Hard Drugs

Jacob Trefethen:
Drug development today is really complicated. You typically need to know which genes or proteins are critical for a disease and to design a drug that can bind that protein and block it. Sometimes that takes decades of work and iteration, figuring out how to design drugs that fit, making sure they're safe and work in the body, not just in cells in a lab.

Saloni Dattani:
And for a lot of diseases, it's even harder than this. Lots of proteins are considered undruggable. They're very hard to develop drugs for, because they're too round or too smooth, or their shape and structure changes too much in the body. So it takes lots of clever work to find out how to block them.

Jacob Trefethen:
What if we could sidestep that entirely? Rather than trying to block the protein, what if we could switch off the gene in the first place? Gene editing tools like CRISPR can help change those proteins and fix harmful mutations, but another approach scientists have been developing is siRNA, which silences the genes instead of editing them, preventing the proteins from being produced.

Saloni Dattani:
You might think only a few diseases are treatable this way, but in fact, siRNA could be used to make lots of diseases more treatable, including high cholesterol, infectious diseases, and even some cancers. In this episode of Hard Drugs, we're going to talk about siRNA and why it's the coolest thing you've never heard of.

Jacob Trefethen:
siRNA is really cool. I think actually for this episode, we have to do a disclosure up top because it's not only really cool, but a lot of companies are working on different siRNA products. It's probably worth saying, despite the fact that we're going to be talking enthusiastically about it, I don't own any pharma stocks. So we're not particularly interested in the industrial part of this question. But Saloni, have you been trading stocks in your free time?

Saloni Dattani:
I have in the past. I haven't for a few years. Now I think it's probably a bit unethical for me to be investing in biotech stocks while writing about the topic. I don't know, it just makes me kind of uncomfortable.

Jacob Trefethen:
Okay. But think of all of those gains you're leaving on the table, Saloni. No, I feel the same way, I own index trackers in the stock market, so in that sense, I indirectly own all sorts of stocks. But because I also work in science funding, I have the same attitude, I don't own individual pharma or biotech stocks.

With that out the way, the thing about siRNA that I often think, before we talk about what it actually is, in some parts, in some industries and some it's hard to predict what's going to happen from the outside. There's been all this progress in different software companies that feels like it's coming out of nowhere. One thing about biotech and about biological sciences is because you have to do so much iteration and so much work in the clinic even after you have a good idea, you actually can predict many years ahead of time, something that has a good chance of ending up working and benefiting patients.

If you were paying attention, mRNA wasn't fully predictable that it would work, there were questions around it, but the concept of mRNA, that it could potentially be used for vaccines and cancer vaccines, that was around in the 2010s and lots of biotech people were very familiar with it. Similarly, GLP-1s, you know, that was a program that existed for a couple of decades before it led to a breakthrough. People weren't sure if it would, but if you were paying attention, I mean, you commissioned an article that announced that everyone would be on GLP-1s four years before everyone was all on GLP-1s and it was true, so...

Saloni Dattani:
I think that's true to some degree, mostly because of how long it takes to develop drugs. The average timeline is about 10 years from when you have a drug to when it gets approved, and during that time, people are already doing clinical trials. You can kind of tell before it's approved that it has succeeded in some of these earlier stage trials. I think it still takes knowing about the field and having skepticism around some of the hype around the stuff, but often you can tell.

Jacob Trefethen:
Yeah. I think for me, there's this kind of distinction between I feel comfortable predicting the future in a broad way, and then in a narrow way, less so. Predicting a- there's so many specifics that go into how a given product will do in a given trial, but the general sense I have with siRNA is, this one's going to pan out for some diseases. I think it's going to be really cool. That, I'm very happy to be held account to account in 10 years' time on whether I was wrong about that at the broad level.

I wouldn't be able to tell you which specific asset's going to work in which specific area. But I think we're far enough along with siRNA as it's been developed that a lot of the original chemistry questions have actually seen a ton of improvement and been solved, as far as I can tell. So I don't know, I'm an enthusiast. How enthusiastic are you feeling?

