The Transcript

Interviewer: Well Crystal, welcome to the Future of Medicine.

Dr. Crystal Mackall: Sounds great. I'm happy to be here.

Interviewer: Great to have you here, and you just presented to our packed room, standing room only, Medicine Grand Rounds. I've been really enjoying meeting our speakers and in particular diving a little bit not just into their science and medicine and talking to them about the future of medicine, but talking about the past as well. I'm really fascinated by how people get into science and medicine. Did you imagine for a minute that you would be here when you were a little kid?

Dr. Crystal Mackall: Yeah, boy. So, I always think that my trajectory is kind of unusual compared to most of my colleagues. You know, I grew up in a working-class town in Ohio. My dad was a steelworker. My mother worked in a grocery store. And myself and my brothers were always very academic. We studied hard. And I think I was in sixth grade when I decided I wanted to be a doctor. And once I get something in my head, that's it.

Interviewer: That's pretty young, sixth grade.

Dr. Crystal Mackall: And, you know, I was a senior in high school and still had that, you know, how do I become a doctor?

Interviewer: And did you know doctors? Were there doctors in the family or friends?

Dr. Crystal Mackall: Family practitioners, you know. No, there were no doctors in the family. I mean, none of my parents or... I guess I had an uncle that went to college. But again, this is a very working class. I was touched by cancer, I guess. My family had some cancer, and it scared the heck out of me. I thought, what a terrible disease. One of my coolest aunts was felled by cancer. And man, I thought, whoa. So, yeah, I went to the medical school down the road, which happened to be a six-year program, which means you get your bachelor's degree in two years and then you go into med school. It's called Northeastern Ohio Universities College of Medicine. You've never heard of it.

Interviewer: I have not. But it sounds great.

Dr. Crystal Mackall: Well, neither has anybody, I think, at Stanford. It's not an academic medical school. It was created by the state of Ohio to solve a problem of a lack of primary care docs. And so they plucked these overachievers out of high school and said, "Now become primary care docs." So I'm kind of a black sheep.

Interviewer: Yeah, didn't quite work out for you.

Dr. Crystal Mackall: Yeah. Anyway, it was a great medical school. I ended up staying in Ohio for my residency for personal reasons. And at that point, realized that I was one of the ones in medical school and residency where I just was that nuisance that kept asking questions.

Interviewer: Right. "Why?" You're the "why" person.

Dr. Crystal Mackall: "Well, why do we do it this way? Well, what's happening here?" And actually, I started doing research while I was in medical school at one of the few labs on campus.

Interviewer: And had you been exposed to that through the lectures and then you sort of followed up with the...

Dr. Crystal Mackall: Yeah, there was a really cool physiology professor named Norm Paradise. And I went to him and said, "Hey, can I work on the rabbits with you?" It was cardiac research, cardiology research. There you go.

Interviewer: That's very similar, because I remember being in a physiology class when I was in sort of pre-med, pre-clinical in medical school. And it was the Langendorff rabbit that...

Dr. Crystal Mackall: Exactly! I worked on the Langendorff rabbit!

Interviewer: There you go. I mean, being able to take a heart out and watch it beat and keep it alive for hours... Well, I became a cardiologist. You did not.

Dr. Crystal Mackall: No, but I had the bug for research. And there I was in Ohio and, you know, I was a doctor through and through. But I was still intrigued by the problem of cancer. It seemed it was the emperor of all maladies. And this is the 1980s. I mean, nothing we were doing in cancer was good. And I did find the oncologists in the hospital, I thought they were the smartest people. You know, they were again asking the questions.

So I applied to the fellowship at the National Cancer Institute. Pediatric oncology—I did medicine-peds, I'm double boarded in both. I didn't know whether I wanted to do adult or pediatric. I ended up doing pediatric. And in fact, Phil Pizzo, who eventually became Dean here, was the chief of the division at that point, the branch. And, you know, I always really give the NCI a lot of credit for accepting me, because I wasn't your typical pedigree. And I went and said, "I want to be an immunotherapist." The reason I went to NCI is because Steve Rosenberg was doing immunotherapy at the time. I read an article in 1984.

