This month, a 12-year-old boy in Washington, D.C., became the first person in the world to undergo a grueling gene therapy treatment that could cure his sickle cell disease. It is a game-changer for a disease whose history has been plagued by the racism baked into our health care system.
On The Dose podcast, host Joel Bervell sits down with Dr. Cece Calhoun, a leading adolescent sickle cell specialist from Yale University. The two dive into what it means to be a young Black person in America with the disease; why it took nearly 100 years for us to get to this point; and how health inequities continue to pose life-and-death challenges for sickle cell patients.
Transcript
JOEL BERVELL: My guest on this episode of The Dose is Dr. Cece Calhoun, an assistant professor of medicine, hematology, and oncology at Yale University School of Medicine, specializing in the care of individuals with sickle cell disease. She also serves as medical director of the Adult Sickle Cell Program at Smilow Cancer Hospital. Dr. Calhoun’s expertise, career focus, and dedication in the realm of sickle cell disease and health equity make her not only a widely respected thought leader in this space, but for me, the ideal guest to cap this series of conversations on The Dose, as historic breakthroughs in sickle cell disease treatment are in the news right now.
Dr. Calhoun’s research focuses on addressing educational and health care obstacles faced by adolescents with sickle cell disease and developing and deploying mixed methods to find effective solutions. She’s devoted her work to designing and implementing evidence-based interventions that support successful transition from youth to adult care. An NIH-funded investigator, Dr. Calhoun collaborates with hematology colleagues nationwide to improve outcomes for patients with sickle cell disease across their lives.
Dr. Calhoun, thank you so much for making the time to join me for this conversation on The Dose.
CECE CALHOUN: Absolutely a pleasure to be here. Thank you for having me.
JOEL BERVELL: Yes. So this month, a 12-year-old boy in Washington, D.C., began what has been described as an extremely challenging and even grueling gene therapy treatment for sickle cell disease. We’ll dive into the history of sickle cell on this episode, but I’m hoping, can you start us off with what is new about this treatment using a gene-editing technology? And as you’ve been working on this for so many years, how would you characterize how much of a leap forward this is?
CECE CALHOUN: So we first understood the genetic aberration that causes sickle cell disease in 1910, but even up until recently, we only had a handful, less than a handful of options to treat sickle cell disease itself. One of those being the only curative option, which was bone marrow transplant. All of the cells in our blood, including our red blood cells, which is affected by sickle cell disease, are made in our bone marrow, and replacing one’s bone marrow with someone who doesn’t have sickle cell disease represented the only option for a cure.
But it’s not as simple as it seems. A bone marrow transplant, especially in persons of color, is extremely challenging because I like to say to my patients, our genetics are as diverse as our skin color. And so it’s often challenging to find an ideal match, making this procedure that’s already high risk, even more high risk. With gene therapy, it allows a person to be their own match, to be their own cure, and in that way, not only is it extremely innovative and exciting scientifically, but it represents a new frontier for people who suffer from sickle cell disease.
JOEL BERVELL: That was such a beautiful way of putting it. Can you explain a little bit about how the treatment works? I think a lot of people are unfamiliar with just how strenuous it can be and just how involved it is.
CECE CALHOUN: Yeah, absolutely. So we make it sound kind of simple that, oh, we take someone’s stem cells, we edit them outside of their body and we give them back. But there’s so much more to the story. Even to get to that one point, a patient has to first be an ideal candidate. We have to make sure that their disease isn’t in a place where they have certain complications that preclude gene therapy. Then once we find them as an ideal candidate, then we transfuse them ahead of time regularly to get them in the best possible shape, all of their organs in the best possible shape to be able to handle gene therapy. Once they’ve been successfully transfused for several months, then we have to get their stem cells. We have to stimulate their bone marrow using a special medication that encourages the proliferation, the growth of those stem cells, and then we hook them up to a special machine that siphons them off.