Saloni Dattani:
I'm also very enthusiastic about the technology. I think, as we'll talk about later on, this thing that makes me very uncertain is, are you silencing the right gene? That's hard. Actually being able to be confident that this is the gene that we need to switch off in order to slow down this disease. Until you run clinical trials, it's very hard to know.

Jacob Trefethen:
Yeah. Well, that's a good time to step back. May I ask you, what is siRNA and why is it so cool?

Saloni Dattani:
The basic concept behind siRNA is that it prevents proteins from being produced, and you can basically choose a protein that you want to silence and decide that it doesn't get produced at all.

Proteins, if you guys remember from one of our first episodes, are used for lots of different things in our body; they create hormones, enzymes, receptors, all kinds of stuff, your hair, your eyes, lots of components of cells and organs, are made of different types of proteins.

If you want to find a way to stop them from being produced, regardless of what kind of protein they are, you have to kind of think back to how they're produced in the first place. You might remember from biology classes that we go from DNA to RNA to protein, and that stepwise progression is going to be really important here.

The basic concept is that DNA contains the code that ultimately determines what a protein looks like, what its building blocks are. When your body needs to produce a certain protein, it reads the DNA in your genome to figure out what the instructions are to produce that protein. Then it creates this intermediate molecule called mRNA: that intermediate molecule gets adjusted a little bit, and then it gets read again to figure out, specifically, which building blocks to join together to create that protein.

You can intervene at multiple steps during this process. You can change the DNA itself, that's what happens during gene editing, and that means that the protein will be made differently. Or you can insert a gene so a new protein is made. Or you can delete a gene so the protein isn't made.

Or more simply, you can just change that intermediate molecule. That's a lot better if you don't want permanent change to your DNA, and that's what siRNA does. It basically targets that intermediate mRNA molecule and tags it to be destroyed, which means the protein isn't produced afterwards. So we have DNA, mRNA, protein, and if you target this intermediate mRNA, then you don't get any protein at the end. siRNA is this short strand of RNA that attaches to a matching mRNA and marks it for destruction. It's kind of like a barcode... or what's a good metaphor for this?

Jacob Trefethen:
A scanner of a barcode, or a barcode itself?

Saloni Dattani:
Something that has a mirror image.

Jacob Trefethen:
Oh, yes, yes. Now I see. Okay. So how about a twin?

Saloni Dattani:
A high five. Oh, a twin.

Jacob Trefethen:
A high five is, yeah, we'll go with a high five. But so you're telling me that there's mRNA, which is the RNA we all know and love. And then there's this other thing, which itself is RNA, but we're calling siRNA.

Saloni Dattani:
Correct.

Jacob Trefethen:
It's just a sort of small strand that's going to start interfering with that mRNA.

Saloni Dattani:
Yep. Imagine you're the mRNA, and you have your hand out, and I high five you. And then someone else comes and destroys you because I've high five you.

Jacob Trefethen:
Never high-five Saloni RNA. S-A-R-N-A, Saloni RNA. Actually, S-A-R-N-A already stands for self-amplifying RNA, which is a totally different thing we're not talking about.

Saloni Dattani:
Right. That actually leads me to a very important question, which is, we should start doing some trivia.

Jacob Trefethen:
Okay, I'm ready.

Saloni Dattani:
Okay. Question one. You have 15 seconds to name as many types of RNA as you can. How many can you name?

Jacob Trefethen:
Oh my gosh. Oh no. Okay. Tell me when the clock starts.

Saloni Dattani:
Okay. Your time starts now.

Jacob Trefethen:
mRNA. We all know and love. siRNA. We're discussing today. RNAi related. Um, uh, miRNA. Um, uh, saRNA, self amplifying RNA.

Saloni Dattani:
You're out of time.

Jacob Trefethen:
I'm already out!

Saloni Dattani:
That's great, though. Do you want to hear the full list?

Jacob Trefethen:
I do.

Saloni Dattani:
I don't know if this is actually a full- the thing is, some of these names are kind of overlapping. They're based on the function of the RNA. They ultimately look very similar, or many of them look very similar. But what they're called depends on what they do. So some types of RNA could have multiple categories.

