you have more information, when things look different, like what will you do? I couldn't have told you. How would our lives change depending on the test result? But what ended up happening is that a friend, Stevie Steiner, a friend of ours who was living here in Cambridge, a scientist at the time and still came over to our house and said, researchers are working on this. You guys should read these articles. And he had a thumb drive with him, and my initial reaction was to draw back a bit and to be like, oh, like we're grieving. Like, I don't know if I want that in my house, but it was only a matter of days before we were interested enough to open it up. And there were a bunch of articles on the thumb drive. And this, I think, is where the curtains kind of parted for me because we had been sequestered on the clinical side, like our whole experience of my mom's illness had been the question of what can the practice of medicine today do for a person who's experiencing this illness? Can they diagnose it? Can they treat it? Can they do anything? And the answers had been so disheartening, right, that I think I had just internalized the belief that this this was rare.
Sonia Vallabh: [00:38:55] No one cared and no one knew anything. And to see that there was sort of a different world behind the scenes of researchers who were thinking about this like that alone was kind of a revelation. And it ended up being the seed of a larger curiosity. Well, okay, they're working on it. What are they doing? What do they know? And this became sort of a consuming hobby where we would try to learn what we could in the evenings and on the weekends. We would have our scientist friends over. They would try to help us understand stuff that was really, honestly very opaque and hard to read, and that became what my brain wanted to be doing. Again, couldn't have predicted it, but it was super clear that that's where my mind wanted to be pointed, and my interpretation of that was, okay, I need to take a little time to get up to speed. I can't probably count on a doctor to tell me if a drug is developed in ten years, so I need to be able to keep track of things myself. And that means taking a little time to build a vocabulary and to become a savvy consumer of scientific information.
Sonia Vallabh: [00:40:10] So when I left my job, that's what I thought I was doing. I thought it was a sabbatical and I started going to a bunch of classes. I started volunteering in a lab, and then I started working and this was like, you know, entry, entry level technician stuff. I started working at a lab, and I think there was a very compelling momentum to it. I was really excited. I was really excited about putting this new kind of knowledge into my head. I was really excited about what was being done around the world and getting to better understand that and calling people and talking to them. And, you know, it was sort of palpable. I think this was a way to engage an unexpected and unwanted thing that had happened to us that was positive and that was exciting. So I seized on it and so did Eric. Actually, it was like three months after I took my first job in science, he also took a job in science. He was more portable. He had like a data science background and became a bioinformatician. And at that point, I think it was clear to both of us that we weren't going back, although it really wasn't clear what going forward was going to look like either.
Tyler Johnson: [00:41:28] I mean, it's it just it almost takes on the contours of like a combination between a really, really nerdy movie about science and a superhero movie and a spy thriller like Mission Impossible. Try to, like, Disarm the Bomb before it goes off or something, right? Like, yeah, it just has this almost cinematic quality to it, right? I mean, I, you know, here you guys are, you've already sort of launched into the arc of your lives. You're kind of doing your thing as an attorney. He's an engineer. Whatever. And then you find out that you have this thing that is, you know, as best science can tell you, going to happen at some point, but you have no idea when. It could easily be decades, you know, thence. So then you start kind of learning about it and learning some more about it and learning some more about it, and then eventually end up working as a tech in a lab. And then, you know, it sounds like sort of the more you knew, the more you wanted to know, and the more you wanted to know, the more you learned. And and then it sort of, you know, turns into this kind of a virtual or virtuous, I mean, cycle. But then at that point, like, so how far did that end up taking you? Where did your where did your scientific exploits end up landing you?
Sonia Vallabh: [00:42:50] So pretty early on, we started a nonprofit called Prion Alliance. It's still around. And one like, you know, sort of model we had was, okay, we have these day jobs. They are not focused on prion disease, but we run this nonprofit. We'll raise funds, we'll try to fund research in other people's labs. This was our first way of trying to be hands on with what was happening in the prion world. But after two years at our jobs, we sort of came to a pivot point where we were sort of saying, if we can make a go of this like, you know, we're pulling in paychecks doing science, that's pretty wild. They're not amazing, but, you know, they do the job. So if we can make a go of this, then we should figure out how to focus our energies on prion disease all day. What does that look like? So, you know, going all in on our nonprofit was one model. People said to us, why don't you start a biotech? I have all sorts of answers. But that wasn't that wasn't what we ended up choosing. And then there was this sort of like high risk, high reward thing, which is we could get our PhDs. The biggest risk to me was we would need to find exactly the right place and exactly the right people, because we can't do this as sort of a parenthetical outside of the quest, as like this block of training years where we're doing something else, and then maybe eventually we get to come back to this, you know, time sensitive mission.
Sonia Vallabh: [00:44:18] The time sensitive mission is now. And if we want to make an impact, we just don't have time to be more traditional. So, you know, we talked to tons of people and interviewed far and wide and did a whole lot of feeling out. Where could our strange story possibly fit? And we're super, super, super lucky to connect with people here at the Broad Institute where I'm sitting right now, who thought that our quest was interesting and were willing to take a bet on us. So we came to broad in 2014 2015 as entering PhD students in the lab of Stuart Schreiber, also under the mentorship of Eric Lander. And you know what a tremendous act of generosity. They sort of took us on our own terms that we wanted to work on, a disease that no one at broad had ever worked on before, and we were going to find a way to do it.
