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#147 CF Series: Bijal Trivedi on "Breath From Salt"

by Kira Dineen
May 7th 2021

This episode launches DNA Today’s Cystic Fibrosis Podcast Series! Over the next three episodes of the podcast we will be exploring cystic fibrosis’ history, p... More

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I'm your host here Dean. I'm also a certified genetic counselor practicing in the prenatal space on the show. We explore genetics impact on our health through conversations with leaders in genetics. These are experts like genetic counselors, researchers, doctors, patient advocates and more. My guest today is the award winning journalist vigil tragedy. She is a fantastic writer. I just have to say right off the bat, we are going to be diving into her first book, breath from salt. And if you're watching this on Youtube, this is the cover of the book and obviously I loved it because I have so many sticky notes and highlights. Um, and I just learned so much from it. So thank you first of all for taking the time to write this book and chronicle, you know, the journey that has been cystic fibrosis. I love at the beginning of the book. You right. It's a new lens through which to view the progress of medicine. Um, it's just amazing how much you've been able to document with this from like the discovery of the condition To the development of groundbreaking treatments.

I mean, there's been so many advances for cystic fibrosis over the last 50 years and a lot of firsts in medicine um before we dive into all that, because I have so many questions to ask you about it. Can you describe what cystic fibrosis is for people that are not as familiar with the disease as we are? Sure, well, kira, thanks for having me on. Um, that's a real privilege and I'm happy to talk to you today. Um, cystic fibrosis is it's a fatal genetic disease and it's a disease that most often is described as, as a lung disease, but in fact it it affects the entire body. It infects that affects the lungs, the sweat glands, the pancreas, the digestive system. And but but it's the, the infections that occur in the lungs that are actually the most deadly and and kill patients and when it was first discovered, patients often didn't make it to their first birthday.

But now, uh the the age uh survival rate is age 47. So that's a huge improvement And that's just in the last 50 years. I mean it's just remarkable how you know as you said going from it was an infantile disease that babies would die young from this and now people are 47 and parents of their own Children. Um so it's just a fantastic example of how far medicine can come in. Just a few decades. Part of the excitement obviously were a genetic show. So that was the part that I was really intrigued in. And I would say a good portion of the book talks about the genetics and the genetic mutations and you know the information surrounding that. So the search for the cystic fibrosis gene was really a race I would say. And you kind of capture that really well and you're going along the journey. There is just the reader what techniques were used in order to figure out which gene, how's the mutations that lead to the disorder? I mean why was this revolutionary? Well they started the hunt for the cystic fibrosis gene back in 1981 and in sort of been in a very serious way.

And in 1981 there was no genome. The human genome had not, the Human Genome Project had not even begun. That would be in the 90s. But that would kick start. Um So there was no map of human D. N. A. We didn't know what genes were on, which chromosomes. It was essentially the Wild West. And so we had this disease cystic fibrosis and no one knew what caused it. So you have a completely it's like having an unlabeled map of America and you have to find a location where the problem is. And you you don't I mean you don't even know the roads. You don't know the town's. Uh so they have to start from the very beginning and and figure out how do we find a disease when we don't even know the cause we don't even know what to look for in the D. N. A. And the human genome has about three billion building blocks.

So they would have to go through all of those three billion building blocks one by one and find the gene that causes cystic fibrosis. So that was impossible to do. So they basically figured out a hack which was a brilliant brilliant hack and that was that they decided to collect the DNA. From families all over the country all over the U. S. And all over Canada. Um And you know D. N. A. From the mothers and fathers and the Children who had cystic fibrosis and as well as their healthy siblings. And they would take the D. N. A. From all those people And what they were looking for was a little piece of D. N. A. That was carried by all the people that had cystic fibrosis but not their healthy siblings. Um So basically You know the cystic fibrosis mutation arose about 5000 years ago. It is thought to have arisen about 5000 years ago.

So they're looking for a tiny bit of DNA a mutation that has been passed down from generation to generation. Um and has now wound up in these Children. And it's a tiny little piece because every time every generation you get less and less from you know, less and less DNA from the previous generation. So it was a it was a massive undertaking and it took basically eight years to find that gene. And it was one of the first human disease genes found. So there are so many firsts with cystic fibrosis, but I think that is probably one of the most significant. Yeah, I think so. And just seeing like, you know, all that it took to get there, as you said, I love that analogy of They didn't even know like where the roads were because, you know, putting into perspective, we didn't have the first draft of the genome until what, 2001 somewhere around there. So this is like 20 ish years before that.