So there's mRNA, tRNA, rRNA, siRNA, lmcRNA, snRNA, snoRNA, piRNA...

Jacob Trefethen:
snoRNA?!

Saloni Dattani:
saRNA, which you mentioned, gRNA, crRNA, tracerRNA, ribozyme RNA, riboswitch RNA, and self-amplifying RNA. And there's probably more.

Jacob Trefethen:
Very good. There's probably more. Yes, I'm realizing there are two different saRNAs though. Because self-amplifying is also S-A.

Saloni Dattani:
Oh, that's right.

Jacob Trefethen:
I think we should leave a challenge to our listeners. By the end of the year, you should discover a new type of RNA.

Saloni Dattani:
I think they'll be able to do it.

Jacob Trefethen:
I think so too. You just got to be good at branding.

Saloni Dattani:
You've just got to split one of the categories into two.

Jacob Trefethen:
Someone who came up with riboswitch was really on to some. I think that some of these definitely sound edgy. It's worth saying, several of these have won Nobel Prizes. Or rather, people have won Nobel Prizes on behalf of several of these.

So isolating each of their different functions is actually pretty useful. siRNAs, which we're talking about today, were not discovered and named that until quite recently, in my memory. And they might end up being amazing drugs. So yeah, listeners, take up the challenge, discover a new RNA.

Saloni Dattani:
Yes, and thank you in advance.

Okay, question two. As you mentioned, siRNA was discovered fairly recently in history. So the first time that this effect was discovered, of silencing a gene, was in 1990. Scientists were trying to genetically engineer a purple flower to make it even darker. But some of the flowers unexpectedly became pale, patterned, or completely white. They didn't know why, but the results of this experiment were one of the first clues that RNA could silence genes. The question is, what kind of flower was it?

Jacob Trefethen:
Ooh. Wow. Okay. Purple flower. I'm going to go with hyacinth.

Saloni Dattani:
I don't know what a hyacinth looks like.

Jacob Trefethen:
Good. It was a joke. My real guess is... carnation.

Saloni Dattani:
Okay. The answer is, isn't this the name of the aunt in Harry Potter? A petunia.

Jacob Trefethen:
Petunia. I could have got that. Gosh, darn it. Now we have to Google hyacinth. Oh, thank goodness. It does look a bit purple. I was not crazy, even if I was wrong.

Saloni Dattani:
Yeah, so this was very interesting because researchers were trying to make this purple flower more purple, like darker purple. So they added an extra copy of the gene that produces purple pigment, and they were like, this is going to make it darker. Surprisingly, it actually became paler. And they were like, what the heck just happened here? And they wrote down these findings, they didn't really know why it was happening. It was only eight years later in 1998 that that mechanism was discovered, that it was RNA that was causing this silencing effect.

So, RNA interference or this silencing effect was discovered in 1998 and the RNA that was responsible was isolated soon after. Since then, how many siRNA drugs has the FDA approved?

Jacob Trefethen:
Okay, so we have to be at the finish line. Let me try and work this out from first principles. So there's a company called Alnylam, which got founded 20 years ago, say, and worked on a lot of these initial problems. I know that they had this wild 20-year ride of science, science, science, science, science, science, science. And then in the space of three years-

Saloni Dattani:
That doesn't sound like a wild ride.

Jacob Trefethen:
Well, you got to ask them.

Saloni Dattani:
That's like a slow train.

Jacob Trefethen:
Chooga-chooga-science-science. They managed to just about stay alive with no approved products, but staying independent, working on this platform for You know, 15, maybe 20 years before an approval. Then I think they got their first approval and then sort of had this slew of maybe four, in two or three years, that's my memory, which is just so impressive that they stuck with it that long and then had these win after win after win.

Let me just invent that in my head, they've had four or five by now and probably a couple other companies have had one or two, so I'm going to say that the total approved number in the pipeline is huge, but approved, is not so many, maybe seven.

Saloni Dattani:
Wow, that was very close. It's eight.

Jacob Trefethen:
Oh, okay. I feel good about that. Good. Thank you.

