A Couple's Quest To Stop A Rare Disease Before It Takes One Of Them | KUOW News and Information

A Couple's Quest To Stop A Rare Disease Before It Takes One Of Them

Jun 19, 2017
Originally published on September 19, 2017 2:41 pm

In 2010, Sonia Vallabh watched her mom, Kamni Vallabh, die in a really horrible way.

First, her mom's memory started to go, then she lost the ability to reason. Sonia says it was like watching someone get unplugged from the world. By the end, it was as if she was stuck between being awake and asleep. She was confused and uncomfortable all the time.

"Even when awake, was she fully or was she really? And when asleep, was she really asleep?" says Sonia.

The smart, warm, artistic Kamni – just 51 years old — was disappearing into profound dementia.

"I think until you've seen it, it's hard to actually imagine what it is for a person to be alive and their body is moving around, but their brain is not there anymore," says Eric Minikel, Sonia's husband.

In less than a year, Sonia's mom died.

An autopsy showed Kamni had died from something rare -- a prion disease. Specifically, one called fatal familial insomnia because in some patients it steals the ability to fall asleep.

Basically, certain molecules had started clumping together in Kamni's brain, killing her brain cells. It was all because of one tiny error in her DNA — an "A" where there was supposed to be a "G," a single typo in a manuscript of 6 billion letters.

Sonia sent a sample of her own blood to a lab, where a test confirmed she inherited the same mutation. The finding threw the family into grief all over again.

"But that grieving period sort of started to resolve within about a week or so," she says. "And we weren't in crisis anymore. We were finding our way toward a new normal, where this was something that we were going to have to live with and deal with and learn more about."

Today, Sonia and her husband live and work in Cambridge, Mass., where they are both doctoral students in the lab of Stuart Schreiber, a Harvard professor of chemistry and chemical biology. Over the past several years, the couple has completely redirected their careers and their lives toward this single goal: to prevent prion disease from ever making Sonia sick.

The two wear bright colors and laugh easily. When they answer my questions, they look at each other instead of at me. They like complicated board games, urban walks and efficient cooking. They are thinkers and problem solvers, which is why, when Sonia got her genetic test results, it changed everything.

The change

"It didn't happen all at once," Sonia says. "There wasn't a day when we woke up and said, 'OK let's change everything about our lives.'"

At the time, Sonia, who has a Harvard law degree, had just started a new job as a legal consultant. Eric was a transportation analyst.

But they couldn't stop thinking about Sonia's test result. They started researching prion diseases online, and invited over friends who are biologists and chemists, to help them understand the science.

"And around that time," Sonia says, "we both enrolled in night classes as well," in subjects like biology and neuroscience.

They were hungry to learn more as quickly as possible; the night classes weren't enough.

"I was basically fresh out of law school and started walking into classes at MIT during the day because this was kind of all I could think about," says Sonia, who at the time wore sneakers every day so that she could rush between work, classes, and a neuroscience lab at Massachusetts General Hospital. She'd started volunteering there, thanks to a professor from one of her classes, and mentors in the lab who helped her learn everything from how to use a pipette to how to work with human brain cells.

"And from there, this is where things happened surprisingly quickly," Sonia says.

The couple started a nonprofit, Prion Alliance, in hopes of raising money for research. Sonia left her legal job to work in the Mass General lab full-time as a technician. Then, Eric left his job and joined a genetics lab, applying his skills in coding to analyzing genetic data, rather than transportation data.

"I was getting left behind!" he says. "Sonia was out there doing all this science. It was her day job now and I was still in my old career and, you know, it was a good job and all, it was meaningful, but it wasn't the mission that it was increasingly clear that we were going to be on."

Just months after they'd finished grad school in law and urban planning, the pair went back to graduate school, this time in biomedical sciences — to study prion diseases.

"You are talking to two third-year graduate students," says Eric.

Life as scientists

The two now share an office and a lab bench, under Schreiber's supervision, at the Broad Institute of MIT and Harvard.

"There's a date in the future when Sonia will get the first dose of the drug that's going to save her life," Eric says. "What can I do today that brings that date closer to the present?"

A posted printout of an email says: "Let's just blast forward and solve problems as they become real and as they need immediate solutions." It's a note Schreiber sent the pair at one point when they were worrying about bureaucratic hoops they had to jump through.

"I thought it was a good philosophy, so we printed it out and put it on the wall," says Eric.

Sonia and Eric are "the best of humanity" Schreiber tells Shots. "Their story is, of course, remarkable, and they personify the concept of patient–scientists. But their deep understanding of science and ability to innovate and execute on one of the hardest challenges in biomedical science are breathtaking."

Schreiber says that his lab, like many others in biomedicine, has long included researchers who are physicians as well as scientists; that dual training and experience brings an important perspective to the research, he says.