And oftentimes this takes several rounds. So this is before we’ve done any editing. Once we get the right amount of cells, the number we need, two things happen. Patients are waiting, but they’re not just waiting, being still, right? They’re continuing to get transfused or continuing maintenance therapy, and then those cells are shipped off to be genetically modified outside of the body. Really, when we think about the two FDA-approved therapies, there are two ways to modify those genes. One, using CRISPR technology, which I think everyone is the one that’s hearing about is very cool, very exciting. And what that CRISPR technology does is allows us to identify a certain piece of the DNA segment and cut out that piece. In this instance, it is the part of our DNA that says, hey, you know those cells you made when you’re a baby, fetal hemoglobin?” There is a gene that suppresses that production. And so that CRISPR technology removes that allows for that hemoglobin F to really, really proliferate, thus offering a cure.
Now, the second way uses a viral vector as a bit of a Trojan horse to introduce new genes into the DNA that produce a hemoglobin that doesn’t sickle at all. It’s a new type of adult hemoglobin that doesn’t sickle. So those are the two ways right now in which we modify those stem cells. So once those cells have been modified, then we come back to our patient, who we have to prepare to receive their own new and improved cells. And the way that we do that is through chemotherapy. We call it myeloablative chemotherapy because it ablates the entire bone marrow — it completely knocks it out. And this is one of the most challenging times during the gene therapy process, because during that time, our patients have no immune system. We are their immune system.
And so the patient has to come in the hospital, receive this really strong chemotherapy to make room for those cells and help the body accept them. Once we give those cells, it’s a celebration moment, but we have to wait on those cells to really take hold and continue to grow. And really, it’s not until those cells are reproducing, fully growing and proliferating, that we say that this person is in the clear. And even still, Joel, we don’t know the long-term effects. We’re optimistic about how this will improve organ function, how this will improve overall quality of life, but it’s still too early for us to even know long-term the benefits that we’ll be able to continue to see.
JOEL BERVELL: Yeah, and you kind of predicted my next question. I was about to ask, how do these two new treatments change living with sickle cell disease for most patients? You just described how strenuous it can be. Is that medically viable for most patients? And then of course there’s a piece, is it affordable or accessible for most sickle cell disease patients?
CECE CALHOUN: That’s a great question, and I would actually add a third component, not just about medical viability or accessibility when we think about cost, but how does this affect their quality of life, their identity, their psychosocial wellness? And these are all questions that we need to answer.
So first, medical viability. So we know that this is a well-studied, clinically trial-tested treatment, right? We know that it is safe and effective for patients, otherwise it would’ve never made it through that whole process. Thankfully, we’re beyond the point where we are arbitrarily experimenting on marginalized populations and we’re never going back there. And so we know that medically this is a safe and effective procedure.
Now, you alluded to accessibility, because we know that these gene therapies are expensive, several millions of dollars, and we still don’t know who is going to pay for gene therapy and how will that be shared amongst not just insurance companies, but hospitals and different health care entities. And so we’re discovering these things now and our own United States government has made a commitment to help provide access to gene therapy on state-by-state negotiations with CMS, but it’s again, still too early to tell. And then when we think about accessibility in the U.S., the majority of patients with sickle cell rely on government insurance. And I’m encouraged by the fact that our government has said, hey, we want to make this accessible and available. But we don’t know how long that will take. And we don’t know what those negotiations will look like. But that’s here in the U.S.
The global burden of sickle cell disease is much, much greater than it is in the U.S. And so we have to think of innovative to reduce cost so that we can actually treat sickle cell globally and not just in the U.S. There’s some really exciting science coming down the pipeline, but I don’t think we know yet the next best steps.
And then lastly, thinking about how this affects the person, not just the disease, but the person. How does it change their identity? How does the quality of life change when now their disease is cured? The best person to answer these questions are the patients who have gone through it.