Saloni Dattani:
Yeah, that was very close. I really like that. It must have been such a great moment to have the first one and then to be like, boom, boom, boom.

Jacob Trefethen:
Can you imagine?

Saloni Dattani:
Actually, it's got loads of these.

Jacob Trefethen:
Amazing. Amazing. It's also like, I don't have that patience. You know, the marshmallow test is like, can you wait five minutes for a second marshmallow? And I don't mean to brag, but I can. Can you wait 20 years for your science to work?! No, I can't. I would have left. I don't have that. I don't have it. I'm not, I'm not useful enough to humanity. You know, I just, the patience ain't there.

Saloni Dattani:
This is also why I don't do science, I kind of got bored of it. I was like, oh my god, every research project takes more than a year, that's too long.

Jacob Trefethen:
Yeah. They need to figure that one out.

Saloni Dattani:
What is the reward for waiting for the marshmallow, though?

Jacob Trefethen:
A second marshmallow.

Saloni Dattani:
Oh, well... I mean, diminishing returns. I just want the first one.

Jacob Trefethen:
She's so rational that she eats them straight away. Three-year-old Saloni tells the examiner, "I actually hyperbolically discount my well-being!"

Saloni Dattani:
Oh my God. So do you know what some of these eight siRNA drugs are for?

Jacob Trefethen:
I know about inclisiran, which is for LDL cholesterol, right?

Saloni Dattani:
Mm-hmm. That's right.

Jacob Trefethen:
My understanding of the others, I don't know the others, but my sort of sketchy impression was that they were more, maybe rarer diseases or less, not, yeah, sort of specific patient populations, whereas inclisiran is really broad, and maybe a ton of people could be on it or successor drugs in the future. But yeah, what's the real answer?

Saloni Dattani:
That is true. Most of them are rare genetic diseases, and I think it kind of makes sense because you're trying to silence a specific gene. Where would you be most confident that silencing a specific gene is going to stop the progression of that disease? That's often the case with rare genetic diseases, where it's a single gene that is responsible for a lot of consequences.

So there are eight siRNA drugs and they target different things, like hemophilia, LDL cholesterol, and various other rare genetic diseases. I sort of feel like there could be more though, just because of how applicable this kind of thing is. If you're able to silence a gene, there are so many diseases that are caused by a gene, that in principle, there must be hundreds or thousands of rare diseases that this could be applied to.

Jacob Trefethen:
I see. You're saying in particular for rare diseases, but they are primarily caused by a single gene, those are the cases you're talking about?

Saloni Dattani:
Yeah.

Jacob Trefethen:
I'm with you. And I feel like one thing we may talk about later is delivery, so where do you need to silence those genes probably matters. But do you have any more trivia for me first?

Saloni Dattani:
Yes. And in fact, that is the theme of the next question, the last question. All of the siRNA drugs approved so far do most of their gene silencing in one organ of the body, even though they treat a wide range of conditions. Which organ is it?

Jacob Trefethen:
I know the answer.

Saloni Dattani:
What's the answer?

Jacob Trefethen:
I feel like I'm that guy in who wants to be a millionaire who gets to the final question and says, I'd like to phone a friend. I want to call my dad. And they say, okay, sure. And then he says, dad, I just won a million dollars.

Saloni Dattani:
I love that scene.

Jacob Trefethen:
The answer is... the liver!

Saloni Dattani:
Yes! You got it.

Jacob Trefethen:
Boom! And I believe the reason as described to me by a friend who works on siRNA is that approximately speaking, is that they attached - they figured out a way, I guess Alnylam probably figured out a way - to attach a sugar to an siRNA molecule that your hepatocytes in your liver really like the look of. Of course, everything goes to the liver through the blood anyway, so once it gets there, that ends up getting absorbed by hepatocytes. Is that a fair crude summary or...?

Saloni Dattani:
There are actually, there are currently two main delivery systems. There are two main ways to deliver siRNA to organs in the body, and both of them are very appealing to the liver. I like the idea that we attach sugar molecules and the liver cells are like "Yummy!"

