Science Straight Up
In conjunction with Telluride Science, "Science Straight Up" delves into how science impacts our everyday lives. Your hosts, veteran broadcast journalists Judy Muller and George Lewis talk to leading scientists and engineers from around the world.
Science Straight Up
RNA Therapeutics: Recoding Drug Design, One Gene at a Time--Dr. Athma Pai
Science Straight Up
Season 4, Episode 6
Dr. Athma Pai
RNA Theraputics—Recoding Drug Design, One Gene at a Time
Hosts: Judy Muller and George Lewis
JUDY: From Telluride Science, this is Science Straight Up
ATHMA: We've wrapped the RNA molecules in a set of other chemicals that allow it to actually remain stable, get to the right tissue, and, and produce the targeting effects that we actually want.
JUDY: Recoding drug design, one gene at a time. I’m Judy Muller.
GEORGE: And I’m George Lewis. The COVID pandemic has made us all aware of MRNA vaccines that target those deadly coronaviruses. But that’s just the beginning of an exciting field of medical research that could pave the way toward ending a whole array of diseases.
JUDY: Dr. Athma Pai is an assistant professor of RNA Theraputics at the University of Massachusetts Chan Medical school. Dr Pai was awarded a one million dollar career grant from the National Science Foundation to support her studying of MRNA splicing and to provide internships for both high school and college students.
GEORGE: Dr. Pai, who spoke at a Town Talk sponsored by Telluride Science, comes by her interest in science quite naturally.
JUDY FROM TALK: we often like to ask scientists about their personal stories about how they got hooked on science. I know you were raised by two scientists, but…
GEORGE: So it's in your DNA.
ATHMA: Yes, for sure.
JUDY: But your passion for the field was fueled by something that happened to you //just as you graduated from high school, elaborate on that a little bit.
ATHMA: Yeah, so I graduated from high school in 2003. And 2003, was the same year that the human genome project was completed. So I obviously had grown up with science my entire life. But this idea that that was in the news, and there was, you know, a nice race to get that, that human genome completed. So it really was a bit more drama to a story. So I made another
JUDY: Explain just briefly what the Genome Project is.
ATHMA: Certainly,//while we have known about DNA and the structure of DNA and the sequences of specific genes for for decades, //the composition and the order of those 3 billion sequences was not actually completely figured out until 2003. And so that was the Human Genome Project, it was a project to complete the genome of the human species. And this was a huge effort led by scientists at NIH, and also a company called Celera, which competed against each other created quite a bit of drama, and made quite a lot of news. So right around that time, someone also gave me a book for one of my birthdays on, on what's encoded in our DNA. And so the combination of those two things make me fascinated with this idea that genetics can really hold promise in ways that had not been realized before. So because of that, I, when I went to college, I knew I wanted to be a scientist, but I kind of played around with a lot of other things I majored in biochemistry, but then also picked up an anthropology major. And ultimately, my research was actually in anthropological genetics. So I spent my research as an undergraduate, really working on the evolution of human species and how we can understand that from our DNA, and how we can actually trace migrations of humans across continents using DNA sequences. So I was able to combine my passion for genetics, my passion for anthropology, and evolution. And, and I've kind of continued to do that, throughout my career.
(NEW TRACK) GEORGE: Now, Dr. Pai’s research centers on RNA therapeutics, developing treatments that can combat viruses or rogue genes that cause disease. She says once you know the genome of the thing you’re fighting, like COVID, you can move to develop treatments pretty rapidly. All you have to do is make sure that RNA, a tricky and unstable little guy, is tamed.
ATHMA: So we've wrapped the RNA molecules in a set of other chemicals that allow it to actually remain stable, get to the right tissue, and, and produce the targeting effects that we actually want. // So what this allows is very fast drug design, and additionally, personalized drug design.
So from the from the time that the actual genome sequence of the SARS cov two virus was published, to the time that Moderna shipped a vaccine samples in test tubes to NIH took 25 days that really highlights the efficiency and the rational ability to design RNA based drugs.// So mRNA 1273 was the first sequence designed and the one that worked. Why did this work? That's kind of the core question, right? And it's because Moderna and many other companies,// had actually spent many years optimizing all of those other components necessary to make sure we can develop the drug quickly. Once we have the sequence, we know we want to target. They had optimized those chemical kind of wraparounds, the delivery vehicles, the right way to design an mRNA sequence. And the right way to make sure that sequence in that molecule remains stable in cells. So we really piggybacked off of dozens of years of RNA research and also tens of years of actual drug development to get to that point.