"But the last decade has seen the emergence of patient–scientists — including Sonia and Eric, but also others in my lab," he says. "And this has had an even greater impact on the lab. They remind us of our mission — to understand and treat human disease."

Still, it's really hard to cure diseases — especially conditions like this one, because the usual way scientists look for a treatment isn't going to work.

Sonia is 33 years old. On average, people with the kind of genetic mutation she has usually start to show symptoms at age 50. But they could surface at any time. Symptoms of fatal familial insomnia have set in as early as age 12 and as late as 84. Once they do, it's a rapid decline — like Alzheimer's disease on fast-forward.

"You're healthy, you're healthy, you're healthy and then you're falling off a cliff," says Sonia. "You wait a little bit too long, and that patient is gone. We need to get out ahead of it — aggressively."

The challenge

They need to keep Sonia from getting sick in the first place. And they need to do it quickly. But right now, Sonia appears to be just fine, and that's actually one of the first obstacles.

Across medicine, there is an understandable resistance to testing experimental drugs on healthy people. That's why, traditionally, drug trials go something like this: Take a group of people who are sick, give some of them an experimental medicine, and wait to see if it makes them get better, live longer, or decline more slowly than people who didn't get the drug.

But Sonia has to convince the medical establishment that, especially in the age of genetics, some people who seem perfectly healthy should be considered patients.

"We have to be willing to act upstream of what we would traditionally call 'illness'," she says.

It's a shift in mindset that she had to come to grips with, personally.

"I feel very lucky to be healthy today," she says. "But I hold a sort of dual reality understanding of my own health, which is that I'm healthy today but very seriously at risk for a very serious disease."

Others in the medical field, like Dr. Reisa Sperling, who studies Alzheimer's disease, are making the same mental shift as they think about the best time to intervene.

"Alzheimer's disease is a terrible disease. Many people fear it more than cancer," says Sperling, a neurologist with Brigham and Women's Hospital and Massachusetts General Hospital.

Like Sonia and Eric, she, too, is on a quest to prevent even the first symptoms of a terrible brain disease.

Sperling is now enrolling people whose brain scans show they might be in the very early stages of Alzheimer's in a clinical trial to test an experimental drug treatment. And she's planning another study in people as young as 50 who have no noticeable symptoms, but are at high risk of developing them.

"It really does primarily come down to thinking about disease as beginning years before symptoms," says Sperling. "If we can shift that thinking — not just in Alzheimer's disease, but in rarer diseases like prion diseases — I think this is the way we win the war."

But before any of that can happen with a prion disease, there's the problem of actually doing the science to find a good candidate drug.

The plan

Researchers don't have one in hand yet, but they have a clear idea of what it should look like, based on studies in mice. Sonia and Eric already are talking to pharmaceutical companies that may be involved in running human trials in the future, and have requested a meeting with the Food and Drug Administration to talk about what a trial should involve.

Other efforts at treating prion disease have focused on preventing the misfolded proteins from killing brain cells, or on preventing them from accumulating. Sonia and Eric have a different approach.

"We're really interested in preventing the misfolding in the first place," says Sonia.

"Sonia's brain is producing this mutant protein," Eric says. "But as far as we know it's not misfolded yet, and the disease process hasn't started. I want her brain to be producing half or less of the amount of that protein as she is [producing] right now, because we know that less is better."

Essentially, they want to muffle the faulty gene in order to reduce the amount of prion protein floating around in Sonia's brain.

But a key question right now is this: Say they make the right drug and give it to Sonia and others with her type of mutation. If the goal is to change nothing about her current health, then how will they know it's actually working?

A traditional clinical trial is out of the question, Eric says.

It would be unethical and untenable he says, to "just treat half of the people with a drug and half with placebo and then wait 30 years to see when they die."

Not only would that kind of experiment condemn some patients to terrible death, it would also be wildly expensive and require thousands of participants. There are only a few hundred people in the U.S. with prion disease mutations.

"Instead, we need a biomarker," Eric says. "We need some laboratory test that we can run on a living human to see if the drug is having its effect."

The answer, Sonia and Eric hope, could be in a very cold refrigerator in the lab where they work. It's full of samples of spinal fluid. In mouse studies, at least, reducing prion protein in the brain seems to delay disease progression.

So, Sonia and Eric are now studying samples of spinal fluid from all sorts of people — from people who already have symptoms of prion disease, from others like Sonia (who have mutations for prion disease but no symptoms yet) and from healthy controls. The aim is to establish how the levels of protein in the samples change over time, to figure out if protein levels would be a good enough measure to say, "Yes, this drug works."

"We have strong evidence that 50 percent [reduction] — if we could achieve that — would be protective," says Sonia, based on preliminary findings in mice.