Interviewer: That's pretty new. That's pretty early.

Dr. Crystal Mackall: It was pretty new. In fact, the only places doing immunotherapy in the 80s was NCI and Stanford. Anyway, so I really put my time in at the NCI to become a bench scientist.

Interviewer: And was that the first time you really were away from your sort of more local environment? Big city...

Dr. Crystal Mackall: Oh yeah. Yeah. But I had a blast. I had incredible mentoring. And the National Cancer Institute, the intramural program of the NIH, was an amazing place to learn how to do science. And also, they were able to do translational research. Honestly, at the time, maybe the only place... for a lot of reasons. You could do bench science alongside the clinic. They have the largest research hospital in the world. Patients came there to get treated, there was no insurance, you didn't pay anything. You only enroll patients on clinical trials.

Interviewer: It's a really unusual situation, and many advances have happened, I think, that would not have been possible in our much more fragmented and much more complex rest of the healthcare system.

Dr. Crystal Mackall: Yeah. So anyway, I stayed there for 27 years. Ended up going up through the ranks and becoming Chief of the Pediatric Oncology Branch, I took the job Phil had. And so I was a doctor before I was a researcher. And I think that is unusual for physician-scientists, especially today. And so you will see that my science always has a very practical bent to it. I always feel this desire to try to bring it back down to earth—how can I bring this to the bedside of the patient if possible? At the same time, I understand the value of science for the sake of science. And so you don't want to collude those. It's important that you understand you just want the truth, even if it's not going to help someone. But my heart is always in the translation.

Interviewer: Yeah, that makes sense. You became well-known pretty early on for your studies in T-cells, and thinking in particular about homeostasis and the regulation of T-cells. Of course, we'll come to the impact that's had on patients, but before we get to that, tell me a bit about how... of the various elements of immunotherapy, what was it about the T-cell that attracted you?

Dr. Crystal Mackall: Well, if you're interested in cancer, it has always been the T-cell. The T-cell has always been the main player in the anti-cancer response. In fact, a famous researcher named Lloyd Old identified for us that cancer patients typically come to us with lots of antibodies to their cancer when they walk through the door. And yet those antibodies don't seem to help. In fact, we've been able to learn a lot from those antibodies, but there's very little evidence that natural antibody-based responses are a defense against cancer. Whereas T-cell responses are where the action has been, or NK cells. So I've always been more interested in the cellular rather than the humoral.

Interviewer: You mentioned in your really excellent Grand Rounds that we just came from, some of the history of cell therapy. And I, even though I to some level know this, I was surprised at just how early people were doing tumor-infiltrating lymphocyte experiments.

Dr. Crystal Mackall: Yeah, it's 40 years ago. Exactly. And this in many ways tells you everything you need to know about how difficult it is to develop this therapeutic class. So even though we're 40 years in and we have, you know, glasses half full—right, there's all these FDA approvals, patients are being cured—but I'm going to tell you the glass is also half empty. Only 20% of patients in the United States who could benefit from the CAR-19s that can cure lymphoma receive it. And that's because it's so expensive, and so difficult to deliver. If you go to countries like New Zealand, they really have very little in the way of CAR T-cells. If you go to even China, where there's a lot of great cell therapy happening, those patients are getting CAR T-cells on clinical trials. Those on the national health insurance aren't getting any CAR T-cells. So this is a monkey on our back until we make it more affordable.

Interviewer: And I think there are two elements there it'd be great to unpack a little bit. One is the multi-decade scientific building on foundations, standing on the shoulders of others, and another is the affordability of the translational therapy. But maybe unpack the first for us.

Dr. Crystal Mackall: Yeah, this is an important topic, and especially for young people. I know when I was young, I was impatient. People will come and they'll want to work in the lab because they want to create something that helps patients. And, you know, sadly at some point you break it to them that this takes decades. It might take a while. And you really do have to adjust expectations.

