MAYA ADAM:

Welcome to Health Compass. I'm your host, Maya Adam, director of Health Media Innovation at Stanford Medicine.

LAURA DASSAMA:

Once my diagnosis came through, everything became clear. I went to the hospital and I got medication to help me. And the effect that those medicines had really transformed me into wanting to understand how they worked, why they worked, and if I could spend the rest of my life figuring that out and how to help other people feel as good as I felt.

MAYA ADAM:

Sometimes the best motivators are deeply personal. My guest today is Dr. Laura Sama, an assistant professor of chemistry and of microbiology and immunology. Here at Stanford Medicine. Laura was diagnosed with sickle cell anemia as a child, and she's dedicated a large part of her academic career to studying sickle cell disease, which is a genetic disorder that hinders the ability of red blood cells to carry oxygen in the blood. As a chemical biologist, Laura combines the principles of chemistry and human physiology to probe cell function in search of new, powerful and accessible ways of treating a disease. She's lived with her whole life. Her journey as a patient and a scientist is a powerful one, and I'm looking forward to learning more about how her lived experience has informed her cutting edge research. Laura, it's such a pleasure to have you on the podcast today. Thanks so much for being here.

LAURA DASSAMA:

Thanks for having me.

MAYA ADAM:

Laura. I'd like to always start by asking our guests to sort of share a personal story, something that maybe motivated them. And I know that your career in many ways stems from your own experiences. Would you mind sharing that with us?

LAURA DASSAMA:

Sure, I'm happy to. So as we'll become clear from this story that is featured in the magazine, I was diagnosed with sickle cell disease when I was about five years old, and this was in Liberian, west Africa. And my diagnosis was really a relief for me because it explained so many of the things that had happened to me up to that point. A lot of the pain episodes I experienced that I couldn't really describe, I couldn't articulate as a five-year-old, and no one really understood why. And so once my diagnosis came through, everything became clear why I had those pains. And for me then the next step was what made them go away. It was often when I took drugs, when I went to the hospital and I got medication to help me. And the effect that those medicines had really transformed me into wanting to understand how they worked, why they worked, and if I could spend the rest of my life figuring that out and how to help other people feel as good as I felt that's all I wanted to do. And so I knew at that point I was going to become some sort of scientist. I didn't know what it meant. I thought I would be a physician, but later I found out that I was more drawn towards research and so that's how I ended up studying size.

MAYA ADAM:

And how did that sort of pivot happen you thought at first maybe medicine, but then was there somebody instrumental in helping you pivot or what changed that direction for you?

LAURA DASSAMA:

Yeah, so in Liberia, if you were interested in science or math, you were going to go to medical school. Those were your options. And so when I came to the US for college, I was studying to go to medical school. I was a pre-med student. And it wasn't until around my sophomore year when I had an organic chemistry teacher ask me what I wanted to do. And I said, well, I'm very interested in understanding how therapies work and how I can help people and perhaps develop new ones, so I'm going to medical school. And he was taken aback by that because he said, that's not where you learn to do that, at least not in most traditional medical programs. If you wanted to figure out new therapies, you'd probably go to graduate school and do research. And I didn't know what research was. And so he walked over with me to a biochemistry lab and said, there is a student who's interested in research, but she doesn't know anything about it. And it took me in and I learned so much. So that was the pivot, and I'm so really glad that someone asked me what I really wanted to do as opposed what was the next thing that was on my list of things to do.

MAYA ADAM:

Wow. What a good story. Laura, tell us a little bit about sickle cell disease. What causes it? What's the experience like for somebody who has sickle cell disease?

