Rewriting the code: The inside story of the first CRISPR cure

Victoria Gray: My mom tells me it started with a bath. I just wouldn’t stop crying no matter what she did. I wouldn’t take a bottle, she rocked me — nothing helped. 

(Music: “Taboret” by Blue Dot Sessions)

Anne Brice (narration): Victoria Gray grew up in Goodman, Mississippi. She was only 3 months old when she began crying inconsolably. At first, her mother feared she’d reinjured Victoria’s arm — it had been dislocated during birth — but at the emergency room, doctors couldn’t find what was causing the pain. They ordered some blood work.

Victoria Gray: Once the labs came back, they gave her the devastating news that I would only, if possible, live to see 7 years old. 

Anne Brice (narration): She had sickle cell disease, which causes red blood cells to become misshapen and block the flow of oxygen to the body. At least 100,000 Americans are living with the disease, more than 90% of whom are Black. And globally, the scale is staggering, impacting an estimated 8 million people in the world, from sub-Saharan Africa to India. 

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For those affected, it requires regular blood transfusions, leads to organ damage and can cause unbearable pain. 

Although the life expectancy of a person born with sickle cell today is around 50 years old, the prognosis was much worse in 1985, when Victoria was diagnosed. Before the era of modern screenings and preventive antibiotics, many died in early childhood from sudden infections or organ failure. 

For Victoria’s family, the diagnosis felt like a countdown.

Victoria Gray: When I was a kid, I knew what I was dealing with was dangerous. I don’t know how I knew. I think I would listen to my grandmother’s prayers and listen to conversations that my mom and my grandmother were having that I wasn’t supposed to listen to. But I knew what I was living with, I knew it was dangerous. So unlike normal kids, for my birthday I would wish for another year of life. 

(Music: “Cedar Stand” by Blue Dot Sessions)

Anne Brice (narration): But she didn’t know that years later, a scientific breakthrough 2,000 miles across the country at UC Berkeley would give her another chance at life. 

This is Berkeley Voices, a UC Berkeley News podcast. I’m Anne Brice.

Anne Brice (narration): Berkeley biochemist Jennifer Doudna grew up on the Big Island in Hawaii. It was rainy and beautiful, filled with plants and animals and bugs that evolved uniquely for that environment. 

Jennifer Doudna: And I found myself wondering about that. I didn’t know anything about DNA at the time, but I only learned later that it really does come down to that code of life. 

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And when I took a class in high school in chemistry, our teacher taught us that science is about solving puzzles and I love solving puzzles. So I started to imagine myself doing some kind of science in my future life. 

Anne Brice (narration): Her dad was an academic in American literature. She remembers when he gave her a copy of The Double Helix, a book about the discovery of the DNA structure. 

Jennifer Doudna: That was my first exposure to what it’s really like to do science — you know, the personalities involved, the competitions involved, the incredible sense of excitement when you figure out something new about the world for the first time. I was absolutely captivated. And my father could see that in me and I think he always encouraged it.

Anne Brice (narration): Doudna joined Berkeley’s faculty in 2002. She’s a professor of molecular and cell biology and of chemistry, and she leads the Innovative Genomics Institute on campus. 

In 2010, Doudna’s lab discovered a pathway that allows bacteria to “learn” about viruses, store that information and use it for protection. 

When Doudna started collaborating with French microbiologist Emmanuelle Charpentier, the scientists realized that the same system could be used to edit DNA in plant, animal and human cells, effectively allowing them to rewrite the code of life. 

(Music: “Baroque” by Blue Dot Sessions)

It marked the revolutionary discovery of CRISPR-Cas9 gene editing. 

The seminal paper on CRISPR was published in 2012 by Doudna and Charpentier. The pair went on to win the Nobel Prize in Chemistry in 2020.

Jennifer Doudna: I’m highly motivated by the fact that I work at a public university and I want our discoveries, meaning the work that all of my students are now doing, I want that to have real-world impact. 

Anne Brice (narration): At Berkeley and other universities, says Doudna, researchers are innovating in ways that couldn’t be done easily in companies. They’re taking big risks driven by curiosity with findings that might not be immediately commercially viable. 