One of the things I love to do is to look at the time it's taken for the future of medicine to arrive, right? Whether you're talking about the story of transplantation, you're talking about the story of monoclonal antibodies... I remember in the 80s, you couldn't get a grant for antibody therapies because we tried that and it didn't work. If you're talking about cell therapy, bone marrow transplant, antibody-drug conjugates is another one that comes to mind... And honestly, we're going to see the same thing with AI-based drug development. You see the hype, then you see the expectations... Gene therapy is another example. And then it falls. In fact, I give a lecture about the long slog. You've got to do the work in the middle. We don't always think about that when you talk about an overnight success that was like 30 years in the making. It often seems like an overnight success, but none of these things happen overnight. There will always be the early adopters, and that's great because you get momentum. But the trick is not letting the field die when that expectation falls short.

Interviewer: Well, and I think your work over the years, but you also demonstrated some of it in the talk today, is that yes, you have the idea, you can implement it—that's hard enough, your first experiment. But then rarely does the first experiment ever work. So the question is "why not?" And you gave a great example of the development, a really amazing development, of this GD2 CAR along with Michelle Monje. Talk us through that a bit, because first of all the disease is horrible, diffuse midline glioma... So maybe mention that a little bit, and then let's talk a little about that trajectory, because it's a great example of the fact that you're really building on work you've done for decades, others have done for decades, and then it suddenly seems to come together over a few years, but it really doesn't.

Dr. Crystal Mackall: Yeah, no, we still have a long way to go there. So I think this is where the practical doctor perspective comes into play. One of the most important things, as you talk about if I'm mentoring a young person who wants to be a translational scientist or a clinical investigator, is find the right disease. We're taking risks. Every time we do one of these trials—and these are in children, mind you, they're vulnerable subjects, and the ethics are even more heightened—it only makes sense if you're dealing with a population who doesn't have other good options. And for me, that's where I think it's clearest that you want the ecosystem to lean in.

Take these really difficult problems. Industry won't touch this. The market is too small. It's considered high risk. This is the same with glioblastoma, mind you. And so this is where academics should be focusing, on diseases where we have no good options and we have an idea. And there, what you need to make something happen is you need infrastructure. And because the hardest one you do is your first one. The second one is a lot easier, and by the time you get to the third... you're always telling my lab, "You've got to do one before you do two." And that's it. I mean, you put gargantuan effort sometimes to do the first one, but you learn so much and then the next one is so much easier. By the time you get to 10, you've got a machine going.

So with the GD2 CAR and the diffuse midline glioma, you have a terrible disease. There's not a person who would tell you that we can't do better. Now you have a brilliant champion in Michelle Monje who understands the biology, thank goodness. You've got investment on our side at not only understanding the science but building the infrastructure. It was a perfect storm. And so we were positioned to be able to contribute early.

Interviewer: And paint the picture, just for the listeners, of... you showed some videos of patients who had been suffering from neurological disorders and movement challenges.

Dr. Crystal Mackall: Yeah. So this is a tumor that grows mostly in the brainstem, sometimes in the spinal cord. And the brainstem is where... it's not your spot of higher thinking, it's your spot where it determines how you move, whether your eyes can move, whether you have balance, whether you have an appetite, and sometimes things like whether your breathing is intact. So it's a scary place to have cancer. It's a scary place to induce inflammation, which we're doing. And so in order to begin this therapy, we needed absolutely everything to be in place. We needed to have the neurologists, the immunotherapists, the cell manufacturers, the regulatory expertise, but we also needed the intensive care doctors at Lucile Packard. We needed the neurosurgeons who placed the catheter and who monitor the intracranial pressure, we needed the neuro-intensivists. It's a huge team effort. They say it takes a village, it's an army is what we needed! And we did it. We really did it safely. I mean, it's not to say patients hadn't had any toxicity, but I think that by bringing all of that expertise to bear, multidisciplinary, we were able to deliver a complicated...

