In this episode of The Future of Medicine, we welcome Alexis Thompson, MD, MPH, pediatric hematologist and internationally recognized expert on sickle cell disease whose work helped lead to the first approved gene therapies for this serious condition.
Dr. Thompson reflects on the extraordinary transformation of sickle cell care over the course of her career. From the early days of newborn screening and simple interventions like penicillin to today’s breakthrough gene therapies, the field has experienced what she calls “an amazing arc” of progress.
Dr. Thompson also walks through the remarkable science behind gene therapy for sickle cell disease, and how CRISPR gene editing and lentiviral vectors (modified viruses such as HIV that are engineered to safely deliver genes) are being used to modify patients’ own stem cells, allowing them to produce healthy red blood cells and dramatically reduce the complications of the disease.
Looking ahead, Dr. Thompson shares her perspective on the next frontier of genetic medicine: including efforts to make gene therapies safer, more scalable, and accessible to patients around the world.
The Intro
“Those early patients were absolutely pioneers. They were given all the information that we had, including our uncertainty that this may not work.”
Dr. Alexis Thompson is a leading expert in the fight against sickle cell disease. At the Children's Hospital of Philadelphia, her groundbreaking clinical research helped pave the way for the first approved gene therapies for this condition.
“To go from diagnosing children, starting them on penicillin, to now talking about gene therapy — there's just really been an amazing arc.”
We explore how Dr. Thompson's work is transforming lives and shaping a brighter future in hematology.
“Being patient, being persistent, really being as hopeful as one possibly could be, to see improvements that matter to patients.”
In our conversation, she reflects on her journey, the hurdles the field has overcome, and the powerful hope that gene therapy offers patients and families.
Welcome to Stanford Department of Medicine's Inside Look at the Future of Medicine.
The Transcript
Dr. Euan Ashley: Well, Alexis, welcome to the Future of Medicine and welcome to Stanford.
Dr. Alexis Thompson: Thanks so much. I really appreciate the invitation.
Dr. Ashley: We just came from a really amazing grand rounds presentation you did, which was incredibly inspiring. Your whole career really has been an incredible inspiration for our residents and fellows. It's incredible to see a disease — sickle cell disease — get to the point where we can really talk about cure. It's just amazing. Just give me a sense, first of all, before we dig in: what is it like to be in this moment and to be thinking in that way about this disease?
Dr. Thompson: You know, it's pretty extraordinary. When I began my career as a trainee, it's remarkable how far we've come. The notion that penicillin would be something that would save lives for children — those papers were published when I was finishing my residency and beginning my fellowship. And as I was finishing my fellowship, places like the state of California began newborn screening, in part because we knew we now had an intervention that mattered for children. To go from just barely scratching the surface in diagnosing children and starting them on something as simple as penicillin, to now talking about gene therapy — it has just really been an amazing arc.
Dr. Ashley: Well, before we jump to that, how about maybe just give us a little primer on sickle cell disease. I know that's not the only disease you work on.
Dr. Thompson: That's true. It's not the only disease I work on, but sickle cell is really an interesting red blood cell disorder. It's caused by a genetic mutation in a gene called beta-globin. We inherit a copy of beta-globin from each parent, and both parents have to have an abnormality for a child to actually have sickle cell disease. Now, when kids are born with sickle cell, they look completely healthy, so there really is no other reason to suspect it — save for a family history and the fact that they now get tested at birth. When they're tested and we detect it, the notice goes to the family as well as the pediatrician, and they're referred to a specialty center to have more detailed conversations about what sickle cell is and what it means for families.
Dr. Ashley: And what is the diagnostic? Is it a genetic test?
Dr. Thompson: It's a blood test — a prick on the heel. These are what we call dry blood spots. Many people have seen their newborn baby with a band-aid on their heel, and sickle cell is one of several tests that are done from that single blood spot. That has allowed us to think about early intervention, which is the primary reason for doing newborn screening — hopefully because we can do something about it. We know that children with sickle cell, if they're started on penicillin and in good, high-quality care, will absolutely survive to adulthood and will thrive. But they do need specialty care.