Jennifer Doudna: That’s really where the whole idea of genome editing with CRISPR started, was with that fundamental science that was done here at UC Berkeley.  

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Anne Brice (narration): To support their work financially, scientists rely on federal funding — taxpayer dollars — largely through the National Science Foundation and the National Institutes of Health. 

Jennifer Douda: For every dollar invested through the NIH, $2.50 is returned to the country in economic advances. That’s a great deal. So I think we need to continue to support science in the way that we have in the past if we want to continue to be the leaders around the world. I want America to be number one.

(Music: “Gentle Son” by Blue Dot Sessions)

Anne Brice (narration): Treating inherited blood disorders, like sickle cell disease, was at the top of Doudna’s list of CRISPR therapies to develop. 

For Victoria, age 7 came and went. Despite knowing that her illness was serious, she describes herself as a happy-go-lucky child. 

Victoria Gray: As a kid, I was aware that there were triggers. But as a kid you’re not thinking about all of that. I still had the mind of a child, a mind full of adventure, hope, love, life.

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Reading was my getaway as a kid. I would get so deep into a story where I would be able to visualize the scenery. That’s how you know you’ve got a good book — when you can get the visual and feel like you’re a part of the story.

Anne Brice (narration): There were times, though, when she couldn’t forget her illness. Times when the pain came on so suddenly that it took her breath away. 

Victoria Gray: When the pain came on, that’s when things changed, because the pain felt like getting struck by lightning and hit by a truck at the same time. And when you’re answering the questions, “Does it burn? Is it an aching pain? Is it a sharp pain?” — it’s everything, so how do I narrow this down? 

So it’s confusing as a kid to live with the disease, and even as an adult trying to explain the pain, it’s hard to find the words.

Anne Brice: Is it throughout your entire body? 

Victoria Gray: Yes, especially as a kid, I would have pain everywhere — arms, legs, chest, back. My hands ached, my feet. It was just terrible. 

Anne Brice (narration): When she wasn’t having a flare-up, Victoria was often fatigued. Doctors worried that too much physical activity would trigger an episode. So she always had to sit out during PE, watching from a bench as her classmates played dodgeball and jumped rope together. 

If her pain wasn’t severe, Victoria’s parents could usually manage her symptoms with medication, rest and fluids. But every three to six months, the pain would become excruciating — a sickle cell crisis, she calls it — and she’d have to be rushed to the hospital. There, she’d spend a week or more getting blood transfusions, IV fluids and pain meds until her symptoms subsided. It was the same cycle, again and again.

She was always treated at Batson Children’s Hospital, now named Children’s of Mississippi. Even though Victoria missed her friends and family and school, the pediatric team made her feel protected and cared for. 

Victoria Gray: Everyone knew me, I knew them, and it just felt like home. They would always just rush in to make sure I was OK. I was always welcomed there with smiles and empathy and the willingness to help me when I was a child, so I wasn’t as afraid. 

(Music: “Waltz and Fury” by Blue Dot Sessions)

Anne Brice (narration): When she turned 19, though, everything changed. Living as an adult with sickle cell disease was much different than living with it as a kid. 

Anne Brice (narration): In 2014, two years after Doudna and Charpentier published their landmark paper on CRISPR, Doudna began focused efforts on using CRISPR to treat sickle cell disease. 

When a person has sickle cell disease, they have two copies of a gene that encode a protein that’s defective at carrying oxygen in the blood. Here, Doudna explains the disease during a talk she gave in April for the campus’s Brilliance of Berkeley lecture series: 

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Jennifer Doudna: Sickle cell disease is one of the best understood of the human genetic diseases. It’s a disease caused by a single base pair change in one gene of the human genome. And when that base pair mutation occurs, it’s in a gene encoding a protein important for carrying oxygen in our blood. It’s the adult form of hemoglobin. When that base pair change occurs, it causes a disruption of the structure of that hemoglobin protein. And as a result, it produces cells that are sickled in shape, and they tend to block blood vessels. 

