Short Wave - A Deeply Personal Race Against A Fatal Brain Disease

Episode Date: November 21, 2022

In the mornings, Sonia Vallabh and Eric Minikel's first job is to get their two garrulous kids awake, fed and out the door to daycare and kindergarten. They then reconvene at the office and turn their focus to their all-consuming mission: to cure, treat, or prevent genetic prion disease. Prions are self-replicating proteins that can cause fatal brain disease. For a decade, Sonia Vallabh has been living with the knowledge that she has a genetic mutation that will likely cause in her the same disease that claimed her mother's life in 2010. Upon discovering she had the mutation, Sonia and her husband made a massive pivot: They went from careers in law and urban planning to earning their Ph.D.s, and founding a prion research lab at the Broad Institute of MIT and Harvard. On today's episode, Sonia and Eric talk with Short Wave's Gabriel Spitzer about what it's like to run a lab with one's spouse, cope with the ticking clock in Sonia's genes, and find hope in a bleak diagnosis. See pcm.adswizz.com for information about our collection and use of personal data for sponsorship and to manage your podcast sponsorship preferences.NPR Privacy Policy

You're listening to Shortwave from NPR. Hey, everyone, it's Gabriel Spitzer here. We just met Sonia Valib and Eric Minnacle in our last episode, and today we're starting out at their breakfast table. Our kids are now five and two and a half, and so our morning routine largely revolves around trying to channel their, like, bottomless energy in, like, remotely the right direction.

Eric is actually our morning superhero. He gets up before anybody else. He prepares a beautiful breakfast with a novel vegetable every day. Eric, you put vegetables in the breakfast? That's next level. I know, I know. Like what? This morning was actually sweet potato greens, but we do all kinds of stuff.

Yeah. Yeah. We're serious about breakfast. And then I go in and wake up our daughter, which has to happen in like the gentlest possible way. And then we get the little guy. Usually the little guy just comes storming. out of his room and he's got these big thomping toddler footsteps and this sort of like whirlwind convenes on the breakfast table. After breakfast, it's the mad rush to get teeth brushed, shoes found,

backpack zipped. And then we head out in different directions. Now our daughter's in kindergarten. And so I walk her to her school down the street and Sonia takes the little guy to daycare downtown. And then you guys reconvene at the office? Then we reconvene. And we already have so much to debrief. And then we get down to business. Business for Eric and Sonia means running a preon science lab at the Broad Institute of MIT and Harvard. There's plenty to do, fundraising, planning, managing staff. That's on top of the actual lab work and research. We hear a lot from other PIs of research labs who say, oh my gosh, how do you guys do it?

I can never run a lab with my spouse. And I'm like, how can you run a lab without your spouse? This isn't a one-person job. This is a tag team job. The job that Sonia and Eric are tackling is a daunting one with the highest possible stakes. They need to invent a drug for an incurable brain disease before that disease takes Sonia's life. Today on the show, what it's like when your research is in a race against the clock and why these partners in both marriage and science believe they have a shot.

You're listening to Shortwave, the Daily Science podcast from NPR. Sonia Valib has a genetic mutation that makes her highly likely to develop preon disease. The disease claims Sonia's mother, Comney, in 2010. And it led Sonia and Eric to a huge pivot from careers in law and urban planning to preon science. They tell the whole story in our previous episode, in case you missed it. Anyway, we wanted to hear more about how they're approaching this personal and scientific challenge, and that's what we're in for now. It's genetic pre-on disease that we've set out to cure or develop a treatment or prevention in our lifetimes. So say more about that.

What does that mean to have a deadline and a deadline that you don't really know what it is? Yeah, racing against a clock we can't see. We need a new drug. And I think we had this, hopefully this blessing that we had enough advance notice that we have time to be ambitious about developing exactly the drug that's needed. to treat this disease with the right mechanism of action. But every day we feel that jeopardy of not knowing do we actually have the amount of time that we imagine we do. Yeah.

So my mom got sick when she was 51. And it was easy for me to sort of fixate on that number and think maybe we have 20 years to solve this problem. But like now, I have two kids of my own and I feel that I am in middle age, which is where she was. and it has changed the emotional tenor of our work for me. I think it was really easy to be strategic 10 years ago and to say we hoping, hoping like heck that we have the luxury of time. Why is Prion disease such a thorny one to tackle in terms of therapies and drug development?

What is it about it that makes it such a hard nut to crack? If you compare pre-on disease to other transmissible diseases, it's very unusual, right? Because it's not like a bacterium or a virus, right? And if you compare it to other neurodegenerative diseases, like Alzheimer's and so on, well, it's so much more rapid, right? And so I think it doesn't, it a little bit falls into a bin by itself where anything you try to group it with, it's the odd ball out. But at the end of the day, it's caused by a single gene, a single protein.

and I think the whole biology of the disease really gives us one very obvious therapeutic hypothesis, which is lower the amount of normal PRP. And I think it's only in recent years that we've started to have the drug modalities where it's realistic to go after it. So the PRP, which is the prion protein, is made by our own cells, right? Yeah, that's right. Why is reducing the amount of that protein overall a promising way to potentially slow down this disease or even stop it?