I got the chance to attend a panel through ICER, the Institute for Economic and Cost Effectiveness Research, and they had a patient there who had undergone gene therapy, and he talked about how his whole life he wasn’t able to keep a job. It prompted him to become an entrepreneur, but he was unable to keep a job because his pain episodes were so severe and unpredictable. But now after gene therapy, he’s able to be consistent in how he shows up in employment, how he shows up for the people in his life that he loves. For me and for many people who work to support sickle cell warriors, it’s about helping our patients not just survive but thrive. And so it’s going to be so wonderful to see how this treatment really promotes that.
JOEL BERVELL: That’s so exciting to think about. What that opportunity and just quality-of-life change, as you mentioned before, making sure to include that in, because that quality-of-life change is going to be massive for so many people. I kind of want to talk about . . . you hit on a point with the international aspect of it. We’d love to dive in a little bit more there. Like you said, the sickle cell burden internationally is way greater than in the United States. What does this look like exporting this specific technology outside the United States? Is that something that as far as you know, is being done or thought about, or is this still in the early stages here only in the United States?
CECE CALHOUN: So these treatments are FDA-approved. What they’ll look like in low- and middle-income countries is to be determined. One thing I’m really excited about in the scientific space is there are some really awesome scientists thinking about how we can actually modify genes in vivo, inside the person rather than having to siphon off those stem cells, send them off to a lab, have the processing time. Is it possible for us to do that within a person, which would take away the need for that very harsh chemo and the facilities and resources that help support that.
But that’s many, many years, many years in the future. I think we have a lot of work to do, to work with our international colleagues to think about how we provide access to all of the great scope of care that we have in the U.S. Even in the United States, we estimate that sickle cell disease affects approximately a hundred thousand Americans, mostly of African descent, Africans on the diaspora. But many of my colleagues, including myself, would say that number’s probably way lower than what actually is the prevalence of sickle cell disease in the U.S. But globally, it’s millions of people. And so there is a sense of urgency, while we are hopeful and excited for this treatment, that we don’t lose sight of the fact that our colleagues abroad also need this.
JOEL BERVELL: Absolutely. I was a microbiology major at Yale actually, and absolutely loved thinking about gene therapies. I remember I was in college when CRISPR-Cas9 was like the technology first came out, everyone was so excited. And it’s anticipated that this gene therapy could be a cure for a number of retic diseases. Was sickle cell chosen as one of the first targeted diseases because of the historic lag in research?
CECE CALHOUN: So I can’t honestly say that I think it was related to the historic inequities. I think the optimistic person in me would like to think so, but I’m also quite pragmatic and realistic. I think there was a synergy of many things that came together that allowed for our patients to really benefit and that allowed for these pharmaceutical companies and scientific leaders to offer an opportunity for cure. And I’m overall thankful and grateful for that.
JOEL BERVELL: You mentioned at the top of this that sickle cell disease was first identified in 1910.
CECE CALHOUN: Yeah.
JOEL BERVELL: That’s getting close to 120 years ago, and that it was several decades before any treatment was developed. I kind of want to take a step back from the state-of-the-art technology that we’re thinking about today, that we’ve been discussing, and talk about what it took to get here, starting with why did this take nearly a century and how, if at all, has race played a part in that delayed development of treatments?
CECE CALHOUN: So when we think about our society, our funding priorities, research, health care and medicine, we know that when it comes to health equity or health inequities, it is our historic prejudices and biases that inform our institutions, our policies, and living environments. Those things can ultimately inform risk factors, treatment, diagnosis, and in many times outcomes of the patients that we serve. When I think about people who have sickle cell disease, I find this to be an exemplar population for how those historic inequities, upstream kind of biases, trickle down to downstream outcomes. So again, 1910, sickle cell disease first described. It wasn’t really until 1998 that the FDA-approved hydroxyurea, which is our bread-and-butter medication for actually treating sickle cell disease. So we’ve been using Hydrea, and that’s the FDA approval. It had been being used a bit prior to then.