Others are optimistic, too

Sonia and Eric are organized, hardworking, and efficient. Ultimately, for them, failure is not an option. But on a day-to-day basis, failure is what science is all about.

"In biology, if everything you did one day goes wrong, and then you figure out why it went wrong, that was a good day," says Eric, who chronicles their struggles on a blog.

It's an achingly slow process. But Eric thinks they will do it — they'll find a drug.

"I'm an optimist that we'll get there in our lifetime," he says, "but not this year and not next year."

He's not alone in his optimism. Sonia and Eric have some powerful colleagues who believe the couple can pull it off — colleagues like Eric Lander, a renowned mathematician, geneticist and molecular biologist. He started the Human Genome Project and founded the Broad Institute where Sonia and Eric now work.

"This is not pie in the sky," says Lander. "I see a path forward for multiple shots on goal. All you have to do is get one through."

Fifteen years ago, he says, solving this puzzle would have seemed impossible. But now he believes the science, the technology, and the knowledge about what certain mutations mean for a person's health have made defeating prion disease possible.

"Human genetics and molecular medicine are reaching a point of maturity where they're becoming much more powerful," he says. "It's exciting and important and there's nobody who's more motivated than somebody who's going to be affected by the disease themselves."

One small success

In one way, Sonia and Eric have already stopped the disease in its tracks.

Sonia is very pregnant. She's due in July to have a daughter — a daughter without a mutation for prion disease. That's something the couple made sure of by screening embryos after in vitro fertilization.

So, they've stopped the transmission of prion disease in Sonia's line of the family. And in a way, that's a gift from Sonia's mom, Kamni, the couple says.

"If my mom was still alive, we wouldn't know any of this and we wouldn't have had the opportunity to choose to have a mutation-negative baby," says Sonia. "But, tragically, it also means that they'll never meet."

Sonia and Eric hope that, by the time their daughter is in elementary school, Sonia will be taking an experimental drug that could keep her as healthy as she is today.

Copyright 2017 NPR. To see more, visit http://www.npr.org/.

AUDIE CORNISH, HOST:

We're going to hear about a young couple on a deadline. Right now they think they have about 20 years together before one of them dies from a rare brain disease. NPR's Rae Ellen Bichell first told us about them today on Morning Edition. Now she continues the story with their plan to stop the disease.

RAE ELLEN BICHELL, BYLINE: In 2010, Sonia Vallabh watched her mom, Kamni Vallabh, die in a really horrible way. First, her mom's memory started to go. Then she lost the ability to reason. By the end, it was as if she was stuck between being awake and asleep.

SONIA VALLABH: Even when awake, was she fully or was she really? And like, when asleep, was she really asleep?

BICHELL: The smart, warm, artistic Kamni was disappearing.

ERIC MINIKEL: I think until you've seen it, it's hard to actually imagine what it is for, you know, a person to be alive and their body is moving around, but their brain is not there anymore.

BICHELL: That's Sonia's husband, Eric Minikel. In less than a year, Sonia's mom had died. The family decided to do an autopsy.

VALLABH: It was more for closure and just the peace of mind of being able to sort of say what it had been and leave it behind us.

BICHELL: The autopsy showed Kamni had a rare type of disease known as a prion disease. Basically, certain molecules had started clumping together in Kamni's brain, killing her brain cells. It was all because of one tiny error in her DNA. Sonia sent a blood sample to a lab, and it confirmed she had the same mutation. That threw the family into grief all over again.

VALLABH: But that grieving period sort of started to resolve within about a week or so, and we weren't in crisis anymore. We were sort of, like, finding our way towards a new normal where this was something that we were going to have to live with and deal with and learn more about.

BICHELL: Today, Sonia and Eric live in Cambridge, Mass. They wear bright colors and laugh easily. They framed a part of their wedding vows translated from Sanskrit.

VALLABH: Inseparably dear to each other (laughter).

MINIKEL: That's a good description of us.

BICHELL: When they answer my questions, they look at each other instead of at me.

MINIKEL: How you been?

VALLABH: Good.

BICHELL: They're thinkers and problem solvers, which is why when Sonia got her genetic test results it changed everything.

VALLABH: It didn't happen all at once. So there wasn't a day when we woke up and said, OK, let's change everything about our lives.

BICHELL: Sonia had just started a new job as a legal consultant. Eric was a transportation analyst. But they couldn't stop thinking about that test. They started researching prion diseases online. Then they invited biologist and chemist friends over to help them understand the science.

VALLABH: And around that time we both enrolled in night classes as well.

BICHELL: Classes in biology and neuroscience.

VALLABH: So it was really a phase of just trying to get as much information into our minds as we could.

BICHELL: She and Eric kept wanting more. Night classes weren't enough.

VALLABH: I was basically fresh out of law school and started walking into classes at MIT during the day because this was kind of all I could think about.