Interviewer: And so even the target, first of all, sort of came together with a conversation between you and Michelle. You told that story.

Dr. Crystal Mackall: I mean, this is the way people imagine science works and it rarely works this way, but Michelle and Chris Mount, her student, make a discovery in the lab. It was a simple experiment. They just took cell lines, early cell lines, and they dumped 250 antibodies on them. They saw what stuck. And the top one was this GD2. "What is that?" Michelle said, "GD2? I think Crystal works on that. Knock, knock, knock." She brings me a piece of paper, "Can you look at this? On the top of the list, GD2. Do you work on that?" "Well, yes, actually. It's amazing."

Interviewer: And you had been working on it for a little while.

Dr. Crystal Mackall: Oh yeah, we started working on it about 2011. This was 2017. But it was one of many things that you were juggling. This was a target that is still is really important for neuroblastoma, the most common solid tumor of childhood, extracranial solid tumor. And it's also expressed on osteosarcoma. So we were interested in it for those reasons. No one in the world knew it was on this tumor, because this tumor hadn't been studied. And this is where Michelle's investment in early autopsies has paid off.

And she's—we haven't had her on this forum yet, but I've talked to her over many years, and she also I think, like you, has an interest in diseases that no one else is paying attention to. And these are devastating diseases. And so this is where once you go into this area where there's this huge unmet need and you have something promising, a lot of the problems melt away. The ethical problems melt away, the accrual problems—we have waiting lists. So you built this clinical cell therapy entirely here at Stanford. Absolutely. Manufactured the... we actually contracted that, but the manufacturing of the cells happens on California Avenue at the Stanford Lab for Cell and Gene Medicine. And, you know, we really... now there are multiple other centers doing it, it's being done in Australia and in England and Texas and a variety of places, but we've treated now over 50 patients. So by far and away, have more experience than anybody else.

Interviewer: And you talked through a few different arms of the study during your talk, but I think many people—and I know this is why you show them these pictures and videos of the patients—just describe one of those to us.

Dr. Crystal Mackall: Yeah. I mean, patients, you know, these are young... typically afflicts kids between four and eight. And you know, I remember we had a little girl who had lost all kinds of weight because she couldn't eat. And she couldn't use the right side of her body. And we give her the first dose, and they come back in a few weeks or a month, and she's gained all kinds of weight because now she can eat, and she's riding a scooter using the right side of her body on the scooter.

You know, we've had several patients who either couldn't walk or they came in in wheelchairs, or maybe they could walk down the hall, but if they had to go to the cafeteria, they needed a wheelchair. And you know, you give them the treatment and you basically gradually see the feeling come back and the ability to move the legs, and then they go from wheelchair to cane to walker to being able to walk. These are literally kids who were wheelchair-bound, who have the therapy and then some weeks to months later are walking. It's remarkable. For a tumor that had no treatment. And honestly, until this time, we didn't know whether there was even the possibility of recovering neurologic function. Like we didn't know if the tumor had destroyed the nerves or rather it was just pressing. So you didn't know if the ceiling or the bar was just to hold the tumor where it was and slow the progression. But what you're actually seeing is neurological recovery. Yes.

And this is the power of youth. You know, when you're working in pediatric diseases or young adults, the ability of these patients to withstand toxicity and to recover is phenomenal. And it kind of is one of the things that really motivates you because you feel like, you can look at a patient and say, "Well, we're not going to be able to help them, it's too far gone." No! They will surprise you. And then the resilience of kids is just something... I mean when you experience it, to say you get goosebumps doesn't even do it justice. You want to cry, you know.

Yeah, just a remarkable story. And I think the other context that isn't necessarily obvious to everyone is that to date, these cell therapies have been very effective in leukemias and lymphomas, liquid tumors. There really haven't been great examples of solid tumors.