When we dig down, every case is caused by the normal prion protein, or PRP, misfolding into a prion. And there are decades of experiments showing that preon protein is essential to this process. And if you engineer animals that lack preon protein, there's nothing you can do to cause preon disease in those animals. By contrast, in an animal that did make the normal amount of preon protein, protein, you would expect that sort of prion seed that you're introducing to spread, to template other copies of preon protein, to cause those to misfold, to create this domino effect, and eventually

to develop into full-blown preon disease, and to be able to sort of pinpoint the single protein that is the fuel to the fire, and then delete it, you know, using some genetic tricks in ways that are possible in laboratory animals and not currently realistic as a therapy in people. But, you know, for the sake of the experiment, delete that preon protein, and now that animal is effectively invincible. Yeah. So what's standing in the way right now of bringing those same techniques to bear on people? The brain is a tough tissue. It's tough to reach. It's well protected. We have the blood-brae barrier that's trying to keep molecules from going. going in and out, except if they have a very special pass to do so. And I think for antisense oliginucleotides, we are the furthest along. ASOs are these basically modified string of DNA. Like you can think

of the sequence as being sort of programmed to go and find a particular RNA. And in our case, it would be the RNA that encodes the preon protein. And it goes and finds it and binds to it, and that triggers that RNA to be destroyed. So the challenges end up being around sort of all of the additional details of drug development. You know, we've been working on a preon protein lowering ASO now for six plus years, and there will be all sorts of questions that really until a human clinical trial, we won't know the answer to. So there are a lot of ways to have a good idea and still have just an incredible.

amount of work to do to execute a meaningful experiment. Sonia, do you feel like it helps or hinders to have such an immediate and life or death stake in this research? You know, in the very beginning, I remember encountering the idea that maybe we would have a quote-unquote conflict of interest. And I've come to see it exactly the opposite way. I think we are the people who most clearly lack a conflict of interest. right. We are uniquely difficult to distract. You know, we're not going to follow the money if it goes

in a different direction. And we don't have the luxury to kind of go off on tangents, much that would sometimes be really interesting to, you know, follow our curiosity into different scientific domains. We've got to focus. And we certainly don't have the luxury to continue advancing projects that we know are not going to lead to a drug. We have to be patient and enough to work within the system and bring all the right partners to the table. But we have to be no more patient, right, than is strictly required to get the job done. I think we're here to be the people who are just a little bit less patient than anybody else. That must be really hard. It's so hard. Can you talk about how this journey has

affected your relationship, changed your relationship? Anything surprising you've learned about your spouse. This is a fun question, Gabriel, because I think we noticed a long time ago that as soon as we got married, people stopped asking us about our relationship. There's this funny thing where, like, when you're dating somebody, people ask, how's it going with so-and-so? And then the day after you're married, you never get asked that question again. He's ever like, hey, how's your marriage?

Wait, why are you asking? Our marriage is great. Thank you for asking, Gabriel. It's, you know, this quest is so difficult and so draining in so many ways, but the saving grace of it is being able to do it with your best friend and the person you love, right? Like, striking out on this adventure and, you know, Sonia and I've already been together for so long and yet still every day learning new things about her and seeing her succeed in new ways. It's like so inspiring. I completely agree with that. I think it's, to me, there's just a slight.

like magic to it where we did know each other so well when we got married. Like I knew him, but there were whole facets of his personality, like yet to be unveiled by all of this hardship that I could not have guessed at. You know, I'm not a big believer that everything happens for a reason, but I am a believer that we can choose to live in such a way that nothing is wasted. And I think these years have not been for nothing in the context of our relationship and our lifelong pledge to get to know each other. Can you now walk me through your evening routine? These days we leave together. We head home. You have a little time to like recuperate. Yeah. We sort of have a little bit of a little bit

a softer transition in our current routine where maybe one of us is cooking dinner and still we can be talking about work as long as it doesn't require both people to be at their computers. So then the kids come crashing back into our lives sometime around 6.30 p.m. And from there, it's just a tornado of, you know, dinner and debriefing the day with them and sometimes, oh, God forbid, bath time and reading before bed. And we actually have a routine. teen with our kids. It's fun because, you know, I ask my daughter, what were the five good things that happened to you today? But then sometimes she'll turn it on me and say, well, you know, do you have, you know, different five things you'd like to tell me about dad? And the other day,

the response that I gave required me to explain what a clinical trial was. And I said, well, sometimes a little experiment involves mice or rats. Well, a really big experiment is when people are involved. And it takes a lot of bravery to sign up and say, I want to be the first person to get a new drug. And she jumped up on her bed and said, I want to be in a clinical trial. She's starting to get a sense of what it is we do all day, and it really inspires her. The other day she brought one of her stuffed animals and said that she had to go to work to develop a cure for the stuffed animal.

Sonia Valib, Eric Valib Minnacle, thank you guys so much for talking. Thank you. Thanks so much, Gabriel. It was really a pleasure. One little epilogue. Because of the risk of inheriting the preon protein mutation, Sonia and Eric's children were both conceived using IVF or in vitro fertilization. Each embryo underwent genetic testing and both children are negative. This episode was produced by Burley McCoy and me, edited by Giselle Grayson,

and fact-checked by Abbe Levine. The audio engineers were Robert Rodriguez, Natasha Branch, and Patrick Murray. I'm Gabriel Spitzer. Thanks as always for listening to Shortwave, the Daily Science Podcast from NPR.