GEORGE: You might remember that the first COVID vaccines had to be kept at really cold temperatures in order to work. Dr. Pai says there’s been progress in that area although there’s a lot of work still to be done.
ATHMA: So that stability is a big problem. Temperature control, I think, is something that many companies are getting over. Because you're able to, you're able to make it possible to store it in normal freezers. However, the stability is still an issue. One of the things that actually is more of an issue with regards to stability, is that if you inject an RNA drug into a into a muscle or bloodstream or something that you know, many of us are used to drugs being injected into it that needs to actually be transported to the right tissue to actually function. And because of its instability, it can actually, it might not make that journey properly. And so that's where I started to touch upon this idea that people are actually developing chemical wraparounds to make sure that it stays stable and stick sticks around for as long as we want it to, but also is able to be carried to the right place very efficiently. I think that those are certainly huge challenges.
GEORGE FROM TALK: You were involved in mRNA research well, before the development of the COVID vaccines, were you surprised at the speed at which all this happened? You // mentioned moderna, going from the discovery of the genome, to shipping the first vaccine samples to the Feds for approval. You know, it took place in a matter of a month or so.
ATHMA: I think I was not quite surprised. Yeah, it was extremely exciting. I was very excited by how fast it happened. Sitting at home, like many of you, I was not allowed to go into my lab, because we were not actually doing vaccine work. But I think that many of us in the field had been following the promise of these technologies for so many years. The// the Chief Scientific Officer of Moderna was actually a former colleague of mine at UMass Medical School. And she'd been giving talks for many years on how do you properly design these molecules? As I mentioned, the the principles of targeting those molecules based on sequence have been known for many years. The principles of how do you actually get that into cells was something that Moderna had actually published many papers on for at least five or 10 years before the vaccine development.
JUDY: Was anyone really paying attention?
GEORGE: Outside of scientific circles?
ATHMA: It's a good question. I don't know. But inside scientific circles, I can definitely say that people are paying attention. So that's why I think someone like me, who had already been following their r&d research was not as surprised.
JUDY: So, RNA based molecules, as I understand it, are our larger molecules than other therapeutics, which makes targeted delivery within the body more difficult, right? Is that correct? So is safety in RNA drug delivery, a focus? Is this a problem? Are there dangerous side effects?
ATHMA: There are side effects the same as there are for any other drugs. //
Speaking from my personal opinion, I, you know, I'm not the FDA, not a physician. The safety is not a huge concern for me. Because I think that again, the principles behind what I was trying to touch upon in my talk, behind the delivery of RNA molecules stays consistent throughout every RNA molecule that's delivered. So once that's optimized, as it has been now for mRNA vaccines, because we've all seen that there are few to no side effects other than your immune response kicking in, which is actually something you want to happen. That same delivery, wraparound or package can be used for any other mRNA vaccine, or any other RNA therapeutic that wants to get into our immune cells. So because of that, you can separate the targeting from the safety considerations very quickly. And that's something that's not possible for small molecule drugs, which often can have their own side effects that are inherent to the targeting principles themselves.
(NEW TRACK) JUDY: Besides the COVID vaccine, Other kinds of RNA therapeutics are going after genetic defects. Dr. Pai talked about a little girl from Longmont, Colorado named Mila.
MILA SINGS: “You are my sunshine..my only sunshine..”
JUDY: She had a rare fatal genetic condition called Batten disease, destroying her brain cells.
ATHMA: They had her genome sequence, they realized exactly which specific mutation in her DNA sequence was actually causing her disease.
JUDY: We spoke to Mila’s mother, Julia Vitarello, via Zoom.
JULIA: I had to be a mom to a child that was losing all her abilities rapidly between six and seven years old, losing her vision, her last words, saying Mommy for the last time starting to have seizures, you know, starting to have a G tube and not eat by mouth.
GEORGE: A researcher at Boston University, Dr. Timothy Yu, came up with a customized RNA injection just for Mila. He even named it MILAsen, in her honor and after the initial treatments, Mila was making progress.
JULIA: The seizures that had kind of built up to about 3020 to 30 a day that were lasting two minutes // Those went down to almost nothing. And then after that, I would say you know, she was able to sit up stronger so it meant that she could swallow so she started eating my mouth again, it was pureed foods, but like she could eat by mouth.