LAURA DASSAMA:

So sickle cell disease arrives from a mutation in the gene that codes for a protein called hemoglobin. So hemoglobin might be familiar to some people because it is responsible for transporting oxygen throughout the body, throughout the blood vessels. So all of your organs need oxygen to survive. And hemoglobin is the oxygen carrier. In people with sickle cell disease, you have a mutation that prevents hemoglobin from functioning properly, especially when it's in low oxygen environments. So hemoglobin will usually become in the lungs when you breathe in air, and then it transports that oxygen throughout the body. So the organs and tissues that are not exposed to oxygen as the lungs are. And what this mutation does is that it prevents the protein from maintaining its integrity when it's in those low oxygen environments. So after it's delivered oxygen, the protein aggregates, which changes the shape of the red blood cells that hemoglobin is in as it's transporting oxygen.

And then those red blood cells go from being a nice FICA shape to a sickle shape, and that's what gives the diseases name. And these sickle shape red blood cells are sticky. They get stuck to each other and they can clog the blood vessels. And when that happens, it leads to these really painful episodes that are called VAs occlusive crises. And so patients can have this systemically through pretty much every organ. Again, that is being oxygenated by hemoglobin. The other thing that happens too is that as hemoglobin begins to aggregate in these cells, the cells will burst and die. And so these patients will have fewer molecules of fewer red cells in their bodies, and that leads to anemia. And so you have the vasso occlusive crises that results in these pain episodes. You have the hemolysis, the lysing of these red cells that lead to anemia, and over time you have poor oxygenation of organs and tissues. And so most adults will have organ damage later in life. And so approximately a hundred thousand people in the United States suffer from sickle cell disease. And the life expectancy of many patients is around 45 to 60 years of age.

MAYA ADAM:

And at what age is it typically

LAURA DASSAMA:

Diagnosed? So in the US and in most Western countries now is diagnosed even pre-birth, right? You can do genetic screening, but then in the US at birth, most infants are diagnosed. This was not the case always and certainly not where I was born, and that was part of the reason for my late diagnosis at five years old. So not everywhere around the world, these early diagnoses are possible.

MAYA ADAM:

And Laura, you mentioned that the hemoglobin binds differently in different oxygen environments. Does that impact the presentation of this disease in let's say high altitude parts of the world? And how does that play a role?

LAURA DASSAMA:

Yes, so it is quite interesting. Yes, at higher altitudes you're going to have less oxygen in the air. And so if you have less hemoglobin already due to the fact that you have fewer red blood cells, if you have this disease, you could have problems oxygenating well. And so it is not uncommon for people with sickle cell disease to have crises when they're in high altitude environments. And so not even anywhere spectacular like the top of a mountain, but even somewhere as high as Denver or Lake Tahoe can cause a problem for people with sickle cell disease.

MAYA ADAM:

Okay. Tell us a little bit about your research, which as I understand it sort of capitalizes on a natural phenomenon that occurs during fetal development.

LAURA DASSAMA:

Absolutely. Yeah. So when we're developing as fetuses, our primary means of getting oxygen is through the mother's hemoglobin. And so because of that, fetuses produce a hemoglobin that is slightly different than the maternal hemoglobin, and it's slightly different because it binds onto oxygen a little more tightly than the mother's hemoglobin will that allows transfer of oxygen from the weak oxygen binder that the mother has to the tight oxygen binder that is ined the fetus. And so this is a natural phenomena, and after in the first year of life, you stop making this strong oxygen binder, phenotype hemoglobin and start to make the adult type hemoglobin. So there are some people who rather than turning off this fetal hemoglobin, continue to make low amounts of it. And it's been observed that if patients with sickle cell disease are making anywhere around 9% or so of their total hemoglobin continue to make this fetal hemoglobin, they have a lot of protection from many of the symptoms of the disease.

And it turns out when I talked to you about how hemoglobin works and what the mutation does that causes sickle cell disease, many of the problems with the diseased protein occurs when it's in poor oxygen environments. But because fetal hemoglobin bind center oxygen more tightly, the red blood cells that the hemoglobin is present in can remain oxygenated for some time. So even in poor oxygen environments, it offers protection. And that protection then keeps this mutated hemoglobin from aggregating. And so people produce, there are people who have mutations or naturally occurring phenomenon that allow them to make 30% up to 30% of their total is this fetal kind and they're fine. And when they have sickle cell disease, they don't have the sickling that leads to the aggregation and the hemolysis that leads to anemia and the vasal occlusive crisis that are all symptomatic of the disease.