You might ask, “Well, why has a mutation like that been maintained in the human population?” And we think it’s because in people that inherit one copy of the sickle cell gene, they don’t have sickle cell disease, they actually have protection from malaria. And so we find that if you look globally at where the sickle cell mutation occurs and what human populations, it tends to be more abundant in areas of the world where malaria is an endemic disease.

Unfortunately, when somebody inherits two copies of the sickle cell gene from mom and dad, then they do have sickle cell disease and they suffer from this disorder. 

(Music: “Code Entry” by Blue Dot Sessions)

Anne Brice (narration): Hemoglobin is a protein in your red blood cells that acts like a specialized delivery truck. Its primary job is to pick up oxygen in the lungs and carry it to every organ and tissue in the body. 

Doudna chose to focus on a CRISPR therapy for sickle cell disease because it’s relatively easy to deliver gene-editing molecules into blood cells as opposed to other cells, say in the brain or the heart. 

During gestation, a fetus’s hemoglobin, also known as “hemoglobin F,” has a higher affinity to oxygen because it needs to pull oxygen from the mother’s blood and help feed the tissues in the fetus. But after birth, the fetal hemoglobin gets shut off and adult hemoglobin is activated. 

Jennifer Doudna: Scientists like Stuart Orkin, who is a professor at Harvard Medical School, years ago asked the question, “How does that regulation work?” 

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And he started investigating: What is it that controls the production of fetal hemoglobin? What turns it off when we’re born? 

And what he found is that there’s a protein called a transcription factor known as BCL-11A, complicated name. This is a protein whose job is to turn off the production of fetal hemoglobin.

This was sort of the light bulb going off saying, “Aha, if we know how fetal hemoglobin is turned off, suppose we could disrupt the production of this transcription factor and turn back on the production of fetal hemoglobin?” That could be a way to override the effects of adult hemoglobin that’s in the sickled form.

(Music: “Whiteout” by Blue Dot Sessions)

Anne Brice (narration): This scientific discovery offered a glimmer of hope on the horizon — but for Victoria, the immediate reality of living with sickle cell was about to become much more dangerous. 

Anne Brice (narration): When Victoria turned 19, she was moved to adult care in a new facility. That’s when everything changed. She felt like the nurses and doctors didn’t listen to her and didn’t take her pain seriously. 

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Victoria Gray: You rarely saw the same person twice. They didn’t know your name and I didn’t theirs. I didn’t feel safe saying what was going on with me. There wasn’t a routine. It wasn’t the same proactive care. 

And once you become an adult, when have your crisis and enter into the ER, you’re no longer believed that your pain is real. 

Anne Brice (narration): Medical personnel suspected she was playing up the pain in order to get opiates or other pain medication. She’d choose smart outfits to avoid being labeled an addict. But it didn’t help. 

Victoria Gray: Less than five-minute waits turn into six-, eight-, sometimes 12-hour waits in the ER for me to get treatment, and it would make things so much worse.

You have this challenge of living with a disease that’s about to kill you on the daily, and now you’re dealing with a medical team that don’t believe your pain is real. It’s enough to make anyone want to just throw in the towel. 

When you’re already living with pain that feels unbearable and you’re trying to be stoic — because if you’re too loud, you get judged. If you’re too quiet, you get judged. You don’t … sickle cell patients have to sit there and ponder what to wear before they go to the ER. So it’s an extra burden and it is so unfair. 

(Music: “Ranch Hand” by Blue Dot Sessions)

Anne Brice: Did you have the feeling that it was going to be the rest of your life like this? 

Victoria Gray: Yes, I did. And I had the feeling that my life would be short, as well. I didn’t look forward to a long life. I stopped dreaming. I gave up on school or doing anything. I was basically just existing in my home, just going out to doctor’s appointments, because I thought that I was close to dying. 

Anne Brice (narration): By this time, Victoria had a family. She had her first son, Jamarius, at age 21, and twins, Jaden and Jadasia, a year later. She says the pain during child birth was nothing compared to that of her sickle cell crises. 