Dr. Ashley: So these red blood cells are kind of unstable and can change shape?
Dr. Thompson: Hemoglobin is the main building block inside red blood cells that carries oxygen, and the mutation is in the molecule called hemoglobin. Most of their red blood cells, under most conditions, look like everybody else's red cells. But under certain conditions — like stress and low oxygen — they change shape. That shape change can ultimately be permanent in those red blood cells, and it makes those red blood cells sticky. They stick to things like the surface of the inside of blood vessels, and to each other, and they clog things up. It's that clogging that causes not only pain, which is the signature of sickle cell, but also damages organs. At the end of the day, that's probably the more important problem with sickle cell — the fact that these red cells are easily destroyed and get hung up in really all the wrong places. They affect the brain, the kidneys, the lungs, and the heart in ways that really shorten the lifespan for people with sickle cell.
Dr. Ashley: What's it like to live with sickle cell?
Dr. Thompson: You almost have to ask someone who's walked in those shoes, and I readily admit every day that I am not one of them. I have a high degree of respect for patients telling their own story. But what they tell me is that the lack of predictability is probably the thing that's most challenging. Many of them can start out thinking they have a full day planned — going to school, going to work — only to find that they're suddenly caught up because they have sudden pain that can be extraordinary and so debilitating that it stops them in their tracks. Some of them will have medication at home that will help some, but many end up in emergency rooms and hospitalized.
Dr. Ashley: So some days they can almost act like normal, but then out of nowhere they can suddenly have severe pain.
Dr. Thompson: Even with the best of care, even with medications including a newer one called hydroxyurea, they may still have these episodes of unbelievable pain. The same is true for people who develop lung disease or kidney disease — sickle cell damages these organs in ways that are silent, causing chronic injury that ultimately causes these organs to fail.
Dr. Ashley: And give me a sense of how common it is — how many people, both in the US and globally?
Dr. Thompson: We estimate that there are about 100,000 Americans who have sickle cell. Ironically, I don't have an exact number because they're not actually categorized well enough for us to be certain, but the estimate is around 100,000. There are millions worldwide, and many of them live in parts of the world where there is no newborn screening, where there is no way to be certain. What we can look at is gene frequency and birth rates to predict about how many people in some of these parts of the world have sickle cell disease. We know there will be children in many of these countries who will die without a diagnosis — they may die of a diarrheal disease or from a fever that is probably malaria, without anyone knowing that their real underlying problem is sickle cell.
Dr. Ashley: One of the things I was struck by in your excellent talk was that in many countries these individuals don't reach adulthood.
Dr. Thompson: It's challenging, and to think that we may have been in that same situation 30-plus years ago in this country. The reality is that 95 to 98% of Americans with sickle cell will survive beyond age 18, which is almost the exact opposite of what you see in other parts of the world. But a diagnosis is an essential part of that, including education of a family. A mom or a grandmom might say, "Oh, this kid has a fever, it's a cold, it'll pass — the other kids in the household are sick, I'll just wait till the morning." You can't do that with a child with sickle cell disease. And so just knowing that you have a fragile child matters. The same is true for malaria. Many people in endemic parts of the world get malaria multiple times; a person with sickle cell can die from malaria because the malaria parasite attacks red blood cells, which are the most fragile cells in sickle cell disease. Tragically, families may be treating that child like all the other children in the household, not realizing what that child needed was special care.
Dr. Ashley: So — not so rare, and absolutely devastating. Before we get to some of the more exciting new things that are coming, I really enjoy hearing people's backgrounds and stories and how they've ended up dedicating large portions of their lives to this area. Take me back — when did you first know you wanted to be a doctor? When did you first know you were going to dedicate your life to blood diseases?