So that's like a lifetime in genetics, you know, and we think about how fast things it is. And especially when when you think about how slow sequencing the genome was back then and you know, I was in the lab for a little bit and it's sequencing was slow and we used radioactive isotopes and it was it was glacial. So uh you know, things have come a long way since then. Yeah, yeah, definitely. And after they did find, okay, this is the gene that mutations happen and that's what causes the disorder. Obviously we said that was such a landmark discovery. There was a lot of excitement now of, okay, we found the gene we're going to be close to better treatments and hopefully a cure. And that led to discussions and clinical trials with gene therapy. Why were some of the reasons why a lot of this didn't pan out and didn't end up working out in terms of all the excitement that was there, Well altering the 80s and the early 90s, there was a lot of excitement about gene therapy.

So people thought, okay, in a human disease, a genetic human disease, you have a broken gene. So what if we could give that patient healthy copy of that gene wouldn't that theoretically fix the problem? And there was a lot of early evidence that this would work. So a lot of animal studies and work was done in a few immune diseases, um, where they proved that if you gave a patient a healthy copy of the gene in their bone marrow, they could produce normal blood cells and they would have a robust immune system and they could fight disease. But of course cystic fibrosis, um, results from a protein that is broken in every cell in the body. Um, so you have to get this this gene, this healthy copy of the gene into every cell. And this was back in the early 90s and there was very I mean gene therapy, the idea of gene therapy and in the early experiments it was all just starting.

It was sort of the beginning of the revolution and the theory was so neat. Right? You know, you got a broken gene found the healthy one. Let's just make lots of copies of the healthy gene and throw it into people. But with cystic fibrosis it's a complicated disease. I mean how do you get the gene into the body? So what they decided to try was they took the gene, they inserted it into a virus. Um and this virus was special, it was a cold virus. So normally this would be something that would cause you a cold. But they took out the bad DNA from it. So it was basically an empty virus shell. They put in the healthy genes, cystic fibrosis gene and then they basically spritzed it into the lungs um of people with cystic fibrosis and they did, it is in a very small quantities because you know, early stage clinical trials are largely for safety and in a tiny part of the lung they found that the gene actually entered lung cells.

What got into the cells started making a healthy type of protein and in a minuscule part of the lung, they had fixed the disease. But when they tested patients a little while later, it seemed that the gene was no longer there, the healthy gene was no longer there, it was no longer making healthy protein. It was a very transient effect. And what was more worrying is when they put this, you know, virus carrying this gene therapy into the lungs. The immune system basically freaked out and as it should, you know, as we know with coronavirus, when you inhale a virus and your immune system goes on full alert to kill that virus to get it out of the lungs. So sadly, what was happening in these patients was the immune system was fighting the therapy and killing it before it could do any good. And so that work in the mid nineties made people realize that, you know, hey, just because you find the gene doesn't mean that the disease is going to be easy to fix.

And that was particularly the case with cystic fibrosis and that was the case with other conditions too. That was trying to be um treated in this fashion with gene therapy and you know, we could have a whole episode just talking about, you know, all of that went into those early years of gene therapy. Um, the other side of it, that was kind of happening maybe similar time or right after um, was just looking at, okay, not just finding the gene, but let's figure out what are the changes in this gene that lead to the disorder. So it's not necessarily just one change. Although there is one that is the most common um you know over time there's been thousands of mutations as we call them um that have been identified but even though there's thousands there's two main ways that it affects the protein. So if we're remembering back to high school biology or wherever you learned your basic genetics we have the basics of the dogma. And so with that we have our our D. N. A. And that's the instructions for our proteins to be made. Um So with that in mind with the mutations that are there, what are those two classes of proteins um are the two ways that it can be affecting the protein?

Well it was it was really interesting because when they first found the gene in 1989 um they expected there to just be one mutation that caused all the disease. But actually the mutation that they discovered only cause 70% of the cases of cystic fibrosis which suggested that there were other mutations out there. And over the next couple of decades they they discovered more than 2000 types of mutations and each of these mutations could break the protein in a different way. So um about 5% of patients with cystic fibrosis have a mutation in which the chloride channel which is the protein that's broken in cystic fibrosis it's sort of jammed so it blocks the passage of chloride in and out of the cell. And those patients need a mutation to sort of pop open that that chloride channel.