Tyler Johnson: [00:45:19] And did.
Sonia Vallabh: [00:45:19] You? Uh, yeah. So we were in Stuart's lab for five years. We defended in 2019 and sort of rolled forward our own prion research lab here. And we're now 14 people focused all day, every day on developing a therapy for prion disease in our lifetimes and also building all that other stuff. You need to get to a therapy, it turns out. So the mission has enlarged itself before our eyes, but we're on it.
Tyler Johnson: [00:45:50] So I want to ask two other questions. One sort of logistical and one philosophical. And so the logistical question is, even though I have not to my memory, I think I may be very early on took care of one patient with prion disease. But because it's rare, I haven't seen it much. And I'm. As I said, not a neurologist. But I have to admit that usually when I have learned about prion disease, it's one of those things where it's almost like, you know, you come to the like basket of stuff to learn about it, and it's like kind of empty. Like there's the basic underlying mechanism. And then beyond that, like if you say, well, you know, what are potential therapies on the horizon or whatever, it's just sort of like there's just, you know, again, to my very layperson's understanding, not much there. But so I guess my first question is just to say, do you see glimmers of hope on this on the horizon? Like, do you feel like your research has made meaningful advances that have gotten us closer to that place where there would be an actual thing?
Sonia Vallabh: [00:46:49] So when I say we're on it, I mean, we're like running full force at it. And I don't know when a disease modifying and and preventive and, you know, proven therapy is going to be available to the patients who need it. But I do think we have a lot of basis for optimism. And I think that really simple underlying genetic mechanism, one gene, one protein is our greatest asset. We have years and years of data that we just inherited this, right. It precedes me and Eric showing that you really can't develop prion disease in the absence of that normal prion protein. And at the same time, you know, it's essential for disease and it appears expendable for healthy life. So I think our clearest, you know, therapeutic hypothesis, and with the best sort of substantiating evidence behind it, is reduce the amount of normal prion protein in the brain. If you came at this 20 years ago, you'd be a bit stuck there. You'd be like, all right, cool idea, bro. But we happen to be at this moment in history where the tools are being born, right? Like in the time we've been at this. The tools are coming online that can actually go after one gene, one RNA molecule and turn off on the one hand trigger for degradation, on the other hand, and what's needed right, to prove those therapies, what those modalities need as a proof of concept is a disease as simple as ours, where you just have one thing to go after and you want to go after it as hard as possible, because there's no such thing as too little of that protein. So that's two of the pieces clear therapeutic hypothesis, molecular machines that could do the job.
Sonia Vallabh: [00:48:37] And then you complete the triumvirate with delivery. And I mean God for the brain. Like not easy. We weren't given an easy task there. But again like it is literally happening in real time that good ideas are being had about how to get enough drug to the right place. And for us, the right place is all 100 billion neurons in the adult human brain. So the technologies that can do this are at these various stages of maturity. I think our job is to like marry the tools to the problem, to make a convincing case that, like, this is a beautiful way to establish proof of concept and to assemble the platter of tools that support a rigorous clinical trial. We need a target engagement biomarker. We need natural history. We need patient registry. We need genetics. We need all the things. So that is a big part of what our lab does. And the other thing we need that if it wasn't apparent to me on day one, it's because I wasn't sitting enough with my own lived experience and listening to it. But I've become just a totally passionate believer in prevention of neurodegenerative disease broadly. And I think prion disease gives us maybe the clearest case we could possibly ask for to start with. Because, as you were saying earlier, some of these things are almost like a logic problem. Prion disease is almost like the logic problem of what if you were going to be killed by a disease that was actually just a lightning strike, would you still cleave to the dogma that a person should be sick before you try to intervene? Probably not.
Sonia Vallabh: [00:50:24] Probably not. And I do think that's where we are. So for symptomatic patients who, you know, are sporadic cases, no genetic predisposition, probably just bad luck. The best we can do is to try to push diagnosis earlier and earlier and earlier. And to physicians in the audience, I would say we have a nearly perfect molecular diagnostic for sporadic prion disease, which is the RT quick prion seeding assay. You can run it at CSF on CSF samples, all you have to do is send a small amount of CSF to the National Prion Center in Cleveland. They will do the test for you. They will turn you around. Results in a matter of days. We didn't have that when my mom was sick. So I think that's that's a huge step forward that we need the neurology community to sort of rally around and help us out with. But for people with high penetrance genetic mutations that cause disease, like me, we need to assemble as a cohort ahead of time. And we need to be asking the question, could this drug prevent or delay disease in these people? And that's a really different question from can this drug prolong or arrest disease in people who are really sick? Right. Separate experiments, separate populations. Neither gating for the other. So this is a lot of what we put our energy into these days, because it's so not business as usual to be trying to make take experimental drugs forward for prevention. I think it requires a certain boldness. And, you know, I think we are in a situation where we have no choice but to be bold.