Dr. Thompson: I can't remember exactly how old I was when I decided I wanted to be a doctor, but by the time I got to college I was fairly certain this is what I wanted to do. I knew two things, and they're not that different from a lot of other people in medicine: I love science, and I wanted to make a difference. I thought my making a difference was going to be as a primary care pediatrician in a community practice — that really was the vision I had. But as a fourth-year medical student, I met one of the people who has been my lifelong mentor: Dr. Kwaku Ohene-Frempong, a pediatric hematologist who was passionate about sickle cell disease — something I didn't know enough about. He was just an absolutely inspiring person. I went on to be introduced to many other people in hematology oncology who were doing some really exciting things. So by the time I finished my residency, I was hooked on hematology oncology. At his suggestion, I returned to his alma mater — the Children's Hospital of Philadelphia — to do my training and to be among some really inspiring people who worked on not only sickle cell but also thalassemia, in an environment where you could really imagine not only making a difference scientifically but also finding ways to treat children and improve outcomes.
Dr. Ashley: It's incredible. Reflecting on your story, it's amazing how often it's a single individual that inspires you. So much of medicine and medical education is about passing that on to the next generation, and I have no doubt that you're doing that.
Dr. Thompson: To his credit, Dr. Ohene-Frempong — his initials are KOF, so many know him as "Kofi" — has inspired not only me but many in this country and globally. He's a native Ghanaian, and I think really dedicated, especially in the later years of his life, to advancing sickle cell in Ghana as well as across Africa, India, and South America.
Dr. Ashley: We'll definitely get to the global implications, because there really isn't another set of diseases where we have both this sort of high-tech, high-innovation element and also the ability to have a truly global and scalable impact. You mentioned it's a genetic disease. We've talked quite a lot on this podcast — we had Jennifer Doudna visit recently, one of the pioneers and Nobel Prize winner for discovering CRISPR-Cas9. You talked about some of the new and exciting gene therapies that are not just coming our way, but in two cases are already approved in the US. Give us a sense of your role there, how you first came across the idea that this disease could potentially be treated with genetic therapies, and the story from there — because it's a pretty amazing moment in medicine.
Dr. Thompson: It really is. It began with the amazing scientists who established that sickle cell was not only a disease of the red cell and of hemoglobin, but that it had a genetic basis — and that the genetic basis was something fairly discrete and very predictable. With that in mind, being a monogenic disorder, it just seemed like: surely if I could just fix what's broken, I would take care of everything. We had animal models where, if you could somehow fix the gene, you got rid of almost everything that caused complications in those mice. It took decades to go from animal models to actually envisioning how you could deliver this in a durable and safe way to human beings. My early years as a young faculty member were those years where some of those building blocks — and some of those early hits, misses, and hits — were taking place across all of science, because many people believed it was just a matter of time before we could figure out how to manipulate genes in ways that could actually treat diseases. To have gotten to the point where you could actually apply this to sickle cell — I was certainly one of many who was just waiting to see that happen, for both sickle cell and the related condition thalassemia, which is also due to mutations in the beta-globin gene. It's also interesting — you mentioned CRISPR-Cas9, and we'll come back to that one. But the other part of that story, the one that came out first, involved lentiviral vectors. We talk about lentiviruses as a unique class of viruses; the most common lentivirus is HIV. The vector that is modified is HIV-1 — yet all the extraordinary research that went into diagnosing and developing treatments for HIV, many of the advances there, helped inform how you inactivate the aspects of HIV-1 that make it such a dangerous virus, in order to actually use it as a delivery device for healthy genes. That also is an extraordinary story. Between lentiviral vectors designed to prevent disease and potentially treat certain conditions, combined with CRISPR-Cas9 — another absolutely elegant tool — who knew that how bacteria protect themselves from being attacked by viruses would result in treatments for human beings? Just extraordinary science, to see both of those approaches now being applied to things like sickle cell.
Dr. Ashley: You laid out the mechanisms so nicely. It would be great to dive into those a little bit, because most people would think: you have a broken gene, so deliver a good one. That is one of the strategies, but there are a couple of other pretty interesting strategies that aren't necessarily as obvious. Tell us about those.