And there was just another large swath of time where there was only hydroxyurea until 2017 when we got Oxbryta, then we got crizanlizumab, and then a couple of other medications are on the horizon. And still, yeah, that’s less than a handful. I have five fingers and I just named for you three medications. And so limited tools in our toolkit other than blood transfusion to actually treat sickle cell disease. And I do believe it’s a reflection of our institutional bias because research is a lot dependent on funding priorities. It’s dependent on what’s most salient to our funding organizations and to our society. And when you’re dealing with a historically marginalized population that experiences unpredictable severe pain treated by opioids, who primarily affects Blacks in America, that racism, that bias, that inequity is going to be super salient.
And when I think about the patients that I see, especially young adults — which is my bias, as you noted in my bio, that’s where my area of interest is — I find that much of the way that they experience their disease isn’t necessarily only related to the complications of sickle cell. It is their experiences of being young Black people in America and that shapes how they experience care, how they’re able to access treatment, and what treatments are available. And so absolutely historic and institutionalized racism and systemic racism have impacted the way that all of us are able to care for patients with sickle cell disease. I think and I remain, like many of my colleagues, hopeful that this advancement with gene therapy represents a new horizon, but that doesn’t take away the challenges that we have faced due to these inequities.
JOEL BERVELL: I think so much about during my emergency medicine rotation, I had a young woman come in, she was probably 20 years old. She was having a sickle cell crisis and she’d been in and out of the emergency department so much, and the doctors kind of got to know her, but they never wanted to do a deep dive into her chart for some reason. I remember I had extra time. That’s the beauty of being a medical student. You can spend more time with patients. And so I did a chart dive and looked at what the doctor that she was working with on her pain contracts and things was saying, and realized that they’d updated her pain contract months before in between there, but had not ever given her updated treatment.
And so I remember I went to my physician I was working, my attending I was working with, and I said, “Have you seen this new pain contract that’s in there?” And he’s like, “Oh, no. She was mentioning something about it, but I was just going to give her the same thing we always give her.” I was like, “Well, here, I printed out for you. Here it is. It looks like this works for her. Why don’t we give her this?” And I remember I went back into the room, she’d been there for a couple of hours, and she turned to me and said, “Are you the one who got him to change my pain contract? He mentioned you were the medical student that said something.” And I was like, “Yeah.” And she was just like, “Thank you for listening.”
Sometimes it’s simple as that, right? Sometimes it’s just listening to that patient and making sure we do our extra due diligence that takes two extra seconds to help people that have been marginalized by our biases, by our inherent beliefs, by the fact that we don’t give Black patients specifically adequate amounts of medication, especially when it comes to things like sickle cell disease. It’s so important that everything you were saying and just understanding that historical context and how that impacts everything today.
CECE CALHOUN: I’ll say this, I think when I think about our colleagues in the emergency department, especially the ones who I know are well-intended and want to do the right thing, what is the system that’s making them triage quickly and have to rely on their own biases that they may not be aware of to deliver effective treatment? And then what is the systemic thing that we can do to help mitigate that? At the end of the day, we’re humans in medicine, and so we have to be aware of our own unconscious bias, and then we also have to put systems in place that help us to mitigate those things.
JOEL BERVELL: So you mentioned some of the funding stream as well. How has that funding stream for sickle cell looked over the years?
CECE CALHOUN: So the National Institutes of Health, which is kind of our primary research-driving funder when it comes to hematologic research, has made sickle cell a priority and is making a concerted effort to not just hear from physicians, but also hear from patients about what their needs are and where they should deploy resources. Also, the American Society of Hematology has been incredible in highlighting sickle cell disease, lifting up training programs that support young hematologists, but always it shifts with the tides, right? Ultimately, NIH funding is determined by the Senate Appropriations Committee. So we have to also think about our government structures, finding advocates within these powerful spaces on the Capitol, and being a voice and letting patients be seen and heard to move these funding needles forward.
JOEL BERVELL: I kind of want to get to the comparison of sickle cell disease and cystic fibrosis.
CECE CALHOUN: Yeah.