At 25, she got married to Earl, a U.S. National Guardsman who had a daughter, Asia, from a previous relationship. 

Victoria felt like she couldn’t give her four kids the lives they deserved. She tried to avoid getting too cold, which triggered her crises, and she was often in pain and fatigued. 

Victoria Gray: All of my kids’ birthdays are in the winter — December and January. 

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So I would be sick a lot of times on their birthdays, in patient in the hospital. So we’ve celebrated Christmas in the hospital. We’ve celebrated Thanksgiving with me being in the hospital. It really took me away from my kids a lot, and that was the most challenging part. 

I had this guilt that I was cheating my children out of their childhood, but I didn’t want to. I just didn’t have a choice. I just felt like I was breaking my kids’ hearts.  

Anne Brice: Did they worry as they … you said your son was especially worried?

Victoria Gray: Yes, my oldest son, Jamarius, he was about in, I think, sixth grade at the time and he kept getting in trouble at school. I was constantly getting calls. 

But I get this call from his teacher and she wants to meet me. So I go to the school, I leave my walker in the car, and she said, “Victoria, I know why Jamarius is acting out,” and I said, “Why is it?” And she said, “Because he’s afraid that he’ll be at school and you’ll die at home and he won’t be there to save you.” 

That was a hard reality to hear as a mom because the truth was I had been praying to God every night to allow me to die. I thought my kids would be OK, that they would get a stepmom and my husband would get a new wife. I thought I was a burden.

But here my son was fighting, literally and physically, for me to live. He didn’t want to lose me.

(Music: “Vessel Five” by Blue Dot Sessions)

So that’s when I got the courage to start fighting and my prayer changed from, “God, if you love me, you’ll allow me to die tonight” to “God, will you allow me to live to see my kids become adults, so I can be there for them in all of their important moments?” 

It was the love of my kids that kept me here, that gave me the courage to look for options. 

Anne Brice (narration): After several years of safety testing, the FDA approved CRISPR to be used in clinical trials for sickle cell disease in late 2018. 

A year later, Victoria was in Nashville, Tennessee, to be evaluated for a bone marrow transplant. 

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That’s when her doctor, Haydar Frangoul, presented her with another option: an experimental trial of a CRISPR therapeutic. 

Victoria Gray: He explained that it was like going into a textbook with thousands and thousands of words, finding one word that’s misspelled, and correcting it without disrupting the story. And he goes on to say, in theory, it would go in my DNA, turn back on the switch that creates hemoglobin F and potentially cut down the amount of crises I have, at least by half.

(Music: “Delamine” by Blue Dot Sessions)

Anne Brice (narration): She was ready. Victoria would be the very first person in the world to be treated for sickle cell disease using a CRISPR therapy. Doudna is still impressed at the courage it took. 

Jennifer Douda: Imagine that. Imagine being the first person who volunteered to be number one when something has never been tested before in humans, and to volunteer to try it. It’s amazing to think of how brave she had to be. 

Anne Brice (narration): The one-time treatment was a long and physically demanding process. 

First, doctors had to collect millions of Victoria’s stem cells. She was connected to a machine for six hours a day for three days in a row. These cells were then sent to a lab to be edited with CRISPR. 

Victoria then underwent one month of high-dose chemotherapy to wipe out her existing bone marrow, which was producing the sickled cells, to make room for the new, edited cells. 

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After about three months, her CRISPR-edited cells were ready. 

Victoria Gray: And on July 2, 2019, Dr. Frangoul infused the new edited cells that I call my supercells right through the same catheter that I received my blood transfusions. 

(Music: “Gusty Hollow” by Blue Dot Sessions)

Anne Brice (narration): Because stem cells have a natural homing instinct, they travel through the bloodstream, find their way to the hollow centers of your bones — the bone marrow — and “park” themselves there. The process is called engraftment. Once they settle in the bone marrow, they start multiplying and producing the new “supercells” that create healthy fetal hemoglobin. 

Victoria Gray: He pushed four vials real fast, and I was just in shock. I said, “Is this it?” And he said, “That’s it, girl.” 