Dr. Crystal Mackall: Exactly. And I would say that ours was one of the first... I don't like to get into who's first or not, but there have been a couple. And this is one of the two or three. Another one is something called Claudin-6 or Claudin-18 in gastric cancer. So there have been a few. But when you see that functional... you go from not being able to walk to walking, you know, that just tells you this is a therapeutic class worth pursuing.

Interviewer: And that overall context... I mean, I think, so you talked at the beginning about being early in with immunotherapy. But you also talked about the emperor of all maladies and the history where we really were just cutting out tumors or using chemotherapy, literally trying to ablate dividing cells. Just talk a bit about that transformation.

Dr. Crystal Mackall: Watching what's happened... Well, you know, the arc of my career really... so I went to medical school in the 1980s, started my fellowship in 1989. And now you are, you know, 2026. So, medical oncology, oncology in adults, has been transformed. Absolutely transformed. At the time, if you couldn't cut it out and you couldn't burn it out, you weren't going to treat it with chemotherapy. And in fact, we made patients so sick at the time. It was a very, very dark time for medical oncology. There was Hodgkin's disease, which Stanford played a major role in, we were able to cure that. Early stage breast. Some just say there weren't, but most patients were getting chemotherapy without benefit.

Pediatrics was an exception. Chemotherapy has always worked better in children. And that's one of the reasons I chose pediatrics over adult oncology. And in the 1980s, we made great strides in pediatrics using chemotherapy.

So now let's fast forward. Medical oncology has become largely an outpatient treated specialty. Patients take pills, or maybe they come in and get an injection once a month. And if you meet them on the street, you won't necessarily know they're a cancer patient. Their quality of life is high. And some are cured, some aren't cured. Many are, but even those who aren't cured have this health span that is notable.

Pediatrics, on the other hand, we have seen very little progress since the late 80s. The standard treatment for children's cancer remains chemotherapy and radiation therapy. And we haven't seen the targeted therapies come down the pike. And this is... it's very sad to me, and I know why it's happening. It's happening because we have a market failure. We've got small markets for children's cancer, large markets for adult cancer. So that's where the focus ends up being. And because therapy is targeted, and the biology of those diseases is different. If you develop a drug for an adult cancer, it doesn't trickle down to peds very rarely.

Interviewer: And some of that's a regulatory issue, because that could be overcome. I mean, the biology isn't necessarily different.

Dr. Crystal Mackall: Um, well, it depends. You know, I spend a lot of time lobbying with the FDA. And in fact, I trained several people who were in the FDA for a long time, a lot of the FDA. I think historically maybe that was the case, and now it is more of an economic issue, that you have to develop drugs for pediatric cancers. Like take Rituximab. Blockbuster drug. It doesn't have a significant role in pediatrics because CD20 isn't expressed on most pediatric leukemias and lymphomas. Herceptin and HER2, same. It's expressed on osteo but not at levels, and that's the only tumor that really has it at all levels. So you need to develop targeted therapeutics for the disease.

And I'm starting... you know, one of the things that I've been very much working on because I can see the future here... We have a treatment for diffuse midline glioma, but we're going to have trouble commercializing it. So we've developed a nonprofit that is focused on trying to create new economic models to develop cell therapies.

Interviewer: Yeah, because it's... I don't know how many you've treated now. 15, 20 patients?

Dr. Crystal Mackall: 50 now.

Interviewer: 50 now! That's amazing. That's great. Which is amazing, but how many other in the world is the question I guess.

Dr. Crystal Mackall: Well, it sort of depends how you count, but there are 200 to 400 children with DIPG in the US a year, but there's about 1,000 total patients with this disease. So it does happen in adults. In the US every year. That's not, you know, that's not enough for a venture capitalist or pharma. But I think there could be, if we went about this in a smart way, we might be able to create a self-sustaining...

Interviewer: Other ways to get these therapies into the range where people could fundraise to get them, or where there are alternative mechanisms where people could donate?