Um and in the book I called this a door jamming mutation because I felt the need, I had to attach a picture in my brain and it helps so much. I'm like a visual learner. So I was like going through with you. I'm like, okay, this is the one that does this. Yes, yes. So the door was jammed and you need a molecule to basically push it open and allowed chloride to move freely. Now, the more common types of mutation ended up breaking the protein in a couple of places. And the problem with this was that, you know, the protein didn't even get to the outside of the cell where it was supposed to be, it was floating around, it was so badly folded, it was like a broken origami structure that had, you know, where you'd skipped a couple of the steps. So the protein, instead of being on the outside of the cell, like a doorway, it was floating around inside the cell. It's almost like you had a door inside your house and it was in the wrong location. So you needed a couple of uh those sort of um proteins needed a couple of fixes, they needed something to get them to the right location in the cell, meaning the outer cell membrane.

And then they also needed another drug to open it up. So they had two problems. So people with those mutations would theoretically need to drugs to fix that protein. Of course, no one knew that it was even possible to fix the protein at that point. Yeah, So this was another, I feel like the book could also be marked by like all the first in medicine that we kind of talked about at the top of the show. And this was another one of like, can we fix a broken protein? And I had no idea that this is like the first drug that actually was able to do this in the first research that was happening with this. So, you know, with your analogy of like, you know the door's jammed or the door is not quite where it's supposed to be yet. So those are the two main problems. Um So when it came to Alright, let's figure out how to fix a broken protein. I mean, how did scientists attempt this? What was the first drug to start fixing this general problem with the protein? Well, when first when the people that funded and sort of came up with the idea that maybe this might be possible.

Um The group was the cystic fibrosis foundation and the head of that foundation um bob bell and uh head of medical affairs at the time, Preston Campbell, they were talking about this problem. They were frustrated. Gene therapy had totally bombed, that wasn't going anywhere so they said, you know, maybe we can hire a biotech company or pharmaceutical company to try and fix a broken protein. Maybe if we can't put a new gene in there, maybe we can fix what's already broken in the cell, maybe that would be easier. And so they went to a lot of pharmaceutical companies and biotech companies with this idea and basically they were, you know, laughed out of the house, nobody would listen to them, they were like you cannot fix a broken protein, that's a crazy idea, leave. Um but one company um aurora Biosciences um they took the cystic fibrosis foundation seriously and they liked the challenge um and that that particular company was launched by um Roger Chen and some of his colleagues and Roger Chen discovered the green fluorescent protein um for which he won the Nobel prize.

And he was intrigued by this idea that you could perhaps um fix a broken protein. And so his protege paul Niculescu um started working with the foundation and he thought it was possible. He thought, yeah, well maybe it is possible to do this. And they started working in cell assays um in animal studies and building molecules testing them on cells that carry this mutation in the cystic fibrosis mutation and trying to fix it. So basically they were doing large scale screening with millions of cells and hundreds of thousands of molecules dumping them on these cells and and seeing which molecules would actually help the protein work. And over years they were able to find a set of molecules that had the right qualities. And then this amazing, amazing team of chemists at vertical vertex pharmaceuticals.

And that was the company that acquired Arora. They started tinkering with these molecules that showed some promise and made them exquisitely accurate. So they made a molecule that was later called collided co that could open that was able to unjam the door for this first type of mutations. They went on to build molecules that was that we're able to fix the most common mutation, lift the protein to the top of the cell and then open it up. So this uh this group of chemists, I just have the highest regard for them. They are brilliant people and you know, they didn't have much support in terms of chemists in the company. You know, everybody thought this was a nutty idea. Uh but you know, they really, they proved themselves and they proved themselves so much so that they showed that orphan drugs could be wildly lucrative. I mean at one point, I don't remember all the particulars with it, but Vertex, the only revenue they had was from this drug.

And so they never thought they were like, oh this is like a side project, we'll see what happens with this. And then suddenly they're like, oh, this is our only source of revenue. Like the tables have really turned, I mean, it takes a lot to get there. As you said, I mean, years and years and years and so much money has to go into developing these drugs because you're starting from screening all these chemicals and compounds and saying, okay, which ones are the ones that could become a drug after a lot of extra work? I mean, how does the money, you know, get funded for this? This is you know, one of the more, you know, it's not by definition of rare disease, but certainly at the time, you know, more so, you know, less people knowing about um the disease. I mean, how did the cystic fibrosis foundation, how are they able to raise all this money through the ventral philanthropy? I mean to afford developing drugs, like they were the main source behind that money? Well, they were the main source of the the early research. So basically when they Made a contract with aurora Biosciences, this this idea was so, you know, adding left field that, you know, they just basically gave them a little bit of money, you know, $1 million.