And I was very emotional. My dad thought something was wrong, and I was like, “Nothing’s wrong. I just can’t believe after 34 years of suffering, this is all it took.”

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Anne Brice (narration): But it wasn’t without any pitfalls. Two weeks after receiving chemo, all of Victoria’s hair fell out, which she’d planned for. 

Victoria Gray: It was a funny moment, me lifting all of my hair off my head like a hat and placing it in a bag. I sent the photo to my kids of my bald head and they called laughing, saying, “Oh, you look like Pop Pop” (laughs) because my dad, he’s bald and he was there with me.

Anne Brice (narration): Then came the mucositis — sores in her mouth and throat so painful it brought tears to her eyes.

Victoria Gray: But I had my dad there and someone from Dr. Frangoul’s team reminding me that I had seen worse and if I got through those crises, I can get through this. 

Anne Brice (narration): She stayed in the hospital in isolation for 30 days while her immune system recovered and the new stem cells started to graft. After that, she moved into an apartment nearby for seven weeks for regular monitoring.  

Then she returned home to Forest, Mississippi. 

(Music: “Cedar Stand” by Blue Dot Sessions)

At age 34, Victoria was walking on familiar ground with a new strength she had never known.

Anne Brice: When did you start feeling a difference? 

Victoria Gray: It was slow. The first thing I noticed was that I didn’t need blood transfusions. My hematocrit and hemoglobin were stable, but I still felt achy. I had been through a lot.

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Anne Brice (narration): Soon she started tapering off her pain meds — Dilaudid, hydrocodone, oxycodone, percocet, hydroxyurea and folic acid. She still needed her heart medications, though, to treat permanent damage caused by lack of oxygen. 

Victoria Gray: It was just one day, about seven or eight months after the infusion that I woke up and I didn’t feel anything. I thought I was dead. It sent me into a panic — I started to pinch my face, I started to pinch my thighs. And I said, “I can feel it, but I must be like Casper. I don’t wanna leave these kids. I have unfinished business.” 

It took me calling my kids into the room and giving them a hug to know that they can hear me, see me, feel me, I can feel them. And once I sent them out, I was like, “Oh, my God. This is what normal feels like?” 

Anne Brice (narration): Slowly, she started to believe her new reality. Whenever the weather forecast called for rain or thunderstorms, she would brace herself for an episode. And she’d always bring a blanket wherever she went. 

Victoria Gray: There were still a lot of things I had to overcome mentally. Like, “OK, is this going to last?” I was the first person, so I’m the prototype. I don’t have anyone to call, you know, so all eyes on me. 

Even once people came after me a few years later, I felt like, “Oh, if anything goes wrong, it’s going to start with me first.” So I’d constantly check myself, like, “OK, how does your back feel? How are your legs feeling? You’re OK.” 

(Music: “Copper Halls” by Blue Dot Sessions)

It was challenging, but I started to embrace my new life.

Anne Brice (narration): She stopped using a walker. She could take baths by herself and grocery shop and make dinner without an in-home aide, like she’d had for years. She got a job at her local Walmart, where she stocked products and built displays. 

Victoria Gray: I was doing a lot of physical activity, and I loved it. I finally got a chance to know and meet people in my community. I had been here since 1999, and people thought I was from out of town when they met me at Walmart. 

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I was like, “No, I live here. I’ve been here.” And I didn’t know them, a lot of them I didn’t recongize. So I loved the interaction, to finally be a part of the community. That’s all I have ever wanted. That’s what I longed for as a kid — to be part of the team. 

Anne Brice (narration): And most importantly, she could be part of her family’s lives. Her daughter joined the dance team, and Victoria could watch her perform in Christmas parades. Her son started football, and she could go to his games on cold nights. 

Victoria Gray: CRISPR not only freed me, it freed my children. 

(Music: “Vessel One” by Blue Dot Sessions)

Anne Brice (narration): In December 2023, the drug Casgevy was approved by the FDA as the first CRISPR therapy for people with sickle cell disease. While Doudna’s lab provided the scientific blueprint, it was the biotech companies Vertex Pharmaceuticals and CRISPR Therapeutics that turned that discovery into a medicine. 