And so what my lab is trying to do, and we're not the only ones doing this, but we're asking if we can turn off this switch within the first year of life, you stop making this phenotype hemoglobin and you make adult hemoglobin. What if we were to find that switch and turn it off so that patients can continue to make phenotype hemoglobin into adulthood? We already know that this is safe because there are people who naturally do this, right? So if we can understand that phenomenon well enough to be able to reproduce that in a very targeted manner in patients, we can offer many of them the protection that you would get from keeping the cells oxygenated. And so we know the gene that is responsible for this, it's been tested, it's been validated in the clinic with genetic editing. The only problem is that it's available to a small number of patients because there are no inhibitors, there are no drugs that target this, right?

So at the moment, you have to go in with CRISPR therapy or other genetic modification tools to prevent this gene from working. And we know that if you prevent the gene from working, you make higher levels of fetal hemoglobin. So we're trying to ask, can we make molecules that can have a similar effect such that patients don't have to undergo the extensive medical intervention that is necessary for gene therapy today, but can we find molecules that they can simply take, right? Whether it's orally available or via a transfusion that can have the same impact. And can we turn on the production of fetal hemoglobin to give these patients a chance of having some sort of a normal life by producing this alternate type of hemoglobin?

MAYA ADAM:

And Laura, let me ask you to back up a minute there. You mentioned that some people will continue producing small amounts of fetal hemoglobin. Is that variation responsible for differences in the severity of the presentation of the disease?

LAURA DASSAMA:

It certainly contributes to it in patients with sickle cell disease,

MAYA ADAM:

Yes. Okay. And are there other factors? Is this either you have it or you don't, or are there degrees to which you can inherit the mutation?

LAURA DASSAMA:

There are degrees to which you can inherit it, and it's not even clear if there is one particular factor that allows you to continue to make this. So we know now of one of the most important factors, but there are a number of things that are responsible for higher levels of fetal hemoglobin in patients. And so we think that we know that if you make as little as nine to 10% of fetal hemoglobin, you see the protective effects. And up to 30% is naturally occurring in people. And so there is a large window of opportunity there. And so what we're hoping to do is find molecules that are tuneable and completely reversible. So if someone needs to produce higher levels of fetal hemoglobin, you can certainly turn that on. And if you need to reverse it for whatever reason, you can turn it off and that is not currently possible.

MAYA ADAM:

And what is the current treatment for this disease?

LAURA DASSAMA:

Okay, so up until last year, the only FDA approved therapy was a small molecule drug known as hydroxyurea. And that also works by increasing levels of fetal hemoglobin. However, we don't know exactly the mechanism by which it does this, right? So it works in some patients but not in others. And for people that are not responsive to it, there is not much you can do, right? Until this year, that was the only way to induce fetal hemoglobin. Recently there was FDA approval for gene editing methods either via CRISPR or S-H-R-N-A that allows you to go in and now deplete a silence, a single gene, the same gene that we're trying to target. We know this is the most important factor of all the factors that contribute to increasing levels of fetal hemoglobin. This appears to be the most important one and have the most dramatic effect.

And that's this transcription factor known as BCL 11 A. And so there are now therapies targeting BCL 11 A, but part of the challenge with targeting BCL 11 A is that it has important roles elsewhere in the body. So you can't just develop a drug to target BCL 11 eight everywhere. It has to be done in a particular organ in the bone marrow. And getting to the bone marrow, access to the bone marrow is pretty hard at this point. And so what these patients have to do is have their stem cells harvested, extracted from the bone marrow, edited somewhere in the lab, and then before those edited cells are transplanted back to patients, they have to deplete all of the existing stem cells in the bone marrow. And that can be problematic for patients. But if that is successful and it happens, you can now transplant these edited cells that lack this transcription factor NUN as BCL 11 A, and those patients can now make new red blood cells. And those new red blood cells all have fetal hemoglobin because that switch BCL 11 A is no longer there. So you are now just making phenotype hemoglobin and it's like it was never turned off.