Dr. Thompson: CRISPR-Cas9 is an extraordinary story — it is now a tool used so broadly. We're very fortunate that sickle cell was the first disease for which it was applied at broad scale for a human disease, and that meant figuring out what you're going to target. There were a number of questions and approaches in terms of which gene to begin thinking about modifying to have an impact on sickle cell disease — and for that matter, thalassemia. The approach of using CRISPR to modify the control region for a completely different gene called BCL11A would not have been obvious. It relied upon some extraordinary research that identified BCL11A as a master regulator. We knew that babies survive before they're born by making fetal hemoglobin — a different form of hemoglobin — and that many of us are born with mostly fetal hemoglobin, which by six months of age transitions to adult hemoglobin. But fetal hemoglobin was good stuff. So the idea was to figure out how to get the body to go back to making it, because those cells don't sickle. BCL11A, as it turns out, is a key regulator of that switch — what we call hemoglobin switching — the naturally occurring event where you go from making fetal globin to making adult globin. Being able to target BCL11A with the theory that, if you could somehow get the body to go back to making fetal hemoglobin, that would be a way to mitigate much of what we see in sickle cell.
Dr. Ashley: Amazing biological story. So you're basically using Cas9 to essentially break this regulator — or turn it down. You mentioned shRNA,which is a silencing approach. You turn down the volume of it, and that leads the body to go: "Wait a minute — I need to switch back to fetal hemoglobin."
Dr. Thompson: You said it perfectly. And then to ask the question: would that be enough? Can you make enough fetal hemoglobin, and can you get it expressed in nearly all of your red blood cells? All of these things had to fall into place to make this approach work.
Dr. Ashley: So what does that look like from the patient's perspective? They have these cells, you take them out, you do the gene editing, and then you put them back in. At some point, you also have to ablate the cells that are left. Talk a little about what it's like from a patient's perspective.
Dr. Thompson: The patient's journey is not a short one, and it's important to recognize that. First, determining the patient is healthy enough to undergo gene therapy is a rigorous process. Part of the preparation involves beginning a short period of chronic transfusion — receiving blood transfusions every month for two to three months — stopping certain medications that may affect stem cells, and then having their stem cells collected. When we first started doing this, we thought the only way to collect stem cells was a bone marrow harvest — actually going into the hipbone with fairly large needles. We recognized we could do it in a much more elegant and effective way by teasing those stem cells out into the circulation, letting them circulate for a short period, and then collecting them in a process called apheresis — hooking someone up to a machine for about eight hours, a couple of sessions, to collect enough cells. Those are then sent to the laboratory, the stem cells are purified out, modified, and checked to make sure they're safe and that we've accomplished what we wanted before returning them. Now, these are regular old stem cells to some degree. If we did not give anyone chemotherapy, they would be out-competed by the cells that have not been corrected. The only way to make space and create a favorable environment for these modified cells is to destroy or reduce the number of the patient's own unmodified cells. That's where the chemotherapy comes in. I wish we didn't have to do that, but it seems to be an essential part. By reducing the number of unmodified cells, it makes space in the bone marrow for these modified cells to set up housekeeping, continue to grow, and get rid of those cells that still make sickle hemoglobin. So the patient is being transfused — no big deal, they come in for several hours once a month. The medication to mobilize the cells has some side effects but is tolerable. When they come in to get their cells back, they receive chemotherapy for about four days via IV — not the greatest stuff in the world, lots of side effects. But the day they get their cells back — it's this tiny little vial that's almost crystal clear.
Dr. Ashley: Really? What size?
Dr. Thompson: Depending on the approach, one uses vials that are opened in the laboratory and drawn up in a syringe — no more than about two or three teaspoons of cells. Another is a packet roughly the size of a smartphone — a small, clear plastic bag with a slightly hazy fluid that are your stem cells. It gets hooked up to the IV and goes in 10 to 15 minutes. They're in the circulation — and then the patient goes back to sleep because they got some Benadryl right before.
Dr. Ashley: So, sweet dreams.