Tyler Johnson: [00:52:08] So let me with that. Then, for my final question, let me ask philosophically if you you know, there's a there is an old story about a guy who goes to the doctor, he's having some abdominal pain. He gets a CT scan. The CT scan leads to a biopsy. The doctor comes back to him after the biopsy and says, oh my gosh, I'm so sorry, but I it turns out that you have pancreas cancer and you're going to die in however long. So the guy goes through this, you know, period of intense reassessment of his life and his priorities and, you know, his decisions and whatever, and decides to become a completely new person in light of this diagnosis. And then a week later, the doctor calls back and says, oh my gosh, I cannot even begin to sufficiently apologize. But it turns out your biopsy result was mixed up with somebody else's. You have a benign tumor, you're fine, and you can just go on living your life. And now this, you know, mythical person is left with having to grapple with what to make of the priorities that he came to in light of a diagnosis that, it turns out, is not actually true. Right. And then has to grapple with. But aren't those probably actually some version of the most important priorities anyway, which you just were now gifted the site to see them, even though it turns out that the thing that gifted it to you was not actually true. So all of that is by way of saying, given that you are in, you know, sort of forever now in this state of suspended animation, in one sense, for people who thankfully have never gone through something so harrowing, what message would you bring to them, or what wisdom would you share with them that you feel like you have gleaned by virtue of this very difficult thing through which you are going?
Sonia Vallabh: [00:54:06] I mean, the way I've come to see my, you know, interesting hand of cards is that I think it is just like slightly heightened or more acute version of like the usual being human thing. And I think we're all constantly caught in this very strange relationship with time, where we imagine we have some unlimited amount of it and therefore we don't need to make changes right away. We don't need to, you know, prioritize super, super harshly. But I don't know, I think I think my, my whole thing is just it's a version of that same story that But none of us have. I mean, it's like, you know, who knows how long I'll live. I'm 40 now. You know, we'll see what we can do. But in the scheme of generational time, geological time, the difference between, you know, my theoretical life expectancy before this ever happened to me and my life expectancy, now that it did happen to me, is not very much. I think the basic premise is still the same, which is that none of us know how much time we have. And regardless, regardless, you know, like join all the gyms you want and like buy the products and like, you know, we like as a culture, we're hilarious. We do all this shit to be young forever. What does forever mean? Maybe like on the margins, another couple years. But like, we are not here forever. And I think that's kind of like the core thing about us. I remember having a conversation with my college roommate many, many years ago and I asked her, how do you think we would be different if we lived forever? And she said, we would be like trees. And when I pressed her on, what does it mean to be like trees? She said, I think that the motivation to do anything right. I mean, we would just it's really the urgency of having limited time that makes us rise to the occasion, do the things, be our best selves, understand what we love in this world, right? I think it's it's true for me, but also everyone.
Tyler Johnson: [00:56:29] Yeah. You know, it it has always struck me. I don't know if you've ever watched the Netflix show The Good Place.
Sonia Vallabh: [00:56:35] Oh, I love it.
Tyler Johnson: [00:56:36] Towards the end of The Good Place. Right. So if you haven't watched it, it's this show about these people who end up in heaven or what they think is heaven. But then it turns out to sort of be hell. And anyway, it becomes very complicated. But the point of all of this is to say that at the end there sort of, in a weird way, allowed to like, make their own afterlife. They can kind of like design an afterlife. And so the architect of the afterlife basically comes to them and says, well, how do you think the afterlife should look so that it can be really awesome for everyone? So they like, go through and do all these things to try to make it awesome for everyone. And then at the end, it's just totally not working and everyone is miserable. And then the like final thing that they figure out that they have to change to make it awesome for everyone is that it has to end.
Sonia Vallabh: [00:57:19] It has to end.
Tyler Johnson: [00:57:20] And so then there's this heart wrenching scene. Well, I won't give away the ending, but there's a heart wrenching scene at the end that has to do with the fact that it has to end in order for it to be meaningful. So. Well, doctor Sonia Vala, we are with you in solidarity, and we want you to know that we wish you all the very, very best. And we deeply appreciate your willingness to come on the program and share with us wisdom and insights that we know are so dearly, dearly One from your life experience. And we just we really couldn't thank you enough for being on the show.
Sonia Vallabh: [00:57:55] Oh, this has been a joy. Thank you so much.
Tyler Johnson: [00:57:57] Thank you so much.
Henry Bair: [00:58:02] Thank you for joining our conversation on this week's episode of The Doctor's Art. You can find program notes and transcripts of all episodes at the Doctor's Art.com. If you enjoyed this episode, please subscribe, rate, and review our show available for free on Spotify, Apple Podcasts, or wherever you get your podcasts.
Tyler Johnson: [00:58:22] We also encourage you to share the podcast with any friends or colleagues who you think might enjoy the program. And if you know of a doctor, patient, or anyone working in healthcare who would love to explore meaning in medicine with us on the show, feel free to leave a suggestion in the comments.
Henry Bair: [00:58:35] I'm Henry Bair
Tyler Johnson: [00:58:37] and I'm Tyler Johnson. We hope you can join us next time. Until then, be well.