Dr. Crystal Mackall: Yeah. Well, what we've ended up on, and we spent a lot of time—I wrote a paper in Nature Medicine a couple years ago talking about coming up with new business models with my colleagues and I... here we are scientists, writing about economic models. But we have to because otherwise how do your treatments get to the... Exactly. How much does it cost now? Give us a sense...

Interviewer: To manufacture?

Dr. Crystal Mackall: Yeah, I mean a number you'll see in academics is $125,000 a product. But we give multiple doses in this case, and we can get eight doses out of one product. So, a lot of the cost is manufacturing, but there's also costs of, you know, the clinical development. It's very expensive. And the commercialization costs are a lot. So we're looking at ways I think for pediatrics and smaller markets maybe you can cut down the cost of development. But we're likely going to have to have a relationship between a for-profit and a non-profit B Corp.

Interviewer: Yeah, I've certainly been struck many times by... obviously the thing that our pharmaceutical companies do very well is develop drugs and then scale them and bring down those manufacturing costs. And that's what the capital market does. In academia, we don't do that. We try to make discoveries that can help the world move forward. How do you bridge those?

Dr. Crystal Mackall: So how do you bridge, if you're trying to scale, even if it's not to millions of patients suffering from these rare tumors, but if you're just even trying to scale to, let's take this from the 50 patients at Stanford to the 5,000... How do you think about that?

Dr. Crystal Mackall: Well, these days, what we're thinking about is using a nonprofit to hold the license, and our nonprofit, by the way, is something called Access for Kids. It's a 501(c)(3). And then partnering that with a for-profit, and the for-profit can do the manufacturing just like any other drug company would, but we would do it at reduced rates by avoiding, you know, some of the equity that goes along with founders—there'd be no founder shares. We would be leveraging public funds. CIRM is already funding our trial. The California Institute for Regenerative Medicine. And really looking for mission-driven investors. And you know, we think that there could be a path forward whereby we could get this thing over the finish line. Remember, if we have a high signal of efficacy, which we think we do and we've met with the FDA on this, the size of the trial—this would be a single-arm trial, the size of the trial would be relatively small. That's a major cost driver. So we think that you could greatly reduce the cost of development for these rare diseases compared to more common diseases. And a lot of that is about partnering to get intellectual property at reduced price. We're negotiating with Stanford on that and it's been going very well. And working with the FDA to diminish regulatory risk. We've been lobbying the FDA to become a bit more flexible on the manufacturing requirements for small markets for cell therapy. We've had think tanks with them and the Parker Institute and Friends of Cancer Research. And we were really gratified that about a week ago they came out with a new guidance saying that for small batch manufacturing they would entertain more flexibility. So, you know, you need to push a lot of levers, one step at a time. Yeah. That's amazing.

Interviewer: Some of the other work you shared recently, I mean I've always been amazed by your work and how you think about sort of architecting cells. I think it's really fascinating and fun to just watch you and your lab do that. But you focused a lot, many have, on T-cell exhaustion, which is just as it says, like the cells work too hard and kind of get exhausted. But you have a couple of elegant ideas for how to overcome that.

Dr. Crystal Mackall: Yeah. It's funny, I came to Stanford in 2016 and I really worked very hard, and I found that what I was doing was studying exhaustion. I was living it myself! You were the personification of exhaustion. We really dove deep into the biology because like I said during the Grand Rounds, the problem with T-cells is they haven't been endowed with Mother Nature's controls. You know, we just create this wham bam blast... They don't sleep and rejuvenate and then get going again the next morning. It's just common sense, they get exhausted. And so we really have studied this intensely—the genetics, the transcriptome, the epigenome, the metabolome. And, you know, probably the best antidote that we have found is to just turn the things off. You can overexpress genes, we've overexpressed several genes that will work. c-Jun is one, FOXO is another. But if you can just give the cell a period of rest, which again Mother Nature's T-cell has already built into its programming, we think that this could endow the cell for the marathon and not the sprint.