JUDY: Sadly, the treatment came too late to save Mila. Her condition worsened again and she died in 2021 at the age of ten. But now, Dr. Pai says Mila’s case could point the way for future treatments of rare diseases.
ATHMA: And it did highlight not just the ability to use these drugs to treat diseases in which otherwise there would be absolutely no treatment and no positive prognosis, but also the ability to do it quite fast. And this is something that many of my colleagues are now starting to focus a lot of their effort on.
GEORGE: Mila’s condition is one of about 7,000 “rare diseases” classified by the food and drug administration. While the diseases are rare, the people who have them are numerous, about 30 million Americans at last count. A big problem with designing personalized RNA treatments for people with these diseases is the high cost, about 3 million dollars for Mila’s treatment.
ATHMA: In these cases, for patients with these rare diseases, often every six months, they have to take another shot of this. So it's a huge cost at the moment. There are many people working on actually trying to bring those costs down. significantly, part of the costs actually, is in the development of the safety considerations, those trials to make sure that that the molecules that are being delivered are safe, effective, clean, so they do not have any contaminants in any way in them. And part of the cost for drug design now is actually in those clinical trial phases, which take as much as 10 to 15 years to conduct. So at the moment, designing a drug for one person does take millions of dollars. The hope is, though, that that would come down as this becomes more commonplace.
GEORGE: Dr. Pai says there’s a whole range of RNA therapies in the works awaiting approval, including one for sickle-cell anemia, a disease that affects primarily Black people. But can that drug be delivered to Black communities at a reasonable price?
ATHMA: It's a very good question. From my understanding, without again, being involved in any of those companies, they are actually working to make them available as much as possible to communities that are otherwise under- served//by the medical system. But I know very little about the details of that aspect of it.
JUDY: Yeah. And you had a list of things that have already been treated, starting with retinitis, which I gathered requires a hypodermic into the eyeball.
ATHMA: That's right.
JUDY: Oh, and there's a lot. But there were a whole list of things that have been addressed already. What do you see as a sort of a, this is going to be kind of a silver bullet for future cancer? //Where do you see this going?
GEORGE: You people in science don't like to use the term silver bullet.
ATHMA: No, we like to be cautious. That's true. I think that it, it holds great promise in treating diseases that are more complex than diseases that that have been currently treated. And one of the reasons is, because you mentioned cancer, cancer is often not caused by a single mutation. In fact, it's actually not caused in the same way in every person, even the same type of cancer, with a few notable exceptions, is caused by entirely different things across every single person who is who comes down to that cancer. So the reason that I see promising in our therapeutics for treating diseases like that, is because you can now start to target genes or, or processes that are are the second things that are happening. And you can increase the levels of those RNA or protein proteins in ways that you were not able to do before. So you can essentially say we're going to force the cell to make things right, instead of shutting down what was going wrong, which is the previous paradigm. So I think that there's there's a great amount of promise in actually doing that, because it changes how we think about the complexities of diseases like that. So yes, I hope it's a silver bullet. But I have no idea. I'd say that.
JUDY: Exciting.
GEORGE: I know that when we spoke before, you mentioned, I think companies like Biogen receiving first level of clinical clearances from the FDA for some of this research that seems to be moving at lightning speed. Can you talk a little bit about that?
ATHMA: Yeah, a lot of this research is going quite, quite fast. Many companies are in phase one, phase two, phase three clinical trials for dozens of other drugs that I did not list because they're not approved. I anticipate the numbers I've seen have been upwards of 25 RNA based drugs being approved in the next 12 months, if not more. For many of these drugs, the mRNA vaccine being one of them. They've now gotten to the point where they're actually skipping some of those initial clinical trials every time they develop a new sequence. And we've all seen this, because when they designed the booster sequence, which is an entirely different sequence, to what we took on in the first round of RNA mRNA vaccines, they were able to skip many of those trials. And that goes back to this idea that you can change out that sequence quite quickly without actually changing all of the other effects of how you deliver the molecule how you get it to the right place, how it works in ourselves. So for instances like that, I think that what my my guesses what we'll see in the next few years is the flu vaccine and the COVID vaccine becoming commonplace as mRNA vaccines, maybe even combinations where there were without having to go through this law. are trying to clinical trials are able to quickly adapt to what is present in the environment, which is not something that flu vaccine actually is able to do right now it has to be decided upon many, many months before.