BICHELL: She wore sneakers every day so she could rush between work, classes and a neuroscience lab where she'd started volunteering.

VALLABH: And from there, this is where things happened surprisingly quickly.

BICHELL: Sonia left her legal job to work in the lab full time as a technician. Then Eric left his job to work in a lab, too.

MINIKEL: I was getting left behind.

(LAUGHTER)

MINIKEL: Sonia was out there doing all this science. It was her day job now. And I was still in my old career.

BICHELL: Just months after they'd finished grad school in law and urban planning, the pair went straight back, this time as scientists, to study prion diseases. They want to save Sonia.

MINIKEL: You are talking to two third-year graduate students.

BICHELL: They now share an office and a lab bench at the Broad Institute of MIT and Harvard.

MINIKEL: Here's the minus 80 Celsius freezer where we keep all the samples.

BICHELL: They have a single goal - to prevent prion disease from ever making Sonia sick.

MINIKEL: You know, there's a date in the future when Sonia will get the first dose of the drug that's going to save her life. What can I do today that brings that date closer to the present?

BICHELL: It is really hard to cure diseases, especially this one, because the usual way scientists look for a treatment isn't going to work. Sonia's 33 years old. People usually start to show symptoms at 50, but they could start any time.

VALLABH: You're healthy, you're healthy, you're healthy, and then you're falling off a cliff. You wait a little bit too long and that patient is gone. We need to get out ahead of it aggressively.

BICHELL: They need to keep Sonia from getting sick in the first place, and they need to do it fast. But right now Sonia appears to be just fine. And that's where the problem is. The mantra across medicine is to do no harm. There's a resistance to testing experimental drugs on healthy people, which is why traditionally, drug trials go something like this - take a group of people who are sick, give some of them an experimental medicine, and wait to see if it makes them get better, live longer or decline more slowly than people who didn't get it. But to help Sonia, they'll have to convince the medical establishment that some people who seem perfectly healthy are actually patients. It's a transition Sonia made herself in coming to terms with prion disease.

VALLABH: I'm healthy today, but very seriously at risk for a very serious disease.

BICHELL: Others in the medical field are making this shift, too, like Dr. Reisa Sperling, who studies Alzheimer's disease.

REISA SPERLING: Alzheimer's disease is a terrible disease. Many people fear it more than cancer.

BICHELL: Sperling is a neurologist with Brigham and Women's Hospital, and she's also on a quest to prevent terrible brain diseases from starting in the first place. She's starting a trial on people whose brain scans show they might be in the very early stages of Alzheimer's.

SPERLING: It really does primarily come down to thinking about disease as beginning years before symptoms. And that if we can shift that thinking not just in Alzheimer's disease, but in rarer diseases like prion diseases, I think this is the way we win the war.

BICHELL: But then there's the problem of actually doing the science. Sonia and Eric are organized, hardworking and ruthlessly efficient. Failure is not an option. But on a day-to-day basis, failure is what science is all about.

MINIKEL: In biology, if everything you did one day goes wrong and then you figure out why it went wrong, that was a good day.

(LAUGHTER)

BICHELL: It's an achingly slow process, but Eric thinks they'll do it. They'll find a drug.

MINIKEL: I'm an optimist that we'll get there in our lifetime, but not this year, and not next year.

BICHELL: He's not alone in his optimism. Sonia and Eric have some powerful colleagues who think they can pull it off, like Eric Lander, a renowned mathematician and geneticist.

ERIC LANDER: This is not pie in the sky.

BICHELL: Lander started the Human Genome Project and founded the Broad Institute where they now work. Fifteen years ago, he says, it would have seemed impossible. But now the science, the technology and the knowledge about what certain mutations mean for a person's health makes defeating prion disease possible.

LANDER: Human genetics and molecular medicine are reaching a point of maturity where they're becoming much more powerful. It's exciting and important. And there's nobody who's more motivated than somebody who's going to be affected by the disease themselves.

BICHELL: Sonia and Eric are working methodically toward their goal. But in one way, they've already stopped the disease in its tracks. Sonia's very pregnant. She's due in July to have a daughter, a daughter without a mutation for prion disease, something they made sure of by screening embryos before artificial implantation. So they've stopped the transmission of prion disease in Sonia's line of the family. And in a way, that's a gift from Sonia's mom, Kamni.

VALLABH: If my mom was still alive, we wouldn't know any of this, and we wouldn't have had the opportunity to choose to have a mutation negative baby. But tragically, it also means that they'll never meet.

BICHELL: Sonia and Eric hope that by the time their daughter is in elementary school Sonia will be taking the experimental drug that could keep her as healthy as she is today. Rae Ellen Bichell, NPR News.

(SOUNDBITE OF TRACEY CHATTAWAY'S "SHIMMER") Transcript provided by NPR, Copyright NPR.