See if this is even possible. See if you can build a robot that can start screening these cells and adding in chemicals and detecting which ones might work. Okay, so if you reach that milestone, you know, another four million to see if we can scale up this project and they basically kept increasing the milestones that needed to be achieved and the way they were funding. It was, you know, the cystic fibrosis Foundation has an amazing volunteer network. Um, so those volunteers were raising some money, but basically they realized they had to launch a capital campaign. And the person who led that campaign was joe O'donnell, who was um, who is a father and his son Joey died from cystic fibrosis. And that's, you know, a primary um thread in the story of breath from salt. And, you know, he is a very successful businessman in in boston and he took it upon himself to, to raise the money that the foundation needed to fund this early development.

So vertex would not agree to fund the research until it was demonstrated that this was a viable idea. This could actually turn into a drug. So until the point where they started doing animal testing and clinical testing, the Foundation paid for all that early research. And then when we moved into clinical trials, the company took over because that's when you need, you know, tens of millions of dollars, um, to start funding clinical trials and and the following research. But basically, you know, no nonprofit, no health nonprofit had ever raised money through philanthropic donations and then used it to invest in a for profit biotech company that had never been done before. So the cystic fibrosis Foundation was, you know, forging another new path, um, you know, and and it led to the development of for successful drugs? It's pretty astounding.

Yeah, I'm sure that a lot of other foundations look at their model and what they were able to accomplish with this and say, okay, how can we see that pathway and mimic that for ourselves? Just because it's, it's, you know, it's really brilliant that they were able to say, okay, we have royalties from, you know, this first drug, let's sell those royalties and the money we get. Let's pour back into research. And just that cycle was just so interesting to me that, you know, and just being able to raise as much money as they did, especially joe donnelly. I mean he raised, Was it like $250 million? Um, at least when the book was published, which was just 2020 that, you know, for just one person. And there's so many other volunteers and so many people mentioned, you know, throughout breath from salt that had, you know, big contributions in there. But it's just remarkable that, you know, one person can really make a difference. And then you start compiling that and, you know, this research is being done. Um, and so many drugs coming out of it. Um, I mean, it was interesting to that how fast things were able to move.

Uh, not only just the money being raised, but how fast the research was happening, how fast the drug development was happening. Um, one of the factors of that seemed to be that the, was it the cystic fibrosis foundation that had the genetic registry, were they the ones in charge of that? That's right, That's right. So one of the early things that the foundation did, I mean one of the amazing things about the cystic fibrosis foundation and I probably sound like a spokesperson for them, but I'm honestly, I'm not. Yes, I often writing this book, I am a big fan. Um one of the amazing things that they did early on was they decided they weren't going to spend money on awareness for cystic fibrosis every penny they raised or as much as they could possibly do, um, would be invested in research to find out the cause of this disease. And then later on after they had found the gene to find a cure for this disease. And um part of that was once they realized, um, You know, that so little was known about the disease.

You know, the foundation formed in 1955, um, with a bunch of very, very desperate parents. Um, people just didn't know about this disease. Physicians didn't know about this disease. So, to start learning about it, they created a registry of all the patients that were seen at their health centers and they started compiling data on all those patients, the names, you know, the ages, what they suffered from. And, you know, once the gene was found, they started um sequencing the gene for each of those patients to say okay these patients have this mutation. These patients have this mutation. And by the time that Vertex actually had a drug to test um bob bell from the cystic fibrosis foundation had made sure that virtually all of the patients that we're seeing that their care centers across the US um we're in this database were in the registry and that every person's mutation was known and that was a key development.

Because when Vertex actually had their drug to test and was ready to launch clinical trials, the cystic fibrosis foundation had this enormous registry of patients that were all subdivided based on the genetic mutation they carried. So they could basically personalize these clinical trials and base it on the genetic mutation. So in many ways this was the first big personalized medicine um clinical trial ever. Um they've done this in certain ways for for types of cancer. But this was the first time for a genetic disease where they had they had designed drugs to cure a particular mutation. Uh so the fact that the registry was there, the patients were lined up, they knew exactly what mutation they all carried. The clinical trials could be um run very smoothly and that's normally where um a lot of drug trials fail because they can't recruit enough patients.