GEORGE: So you see, if there's a new strain of flu that appears, you can have the vaccine pretty fast?
ATHMA: That's right, you can change that strain over the course of the flu season. And you can deliver it with the mRNA vaccine. Because you can put multiple, multiple mRNA molecules in the same delivery package. So yeah, I think that does change the paradigm of clinical trials. It's used now. But in specific instances, right, I don't, I don't think that they're gonna cut corners. With respect to things that have never been seen before. Have not been tested before.
JUDY:
JUDY: We should probably open it up to the audience, because we want to give you some time. If you have questions.
AUDIENCE MEMBER: Thank you. That was fascinating. It seems to me, although I may be misunderstanding that there's a difference between your two final examples, that in Mila's case, they were attacking something in her own DNA, whereas in the COVID SARS case, we sequenced the virus’s DNA and we're attacking it. Are those two fundamentally different processes or am I misunderstanding
ATHMA: No, no, you caught that quite well that they are fundamentally different processes and I think actually highlight the diversity of ways in which RNA based drugs can be designed and the diversity of processes they can target. So you're entirely right then in the mRNA vaccine, we what, what the vaccine does is actually deliver an RNA molecule and a messenger RNA molecule. So the full composition of that RNA molecule that can create a protein for a portion of the spike protein in the, in the virus genome. So that's a, that's a protein that our, our cells do not normally create. But what happens is that when the cells create that protein, because the instructions to do so have been delivered, it's able to mount an antibody response or an immune response to it. And that immune response is then what sustains and makes ourselves remember, we've seen that before, we don't need to get really sick, right? And that's the reason that vaccine works in Mila's case, is entirely different. And you're right again, that what what that therapy does is actually target a mutation. That was a spontaneous mutation that arose in her genome that underlies her battens disease. //And so I like those two examples, not just because they highlight the two spectrums of the amount of people they can affect, but but also as you brought up, how they they're really different in the fundamental way in which they worked. But the principles underlying the RNA technologies are actually very similar.
JUDY: So we got another over here? Yes.
AUDIENCE MEMBER: You've spoken about both benefits and safety, I guess, risks in general, as a researcher, could you share with us some of your thoughts about ethics of this type of research and how you deal with them?
ATHMA: Certainly. Yeah, so my lab actually, you know, we really deal with cells in a dish, where we try to understand kind of inherently // how these fundamental processes actually normally occur in ourselves. But there are certainly a lot of ethical considerations, because even the work that we do, those cells in the dish came from a human being. And they are usually derived from, from cells from a cancer patient, who, these days, has gone through an extensive informed consent process to make sure that they understand where their cells are being donated, and how they're being used. But that wasn't always the case. And so a lot of this research, you know, in the past, was not really conducted ethically. I think scientists like myself and many of my colleagues are trying to make strides to overcome that. One of the ways is making sure that all the cells that we use is ethically sourced, and all of the people who donate them are perfectly aware of what what they're being used for. Another way //is ensuring that any of the technologies that we might develop // is able to be to be distributed equally and equitably throughout the community, especially to populations that need at the most. So in a lot of human genetics research, researchers are also actively ensuring that the the patient populations they sample DNA or cells from is also equitably distributed throughout different ethnic groups, populations, throughout the country and throughout different cities and throughout the world, in order to make sure that the research is not just being conducted on a very small subset of usually privileged individuals, but rather is able to kind of span the global population in a better way.
GEORGE: I'm afraid that's about all the time we have Dr. Athma Pai. Thank you so much for sharing this very exciting and timely research.
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JUDY: That does it for this edition of Science Straight Up. Our presentation was recorded at the Telluride Conference Center in Mountain Village, Colorado and a big thank you to the Telluride Mountain Village Homeowners’ Association for providing the venue. Our audio engineer was the incomparable Dean Rolley of Dragonfire productions.
GEORGE: Alpine Bank is a Telluride Science keynote sponsor. The executive director of Telluride science is Mark ˚Kozak and Cindy Fusting is managing director. Annie Carlson runs donor relations and Sara Friedberg is lodging and operations manager. For more information, to hear all our podcasts, and if you want to donate to the cause, go to telluride science-dot-o.r.g. I’m George Lewis.
JUDY: And I’m Judy Muller, inviting you to join us next time on Science Straight Up.
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