Dr. Thompson: It's an amazingly anticlimactic day, yet that is the day they begin a new life. It takes a little while. Stem cells have homing properties and know to go back to the bone marrow. So you put them in an IV, but they make their way back to the bone marrow, set up housekeeping, and then begin to divide — essentially building new factories making new cells that are fixed. And we hope it's permanent. We want to make sure that these cells are returned in high enough numbers and that they're durable. The cells will reproduce themselves over and over inside the bone marrow space. During that time, the patients are in the hospital and not necessarily having the best of times, largely because of the side effects from the chemotherapy. As they recover, their tissues heal. Many of them have mouth sores from the busulfan, but when you start making new white blood cells, those heal up. Many of them start feeling better before they leave the hospital because their white blood cells are coming back, their platelets are coming back, and then their red blood cells come in. Then they go home — and for most people, that is the last time they're ever hospitalized.
Dr. Ashley: Let's pause there for a moment. You showed these amazing plots in the early data from the different trials — I think you call them the swimmer plots — where you see an individual patient on a row and a little red dot every time they have a hospitalization. On the left side, it's just red dot after red dot, because that's the lives these patients lead — intense pain crises. And then there's this moment when they have the therapy you just described, and for most of the plots the right-hand side has the odd little red dot, but almost nothing.
Dr. Thompson: I'm not sure I could have actually foreseen that when we first started, that this would be so transformational. In fact, when I did the first patient at my institution — now nearly 12 years ago, and she had thalassemia — at the time we said, "If this works, this could be transformational," but it was really not certain. Those early patients were absolutely pioneers. They were given all the information that we had, including our uncertainty that this may not work. I don't know that we could have actually gotten to where we are were it not for their courage.
Dr. Ashley: And those plots are also much longer on the rightside.
Dr. Thompson: Talking about a patient 12 years out, able to go to college, to graduate school, to return to her parents' country of origin, all without blood transfusions or continuing medication, living her best life in the ways that she wanted. She was very clear: "No, I want this. I have dreams for myself, and if this can help me achieve them, I want this." I had nothing but admiration for her and really for many of those early patients. Today I'm far more certain. Having now had hundreds of patients undergo gene therapy, I'm much more confident — it's not without some risks, but I'm more confident that this approach will work. It's just remarkable. The idea that we could talk about curing a disease, especially one as devastating as this, makes for a remarkable moment in medicine.
Dr. Ashley: And it must be really exciting to be there and to be meeting these patients before and offering them this hope. We talked about the burden of disease globally, and these are incredible therapies. You mentioned hundreds of patients — and that's amazing — but there are hundreds of thousands in this country and millions around the world. These medicines are not cheap. How much do they cost, and how do we think about scaling — and importantly, how do we think about the large population of the world, because we have a responsibility to the entire world?
Dr. Thompson: The two commercially approved products are $2.2 million and $3.1 million — that is the retail price. When compared to the lifetime expenses of sickle cell disease for individuals who are a match, it compares favorably. That does not at all mean it is inexpensive, and it's a major hit to the system when an insurance company or a state is being asked to pick up that tab at one moment in time. It has taken a lot to imagine that. Many of us hope that, over time, we can find ways — even with current approaches — to make them less expensive. To think that we could make infinitely more expensive products when that is the price point we're already at is not sustainable, and I don't believe anyone thinks it is. So the question is: how do we approach innovation and transformation while making it a model that works for more people?
Dr. Ashley: Your point is so well taken, because people hear that sticker price and there's sticker shock. But if we go back to the swimmer plot and all those red dots — you don't get in and out of a hospital with a crisis without the system or somebody paying tens of thousands of dollars.
Dr. Thompson: Absolutely correct. It's always hard to put a price tag on shortened lives — economists have an extraordinary way of estimating that — but when we think about the number of people with sickle cell dying in their 30s and 40s and the years lost in terms of their productive lifespan, that's also an extraordinary calculation. And if gene therapy works and is applied before major organ injury, that too is favorable.
Dr. Ashley: Cost-saving in the end.