MAYA ADAM:

Laura, could your approach have other applications outside of sickle cell anemia?

LAURA DASSAMA:

Yeah, so the strategy, I can tell you why BCL 11 eight doesn't have any drugs that targeted other than this really convoluted gene therapy method. It's considered one of the undruggable proteins. And by undruggable proteins we mean that the traditional molecules that you use, really small molecules that will find crevices and pockets in a protein and block the function by binding to those crevices and pockets are lacking because vcl lemonade looks like a spaghetti, right? It looks like a noodle. It's floppy, it's disordered. And so finding those nice binding pockets is really challenging. And my approach has been to be inspired by the native function. How does this protein work in the cell? It interacts with other proteins, it's part of large complexes, it has friends. Can we be inspired by how it interacts with those other proteins to find ligands that maybe don't look like your traditional drug, but mimic the natural interactions that this protein has?

And once we have those ligands that are now selective, can we functionalize them to do something to BCL lemonade? And so my work has been can we, rather than trying to just prevent its function, can we just destroy it? So what we've done is found these large ligands that will bind to BCL lemonade. They don't look like traditional drugs, but they do bind to vcl lemonade because it looked like the nice native binding partners. And then what we do is we instruct it upon binding. Why don't you decorate BC lemonade to look like it needs to be destroyed by the cell? So the normal machinery, the cell has to destroy proteins is now used to deplete all of this protein. And so this is a strategy we're looking to try to expand to other proteins that also are so-called undruggable. They have all of these floppy regions that you can get nice small molecule inhibitors to bind to, but we can be inspired by their native interactions and use those native interactions to now decide to either destroy the protein or change its function in some other way. And we're applying this now to a wide variety of other targets.

MAYA ADAM:

That is brilliant. Wow. So much to take in and I'm so impressed by how you explain it because I almost followed you all. Alright, so let's say that you are successful. You did mention that the standard of care is different in different parts of the world. How accessible and how scalable is this solution if it's in its perfect form?

LAURA DASSAMA:

In its perfect form, the way I imagine it, it will be something that you either acquire once every three or four months at your physician's office and then you're set for a few months rather than taking a pill perhaps every day or having this really expensive gene editing method that has other risks associated with it. So we're very far away from that. But my hope is that no one with sickle cell disease will walk into their doctor's office and be told you have only one option. You'll have a variety of options for therapies, and they'll all have challenges and very positive aspects and attributes to them. So what I'm hoping for is that our efforts will inspire a lot of other people to also go after this target to think about how can we make our therapies effective, efficient, but also accessible, and how can we give patients the options?

MAYA ADAM:

Laura, that brings me to another question, sort of a behind the scenes question. You mentioned that other groups are also trying to study this, and I wonder, in the scientific community, do you find a sense of collaboration between these research groups or is it a competitive kind of relationship? How does that work?

LAURA DASSAMA:

It's a little bit of both. I think we all would love to be at the forefront of a major discovery, but I think the fact that, I mean, over the years it's been surprising to me both as a researcher and as a patient, how much interest has grown in sickle cell disease. I think part of the reason is we've now had a lot of new tools that we can apply to these disorders that were maybe very rare diseases and perhaps not very tractable before or not also attractive because for whatever reason, they were not seen as things that would benefit a large amount of people or the right population, the right demographic. But there's been sort of a rallying cry I think over the last few years to really go back, use some of the modern tools that we have today, tools in genetics tools in chemical biology to tackle some of those problems. And I think that's been very heartwarming to me both as a patient because whoever gets there first, I get to benefit and people like me would benefit from new therapies. And ultimately that's what we want. To that extent. There is a lot of collaboration. There is consensus around let's do this, this is the right time. We have everything in place, but then there is also competition. We would love to get there first. We would love to inspire others. So I think we're trying to do both. Right?