JOEL BERVELL: One fact I often think about is that three times as many people in the United States have sickle cell disease when compared to cystic fibrosis, but the two diseases received about the same amount of government funding between 2008 to 2018. And the private fundraising apparatus is pretty similar. Is that frequently cited contrast between sickle cell disease and cystic fibrosis, an apt illustration of glaring gaps in patient care, especially based on patients’ race and social/economic status?
CECE CALHOUN: So I’d say this, the facts are the facts, right? It is true sickle cell is more prevalent and it is underfunded as compared to CF. I mean, that’s just the numbers. Neither one of us can alter those numbers in a way that tells any other story. And I would be remiss, I would be ignorant almost, to think that there is no role of socioeconomic status or race in the deployment of these funds and supports, not just from the NIH or professional organizations, but from foundations who also support CF. There’s a paucity of private funding that goes into sickle cell disease. It’s always my hope that as we can continue to provide exposure and teach people about sickle cell and bring awareness that we’ll find champions, and they do exist in the U.S.
But absolutely there’s a funding disparity which results in a lack of treatment, which results in a lack of resources, whether it is qualified physicians that are willing and able to treat people who have sickle cell disease, whether it is access to medications or other resources, whether it is access to tertiary care centers. All of those things show up as health care resource disparities. And then that results in health outcomes disparities, right? Like, adults with sickle cell disease are three times more likely to have a stroke compared to age, race, SES-matched person without sickle cell disease. The life expectancy of sickle cell disease is 20 to 30 years less than age, race, SES-matched without sickle cell disease. These outcomes are just astounding, and they are very much shaped and woven together by inequity.
JOEL BERVELL: Yeah, and those inequities literally affect people every single day in ways that I think a lot of people don’t understand.
CECE CALHOUN: It’s life and death. It’s life and death.
JOEL BERVELL: So what will be monitored most closely when it comes to this 12-year-old patient that it’s going to be receiving this treatment? What learnings do you think you’re looking for?
CECE CALHOUN: So many things. So of course, how is he doing? How does his body accept these new and improved cells? How do the complications that he experienced before undergoing gene therapy, how does that evolve post-gene therapy? Is he no longer having pain? How is his quality of life? And then medium- to long-term, I would say, how are his organs doing?
As we see young people with sickle cell get older, we see lots of what we call end organ damage, challenges with the kidneys due to sickle cell disease, challenges with the liver due to sickle cell disease. Many, many patients, even our young ones, younger than 18, have strokes related to sickle cell disease. Which if we have time out, I’ll tell you a little bit of story of how I ended up in this space. It was because I saw an 8-year-old who’d had a stroke. So we want to see how do his organs fare? How does he fare? And then I think it’s going to be really, really wonderful to see him bloom into his full potential. So that’s what I think about when I think about quality of life. And then I think he will be the person that teaches all of us lessons about how to continue to care for people who have undergone these therapies with curative potential.
JOEL BERVELL: I actually would love to hear that story about how you got in. Please, please, tell it.
CECE CALHOUN: Of course. So people always ask me, they’re like, “Cece, does somebody in your family have sickle cell disease? Why do you care about this?” And I’m like, “No.” And I think it was a combination. I’m very lucky of a few things. So I went to undergrad at the University of Michigan — Go Blue! — and during that time, it was a really awesome space for exposure to research and the impact that you can have through research. But also a young student, my orientation is activist. And so for me, I was like, I know I want to go in health care. It doesn’t seem right that some people have access to their meds depending on where they live, or it doesn’t seem right that if you live in a certain zip code, you get better care. And so I wanted to impact this. And so I knew that going into medical school.
And when I did my rotations in med school, my peds rotation was on the hemoc [hematology-oncology] floor, and that’s where I met this young lady. She was 8 years old, and she had had a stroke. Seeing her represented for me, it was like the intersection of so many things I care about. It was a marginalized community that I wanted to fight for. Could be my cousin. Could be my sister, right? Could be my daughter. It was a disease process that we didn’t know a lot about because of inequity. So I said, this is room for me to make impact and do better. And then it was kind of the science that I loved.