Jacob Trefethen:
Hey, it will work on me.

Saloni Dattani:
Okay. That's all the trivia that I have. But now I'm curious. You have a friend who works in siRNA. Is it the same person that I know who works in siRNA?

Jacob Trefethen:
I don't know. Is your person Irish?

Saloni Dattani:
I don't think so. Oh there are two people who work in siRNA, what?!

Jacob Trefethen:
They're interfering. That was a... I guess there's at least two people now. Who's your person?

Saloni Dattani:
Impressive. Mine is Jacob 2.0.

Jacob Trefethen:
There's another Jacob?

Saloni Dattani:
There's another Jacob who wrote this amazing article for us that Works in Progress. His name is Jacob Witten.

Jacob Trefethen:
Oh, he sounds awesome, yeah. I bet he's a good friend too and likes gelato.

Saloni Dattani:
Do you also have this competitive feeling around people who have your name?

Jacob Trefethen:
Well, I... yes, a little bit when they're friends with you, but luckily there are not too many Salonis. In fact, I don't even think I have a Saloni 2.0 yet, so I can't even threaten you with a Saloni 2.0.

Saloni Dattani:
I really like that my name isn't very common because whenever I do occasionally meet another Saloni, I'm like, "There can only be one of us."

Jacob Trefethen:
"Mark her for degradation."

Saloni Dattani:
High five!

Jacob Trefethen:
Yeah, okay, other Salonis listening, never high five Saloni 1.0.

Saloni Dattani:
This also makes me wonder about, well, I have a question for you about how, based on siRNA, which is: if you can silence any habit that you have, what would it be?

Jacob Trefethen:
Ooh, gosh. Only one? Monogenic? Let's see.

Saloni Dattani:
Just one.

Jacob Trefethen:
Oh, my gosh. I would silence my inner critic. No, I would silence my... ugh..

Saloni Dattani:
Snoring. Do you snore? No. I don't think so.

Jacob Trefethen:
I snore a little, but it's sort of gentle, apparently.

Saloni Dattani:
Aww, that's fun.

Jacob Trefethen:
Do you snore?

Saloni Dattani:
I don't know.

Jacob Trefethen:
What would you silence?

Saloni Dattani:
Well, sometimes I drool when I'm sleeping. I think it's because- so I got braces a few years ago and I think my jaw actually changed shape slightly. Now it doesn't know how to keep it shut, you know? Sometimes I'll wake up and there's just like... drool.

Jacob Trefethen:
You're like a dog. Yeah. Okay. Well, that's a good one.

Saloni Dattani:
So what is your answer?

Jacob Trefethen:
I guess I would silence my... Well, I used to be addicted to chess.com, and so I managed to control that non-pharmaceutically. But if I had siRNA back then, oh my gosh, I would have been injecting that and inhaling that.

Saloni Dattani:
What's your strategy?

Jacob Trefethen:
Of how to drop off. Yeah, yeah. Yeah. I mean, this is actually, this I think might be, this anti-addiction advice does work for me. For me, I just had to find it uninteresting, that's the key, I had to find it unstimulating. So it was all about getting to a point where playing the five-minute chess was in fact boring to me. And, you know, that's a real set of mind games you got to play with yourself, but I couldn't find other ways to quit, I had to somehow actually find it boring.

Saloni Dattani:
So how did you find it boring? Did you just play it a lot?

Jacob Trefethen:
No, that... I did play it a lot, but... I think it's to do with how do you change your environment and what people value around you and what you value. It's a real set of mind tricks, I don't think I can summarize it, but I'm glad that I achieved it in that case.

Saloni Dattani:
Interesting. I had the same sort of thing with online poker, which I used to be addicted to. And I actually-

Jacob Trefethen:
Wait, you were addicted to online poker?

Saloni Dattani:
Well, I used to play on my phone.

Jacob Trefethen:
I was addicted to online poker. How have we never known about this?

Saloni Dattani:
Wow! I didn't know that.

Jacob Trefethen:
That's crazy.