And so exactly one of the challenges in the field right now, a lot of them, there are so many ways to enhance the cell. And people aren't doing benchmarking, because it's not that exciting but it's important. And so we're doing a lot of benchmarking these days about what should go to the clinic. My hunch is that the things that are going to allow the cells to rest are going to win.

Interviewer: And you showed some of the mechanisms you're thinking about which involve changing the actual receptor. Does that cell then rejuvenate the receptor after a period of rest?

Dr. Crystal Mackall: Yes. Yeah, so again, just like what we know that when a cell gets activated, one of the things it does is chop a lot of its receptors off and shed them into the environment. But as soon as the activation is diminished, and we're talking about eight hours—so it generally sheds these molecules within about 30 minutes, once the activating stimulus is gone by about eight hours you have full blown... it's recovered. So the beauty of proteases... I think if you look, many people are thinking about controlling genes via transcription, and I understand why it's a major lever. But transcription is a slow on and a slow off. Protease, fast on, fast off. So my lab has sort of leaned into proteases. And this recent platform called SNIP is particularly attractive because it's such a small payload. It's a 15 amino acid element that you can integrate into pretty much anything you want. And it's fully human and self-regulating in essence. Yeah, it's really, really elegant. This Jeremy... a grad student really deserves all the credit, it was his brain child.

Interviewer: Yeah, no, it's one of the amazing things about being here is just to see these young people come up with these amazing ideas and try and help them kind of achieve them. Probably the most amazing thing about Stanford, and there's a lot of amazing things, is the quality of the young talent. My goodness.

Dr. Crystal Mackall: I agree with that.

Interviewer: Well, we're here on a podcast called The Future of Medicine. You ended with maybe one of the hottest topics currently in cell therapy, which is in vivo cell therapy. And we talked a lot about manufacturing and the challenges and the cost and the economics. Do you believe the future is in vivo cell therapy?

Dr. Crystal Mackall: You know, I, as I step back and look at what so many of us in medicine are trying to accomplish today, whether it be the oncologist or the immunologist, the person treating autoimmunity or treating degenerative disease or fibrosis... so many of these problems that we really haven't cracked. We've had biologics, we've had cell therapy, targeted agents. And we now understand that if you can deliver things inside the cell, you can pretty much accomplish everything that these therapeutics are doing. And you may be able to do this without small molecules. And so I believe that the future of medicine is going to lean even more heavily towards biologics, but rather than be cells and proteins, these are going to be nucleic acids. It's all going to be nucleic acids. So you're going to deliver RNA, you're going to deliver DNA. And you're going to deliver it to whatever cell you want to deliver it to. You had a nice phrase there which is "the future may be turning cell therapy into gene therapy".

Exactly. And the same is true with antibodies. I mean, why do we need to make the antibody outside the body, grow up a bunch of protein, purify it, and inject it? Perhaps we just encode for the antibody and let the body make it. Lipid nanoparticles and their ability to target a cell of interest and to deliver whatever payload, transiently or more long-term. So I do believe that gene therapy, nucleic acids as therapeutics, will continue to grow and be a really exciting area.

Interviewer: Do you think we can reach the same levels of efficacy as with the cells that we bring from outside and manufacture outside?

Dr. Crystal Mackall: I mean, I don't think at the beginning. I think we'll probably have the typical hype phase. Right now everybody's very excited because there's been some early clinical data. But there's going to be some challenges. One of them might be rejection, like I talked about today. But those are all, you know, if we give the time and the scientific wherewithal and the funding, those are solvable problems.

Interviewer: You've been an incredible scientist, physician from the earliest age. You've been an incredible leader not just here at Stanford but around the world of walking us towards this new horizon of curing and managing disease with cell therapy. Thanks so much for joining us.

Dr. Crystal Mackall: Thank you, Euan. Thank you for having me. It's been my real pleasure.

Interviewer: Alright. That was it. Okay. Hopefully not too painful. Thank you.