MAYA ADAM:

Yeah. On that note, you talk about your role as a patient and a scientific researcher in this space. What is the role of the patient voice voices like yours in shaping research and medical treatments?

LAURA DASSAMA:

Yeah, I would say traditionally the patients had no say in this, right? You were just hoping that when you showed up to your physician's office, they had something that they could do about whatever disorder you had. But I think it's become clear, especially now with some of the new therapeutic modalities that are doing things that have never been done before. It's really important to understand what do patients want. We can go ahead and develop the most effective therapy if patients are not willing to take it for whatever reason, it's going to sit on shelves and not be used. So I think ultimately patients are saying, we want options. We want more options. We don't want to be told this is it. This is all we have. You need to irreversibly change your DNA if you are going to or live with the symptoms of your disease.

And so I think it's been really important. And I think some of the companies that have been pioneering these genetic editing methods, I've done a lot to engage with the communities to which they're targeting their therapies too. And I think that's a good sign because you need to bring people to the table. Patients are not always uninformed or misinformed, and even if they are, I think is part of our jobs, to let them know that at least reveal what happens behind the curtain, what we're doing and how we're hoping these therapies are going to be helpful and how they're going to be used. And so I think there's more of that these days than has been in the past, certainly than when I was growing up. And so I am fortunate to have a team, a medical care team at Stanford that is fantastic. And I speak with my hematologist as if we're colleagues, right? And she values my opinion and I value her opinion. And I think that's a wonderful collaboration between physicians and patients. I would love to see more of that, particularly for disorders that are rare diseases or target a certain demographic.

MAYA ADAM:

Do you ever get discouraged or frustrated with this work? And if so, what do you do to keep going?

LAURA DASSAMA:

Do I ever, that's with all of my work. I don't think I've ever met a scientist who has not been frustrated or discouraged. At some point, I often have to remind myself that it's not always about me. I am motivated to do this, not just for myself. So I always have to think of who might benefit from this perhaps in the next 20 years, 30 years. And is it going to be worthwhile if we manage to advance something even a little bit or even encourage someone else to have an idea that can be transformative in a few decades? Would it be worthwhile? I think so. So a lot of what we're doing has not been done before. It's hard. We're discovering new things. We're engineering new things, we're building things, we're building knowledge, and we're doing it with a small group of people. I have a group of 10, 11 scientists in the lab, and many of them are in various stages of their training.

No one comes in knowing the perfect solution, and we're trying to figure this out together. So there's the educational aspect that the scientists in the lab are learning to become independent scientists and build something new, but also working towards developing a product on multiple products that could help others beyond ourselves later. And I think waking up and knowing that, okay, I am not the only one who stands to benefit from this. If we manage to advance this even a little bit to a point where someone can benefit in the future, it's worth it. And so that keeps me going through the days and weeks of disappointing results and things that just absolutely make no sense.

MAYA ADAM:

Laura, thank you so much for making the time to speak with us today, for sharing your story and your work. I learned so much, and I really appreciate this time that you've spent with us. Grateful to you and your team for everything that you're doing. Thank you.

LAURA DASSAMA:

Thank you, Maya. This has been a pleasure. I hope it was not too dense and it's perfect. I appreciate you guiding the questions and talking to me about this work that I'm so passionate about. Thank you. I can hear that. Thank

MAYA ADAM:

You so much, Laura. Bye-bye. Bye. Thank you for listening to Stanford Medicine's Health Compass podcast. If you like what you heard today and want to keep up with Health Compass, you can subscribe on Apple Podcasts, Spotify, the Stanford Medicine YouTube channel, or wherever you listen.