Saloni Dattani:
But I actually, I think I eventually made so many free tokens and then I'd like lose a few games and I'd just be like, "This sucks now! I hate it!" and then I just stopped playing entirely.

Jacob Trefethen:
Okay, that's good. Also, your version of addicted sounds healthier when you said free tokens, let's just say mine went a little bit different.

Saloni Dattani:
How much were you spending on this?

Jacob Trefethen:
I was a net winning player, but let's just say there were some nights that maybe the answer to that was not the kind of thing you would disclose on a podcast, so yeah.

Saloni Dattani:
I had a friend at university who played, he was this like maths guy, so he'd play like multiple games online at the same time.

Jacob Trefethen:
Oh, I used to play.

Saloni Dattani:
It was just like a statistical. Oh, you did the same thing?

Jacob Trefethen:
Of course, I did 12 to 24 tables at one time.

Saloni Dattani:
What the hell? Okay, so this-

Jacob Trefethen:
My brain is absolutely rattled by teenage years. What's going on up here is not normal.

Saloni Dattani:
Well, now I want to know what you did with this, but I remember asking this guy, how much money have you made by playing online poker with like 12, whatever, how many other games he was playing at the same time.

And he was like, he's been playing for like a year and he said, three pounds. He basically put such small amounts into each game, and it was basically just trying to train himself to get better at it rather than trying to earn money.

Jacob Trefethen:
Okay. All power to him. Yeah, I mean, that's a really, it's very hard to achieve being plus or minus three pounds after a year, so that's very impressive.

So siRNA got discovered in the 90s, right? So how come it's taken a while to develop these drugs? Once you already had some understanding of siRNA, why did drug development take a while?

Saloni Dattani:
Right. This is the 20 or so years that you mentioned that Alnylam was working on this, just trying to figure out all the science of how to make these new drugs.

The basic reason is that siRNA doesn't really do very much if you just inject it into people on its own. There are lots of enzymes in our body that naturally try to break it down. Also RNA itself is very unstable chemically. Unlike DNA, it has this extra oxygen atom. That oxygen atom makes it very prone to being destroyed or accidentally broken down.

So it took about a decade to turn, or more than a decade to turn siRNA into real drugs, and that was because scientists had to figure out how to keep the RNA stable in the body and make sure that it got delivered to the right cells in the body.

I think that you might be able to just guess some of the ways that this could happen. What would you guess, if you were a drug developer and you had an RNA molecule that is very unstable because of this oxygen atom, how would you make sure that it sticks around?

Jacob Trefethen:
Well, I mean, mRNA, the solution there was put it inside a lipid.

Saloni Dattani:
Put it in a bubble.

Jacob Trefethen:
Put it in a bubble. Yeah. So I guess that would be my first thought. Did they try that?

Saloni Dattani:
Yeah. That is one thing they tried, so they encapsulated it in a bubble. Just like with mRNA, they used a lipid nanoparticle, basically just a fat bubble. And there's another way as well, can you guess what that was?

Jacob Trefethen:
Well, I mean, I'm sort of guessing based on other knowledge, but I don't know if this solved the problem you're pointing out or not. But if you conjugate it to something more stable, does it become more stable?

Saloni Dattani:
I think so. I think you can tweak the chemistry, you can take off that oxygen and like replace it with something else.

Jacob Trefethen:
I was actually thinking of something too complicated, which was to add, but you're saying remove.

Saloni Dattani:
Yeah, yeah. I'm saying switch the oxygen for something else, like fluorine or something. So if it's the oxygen that makes the RNA unstable, then why not just remove the oxygen and give it something else instead?

Jacob Trefethen:
Great.

Saloni Dattani:
Simple.

Jacob Trefethen:
I'm glad I thought of that. Yeah.

Saloni Dattani:
Okay, so now we figured out how to keep it stable, but how do we now make sure that it gets delivered to the right organs? As we talked about, all of them so far go to the liver. How do we make sure that, however you figure out how to stabilize this siRNA, how do you figure out to also get it to the liver?