But here all the patients were ready. They were used to actually participating in medical research because the Foundation had made it clear that unless you participate in medical research, you will not get a drug. So the patients were good at advocating for themselves. I mean, they're amazing people and they participated in so many trials, but they really made sure that they had these drugs developed for them. Um so it was, you know, another first and now, you know, parts of this book read like Emmanuel, I think for other rare diseases, um because you know, they talk about launching a foundation, getting a registry, finding the cause of the disease, and then strategically investing in pharmaceutical companies to develop treatments um that are very specific. So, I think, you know, the cystic fibrosis foundation laid the roadmap, but it's a roadmap that others can follow.

Yeah, certainly. I mean, reading it, as you said, it is kind of like a manual and just taking you through and also that you weave in, you know, so many families and patients stories within the book too. So it really does read like a story you're reading about people's lives and how it unfolds and you know, who is getting what drug and the clinical trials and you know, when one sister experiences, oh wow, I'm starting to see relief from symptoms, I must have the actual drug and then the other sister is like, oh, I think I might have the placebo and you know, really just feeling like you're, you know, along with them for the ride. Um so it's just, it's such a fantastic read. Um you know, again breath from salt for people that want to look it up. Um I think, you know, I was saying this before we started recording that I feel like this should be required reading for anyone going into healthcare and medicine, because it just, it teaches you so much just through the lens of one condition, but just so much of just different areas of medicine. So, you know, I think I am certainly not the only one that I really enjoyed the book and I just have to say you're such a fantastic writer.

I think sometimes it can be intimidating to pick up, pick up a large book and you're like, okay, there's gonna be a lot of medical terms, but you break it down so beautifully with like, so many, you know, different um ways of explaining things that, you know, you're you're right there with you. So I just, you know, I'm just a huge fan and I just really wanted to thank you for taking you know, so many years to put this all together so that someone could just pick it up and read the history of cystic fibrosis. I have to I just haven't wanted to add in there in addition to your very kind comments, thank you for that. Um you know, there are so many patients stories and one thing that was really important to me with this book was to tell the story of um this disease and all the science through the lens of the patients and the families. So without the patients and the families there would have been notebook and people were really generous um when it came to telling me their stories, I mean these are very heartbreaking stories in certain, in certain cases and people were open with me, they shared everything.

I mean lots of medical details. And if it weren't for those families, there wouldn't be a book because it's their stories that I found so compelling and I wove the science and the history into their lives. So, um you know, they are the backbone of this book and that definitely comes through, especially I think with the O'donnells being really at the center of the book and all the other are their families with it. Um thank you so much for just coming on and I think we covered so much, but there's way more in the book. So people definitely need to check that out. Um where can people find it if they want to read it? Um it's on amazon and it's on all independent booksellers as well. Um Indy indigo books, Barnes and noble. Um or you can go to my website, I have little buttons for them. Um I can't remember off the top of my head. Yeah, my my website, you can find out about the book and and anything else. Yeah and we're going to link to all of that in the show notes for this episode which is available at DNA podcast dot com.

So if you only can remember one thing just go there and then we'll have all the information there. Um And if you have any questions about cystic fibrosis or about breath from salt, certainly email in info at DNA podcast dot com. Head over to our social media so you can enter to win your own copy of breath from salt Search DNA today on instagram, twitter and facebook. The giveaway will end on june 4th 2021 winners must have a U. S. Or Canadian shipping address. So definitely head over there so you can win your own copy of breath from salt and please if you have a moment go onto apple podcast leave us a rating and review So that others like yourself can find the show. So thank you again for coming on and just sharing your wisdom with this. Um I'm just such a huge fan and everybody needs to check out breath from salt. So before ending the show, I want to remind you about picture genetics with their exclusive 25% discount for you as a DNA today listener. Picture genetics is different from a traditional direct consumer test because it's clinical grade testing with every case reviewed by a health care provider.

Results are focused on health with medically actual and useful information for you and your family. I did a couple of their kits including their picture parenting one. Here's how it worked. I sent off a tube of my spit to the lab who sequence a bunch of genes including CFTR, which you now know as the cystic fibrosis gene. This means they read through each gene to see if there was a mutation or pathogenic variants as we genetic counselors call them. Then a geneticist looked at my results and created a beautifully easy to read report informing me about my carrier results. And here's my favorite part. There is also genetic counseling offered. So you speak with a genetic counselor about your results. Order your own kid at picture genetics dot com and use code DNA today for 25% off and free shipping again. That's picture genetics dot com. Get actual genetic insights today to benefit your family of tomorrow and thanks for listening and join us next time to discover new advances in the world of genetics.

#147 CF Series: Bijal Trivedi on "Breath From Salt"
#147 CF Series: Bijal Trivedi on "Breath From Salt"
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