Now, in hindsight, having completed all of my training, I know that ideally we would’ve been screening that young woman — or little girl, I should say — for risk of stroke using transcranial Doppler. Because of research studies, we know that if we screen and we see abnormalities, we could have started her on chronic transfusion to prevent that stroke.
JOEL BERVELL: Wow.
CECE CALHOUN: But I also know that test might’ve been ordered, but she may not have been able to get to the hospital, or her parent might have been a single parent and may have had to choose: “Do I go to work to feed my family, or do I take her to this appointment?” And I think it’s so much more complex than what meets the eye. And when we think about one of the resource disparities that when it comes to sickle cell, it is a lack of providers, again, who are trained and willing to see these patients. And so I have to shout out you and all your med school colleagues, brilliant future of medicine, we need you because we need empathetic, compassionate, activated activists in these roles if we’re going to mitigate health disparities. And I’m biased towards hematology, but it’s in every area of medicine. There’s room for us to make a difference.
JOEL BERVELL: Well, thank you for what you do and for taking that spark of activism to literally change lives every single day as you’re going to work and just being an incredible . . . I can tell your patients must love you so much.
CECE CALHOUN: I love them, too.
JOEL BERVELL: But I mean, how do we take this and scale it? There’s nine FDA-approved centers around the country, cleared for treatment and scaling. You’re one person doing incredible work. There’s only nine of these FDA centers. What about those kinds of centers?
CECE CALHOUN: So more are coming, including Yale. So we’ll be a treatment center as well. But I think part of it is one, awareness. When I talk to my patients, my young people about, “Hey, what do you need to successfully navigate health care?” A lot of people say, “People don’t know about sickle cell disease. It’s an invisible disease. They don’t understand what I go through.” So we have to bring awareness if we want to bring any kind of resources, whether it’s funding, whether it is more treatment centers, whether it is encouraging young people like yourself to say, “Hey, I want to take this passion and bring it to this community.”
I think we also need to continue to be persistent. Yes, gene therapy is here, but it should be only the beginning. We still need more. I have worked with so many brilliant people in my life that I know that we have the capacity to do better by patients scientifically, and I’m excited for the advancements that we’ll see over my lifetime because when I told you that the life expectancy was 20 years less, that’s data from 2021. That’s not old data. So we have a big, big move to make in improving the overall life expectancy for people with sickle cell disease. We need to do better.
And then I think this is all on a foundation of how we address health care inequities overall, how we think about our individual biases, our systemic racism and systemic inequities, how we think about our institutional inequities, how we activate and galvanize. It’s not up to one person or one group of people. It’s a journey that we have to all go on together.
JOEL BERVELL: And like you said, it’s not up to one person.
CECE CALHOUN: No.
JOEL BERVELL: But I do want to say thank you to you for all the incredible work you’re doing. This was such a joy having you on the podcast. I think people are going to get so much more of an understanding of what it’s like to be a sickle cell patient, but also the innovations that are coming and the exciting ways that the world is changing and becoming more equitable for a lot of communities who haven’t seen it before.
Dr. Calhoun, thank you so, so, so, so much for being on the podcast. I really do appreciate it.
CECE CALHOUN: Joel, thank you for having me. It’s been a treat to be in conversation with you. I hope we get to talk again, and I hope you decide to do hematology.
JOEL BERVELL: I might have to now. You’ve convinced me.
CECE CALHOUN: Awesome.
JOEL BERVELL: This episode of The Dose was produced by Jody Becker, Mickey Capper, and Bethanne Fox. Special thanks to Barry Scholl for editing, Jen Wilson and Rose Wong for art and design, and Paul Frame for web support. Our theme music is “Arizona Moon” by Blue Dot Sessions. If you want to check us out online, visit thedose.show. There you’ll be able to learn more about today’s episode and explore other resources. That’s it for The Dose. I’m Joel Bervell, and thank you for listening.