Dr. Thompson: One can only hope. It's not for everybody, and it's important for us to be as candid as possible about known risks, including risks that are not yet known. Some have found that their disease is manageable with medications and family support, and not everyone is rushing to have gene therapy. But many are very excited that the investment is being made and that research that could be transformative is focused on sickle cell disease. I think for many people in the sickle cell community — even those who are not personally interested in gene therapy — it's extraordinarily rewarding that when they often felt their disease was so neglected, and they as individuals were neglected or invisible, there has now been so much attention paid. Many of them are just so proud of actually being part of the conversation and being involved in this major advance in science.
Dr. Ashley: You spoke so eloquently about the idea of bending the arc of the moral universe toward justice — because this is a disease that has historically affected underrepresented groups, not just in this country but around the world. Making these therapies available more broadly can be a route for all of us toward correcting those historical inequities. Talk a little more about what that means to you.
Dr. Thompson: Some of it is really about having to be patient. The early part of the arc was simply the discovery of the condition itself, the fundamentals of sickle cell disease. Then being able to find one or two medications that bent the arc a little bit. Knowing that newborn screening — that simple heel prick — combined with education and some penicillin could move things a little bit further. But then long periods of time where discovery wasn't really moving the needle toward things that matter to patients. Being patient, being persistent, really being as hopeful as one possibly could be — hoping that arc would continue to see improvements that matter to patients. Are we there yet? No. Is gene therapy a breakthrough? I believe it absolutely is. Will it get every patient on this planet to where they want to be? I don't think so, at least not in its current forms. But these are major breakthroughs — not only for sickle cell and related diseases, but across all of science. The application of this approach, I think, we're just beginning to scratch the surface on. Making it safer, faster, and cheaper are achievable goals.
Dr. Ashley: This is, as you're pointing out, the tip of the spear for all genetic disease to come under the potential realization of these sorts of cures — and this one, of course, with such huge impact. You talked toward the end of your talk about the possibilities for the future. We could feel, as you described what the patient goes through, that the chemotherapy part is the worst part. If there were a way to not have to ablate your own cells and to deliver a therapy into the body as it is — what are the chances we could be looking at that?
Dr. Thompson: I think there are a few approaches that are really promising. One I didn't mention earlier, but that has great promise, is a way to selectively deplete the stem cells that are abnormal. The most promising approach uses an antibody that identifies a marker on a stem cell and depletes only that stem cell, sparing all the other healthy cells in the body from the ravages of chemotherapy we currently subject the entire patient to. If I could only reduce the cells that are defective, it would allow me to do that while simultaneously putting in healthier stem cells. So antibody-mediated or some other method of depleting stem cells is certainly one approach. The other is trying to find ways to deliver the correction without requiring myeloablation — and that points toward in vivo gene therapy, which is already being launched in other conditions. For instance, where one of the genes of interest is expressed in liver cells, using what are called AAV, or adeno-associated viral vectors. There's a lot of early work in a number of different conditions that makes me very hopeful about that. That approach is imperfect for hemoglobin disorders because AAV viruses don't tend to target the bone marrow. But as a proof of principle, it begins to look at ways of thinking about delivery without the destruction our current approach requires. Lipid nanoparticles are also an amazingly promising device for packaging materials that could be injected into the body, targeted by the lipid nanoparticle to a particular tissue, allowing the modification to take place entirely within the closed system of the human body. That would be extraordinary, and I think it's possible. There is still some work to be done — we are still years away from that approach — but the proof of principle has already been established. I'm hopeful that sickle cell will yet again be one of the diseases strongly considered as a target for lipid nanoparticles in bone marrow-based or hematopoietic stem cell-based conditions.
Dr. Ashley: It's been an incredible journey — for you, for the community, for the patients who've been suffering, and for their families. Really a fun conversation. Thank you so much for coming to Stanford and sharing this incredible work, and thank you for joining us here on the Future of Medicine.
Dr. Thompson: It's been really my pleasure. Thanks for the invitation. So good to see you.