Casgevy has since been used to treat dozens of people globally, with over 150 more patients in the first phase of stem cell collection. 

One of the big reasons more people haven’t been treated yet is its high cost. At more than $2 million per patient, it’s out of reach for most people. 

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And while many private insurers do cover it today, it has strict eligibility criteria. Not to mention the cost of travel, the long stay in the hospital and renting an apartment for several weeks after the procedure.  

These barriers to treatment are something that Doudna thinks about a lot. 

Jennifer Doudna: We want to make sure that the technology continues to advance, and not just as a technology in academic papers, but in real-world applications. 

And I think for that to become a reality, we must continue to drive down the cost. That’s something that I’m very excited about. It’s something we’re working hard on at the Innovative Genomics Institute and with our commercial partners, and I think it’s going to be achievable. 

Anne Brice (narration): CRISPR therapies are coming along for a number of other diseases, too, she says.

Jennifer Doudna: There’s a lot of effort going on currently to use CRISPR to target immune cells and to use CRISPR reprogramming of immune cells for cancer therapies. There’s excitement about using CRISPR to change genes in the liver that could be protective against high cholesterol and as a result, reduce heart disease. 

And in the longer term, there’s excitement about using CRISPR in the brain, where we see opportunities potentially to reduce the risk of neurodegenerative diseases like Alzheimer’s disease. 

(Music: “PolyCoat” by Blue Dot Sessions)

Anne Brice (narration): That future arrived in early 2025, when a 9-month-old named KJ became the first person to receive a personalized CRISPR treatment for a fatal liver disorder. Within weeks of the treatment, he was home and thriving. It was a milestone that proved the technology could be customized to save even the rarest of patients.

Jennifer Doudna: So when I think about the next 10 years of CRISPR, I think we’re going to see initially more therapies that affect the blood and the liver because we already have a pipeline for those. But perhaps over the next five years, we’ll start to see other tissue types coming online as the technologies for delivery continue to advance. 

Anne Brice (narration): Victoria hasn’t had a sickle cell crisis since her one-time CRISPR treatment nearly seven years ago. 

Last December, she left her job at Walmart to become a full-time patient advocate and public speaker. She travels around the world, sharing her story at biotech companies, patient organizations and medical conferences. 

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Victoria Gray: I think it’s important to share my story, the good parts and the bad parts, the joys and the pain, to bring a human side to the experience, because we’re more than just patients. We’re real people with real lives. We’re mothers, fathers, sisters, brothers, friends. 

Anne Brice (narration): When she speaks to insurance company reps, they tell her that after hearing her story, they feel more confident covering the $2 million product knowing it’s a one-time treatment that changes lives and benefits society’s workforce. 

(Music: “For We Shall Know Speed” by Blue Dot Sessions)

Victoria’s oldest son, Jamarius, is in college now and her twins are in high school. Instead of her mom calling all the time worried, asking her how she’s feeling, her mom now calls her asking for favors. 

When a new patient comes to Dr. Frangoul with questions about what the treatment process is like, he sends them to Victoria. She talks with them one-on-one about what to expect and gets updates about how their lives have improved receiving the therapy. 

Victoria Gray: That’s the type of feeling, like … that gives me the chills. That brings me so much joy, to see that other people are not just believing, they’re really getting the opportunity to live. 

Anne Brice (narration): I’m Anne Brice, and this is Berkeley Voices, a UC Berkeley News podcast from the Office of Communications and Public Affairs. Music by Blue Dot Sessions. 

You can find Berkeley Voices wherever you listen to podcasts, including YouTube @BerkeleyNews. 

This is the third episode of our new season of Berkeley Voices. In six episodes, we hear from UC Berkeley scholars working on life-changing research and the people whose lives are changed by it. New episodes come out on the first Thursday of every month, from November through April.

We also have another show, Berkeley Talks, that features lectures and conversations at Berkeley. 

You can find all of our podcast episodes, with transcripts and photos, on UC Berkeley News at news.berkeley.edu/podcasts.

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