Jacob Trefethen:
I think it's going to literally get there in the sense of, it'll go through the blood and it will circulate via the liver. Then how do you get the liver cells to take any interest in it? I know the sort of broad answer to that, but I couldn't tell you chemically why it works. I know they they attached a sugar, GLANAC or something like that?

Saloni Dattani:
GalNAc.

Jacob Trefethen:
GalNAc, there we go, to the RNA and sort of conjugated it. I was about to go on an aside about vaccines, but I won't. Self-restraint, self-restraint. Is that sort of broadly correct, but could you tell me why it's correct? I don't know.

Saloni Dattani:
I think there are two options. We have the two different ways that you can stabilize the RNA. One was put it in a bubble. The second was change the oxygen for something else.

If we start with the put it in a bubble thing, what's really helpful about these lipid nanoparticles is that they're naturally just taken up by the liver, because the liver sees something that's lipid, like cholesterol, and it just thinks, "You look like a cholesterol, I'm going to take you up as well." So it sees this siRNA in a lipid nanoparticle and it just takes it up.

Okay, second option: you don't put it in the liver, but you just switched out the oxygen atom for something else to make it more stable. Then you can add these sugar molecules onto the siRNA. What is helpful about sugar molecules is that there's this receptor on liver cells called GalNAc receptors that detect those sugars and then eat it up. So if you add those sugar molecules to the RNA, the liver's like, "Yummy!", and then it eats it up. That's how you get to the liver. Then I guess the sugar molecules are like an address label or something, and they say, "hey, go to the liver and get picked up by these GalNAc receptors."

Jacob Trefethen:
Do you know how many get picked up per liver cell?

Saloni Dattani:
I wish I knew that, but I'm actually very bad at trivia. This is why we do it this way, I ask you the trivia questions.

Jacob Trefethen:
Well, yes, I don't know the answer to that one either, so we can leave that to people who are more informed than us.

Saloni Dattani:
I think what's cool about this address label idea is that it makes you think, if you chose a different address label, would it go somewhere else? That's what scientists are trying to do right now. They're trying to add different address labels to these siRNA molecules, to make sure that they get absorbed by other organs.

With the delivery problem, what's hard is that if you don't have an address label and you want to get it into some cells, like in the brain or something, occasionally that'll mean you have to use a different way of administering the drug. Maybe it's a spinal injection or something like that, and that's one of the options that people are using to develop siRNA drugs for either Huntington's or Alzheimer's, I can't remember which one, but that makes it much less appealing because the way that you administer that drug makes it just much less appealing to patients themselves.

Jacob Trefethen:
There are people working on subcutaneous injections, so injection into the fat, that's not so painful, but that's not yet been proven out for Alzheimer's.

Saloni Dattani:
Wait, so how does it go from the fat into the brain though?

Jacob Trefethen:
The hope is it goes from the fat into the bloodstream, and then it's designed in a way where the address label is going via, for example, a transferrin receptor, which is one of the main shuttles into the brain.

Saloni Dattani:
I like this idea that there are shuttles that- We have a blood-brain barrier. It mostly keeps everything out.

Jacob Trefethen:
Leaving the station.

Saloni Dattani:
It's mostly like, "No infections, please!" We're going to keep most big drugs out of the brain. But occasionally there's a little shuttle system that's like, "Want to get on the bus?"

Saloni Dattani:
Okay. If you had a technology like this, siRNA, that could silence specific proteins, what would you use it for in terms of diseases?

Jacob Trefethen:
My head immediately - I'm a broken record because I've talked about hepatitis B on other episodes - but my head goes to hepatitis B. The reason is that we're talking about, we've already cracked this when it comes to the liver, so if there's a problem that's happening in your liver, that's a pretty good contender.

Saloni Dattani:
Right. Hepatitis is in the liver.

Jacob Trefethen:
Exactly. It's in the liver. What happens with hepatitis B is you have these viral DNA that gets integrated into your DNA or forms its own cccDNA, this kind of little closed circle of DNA, and starts spitting off RNA and then viral proteins.

But if you could just have some siRNA hanging out down there in the liver, such that every time it spat something off, you'd interfere, that sounds amazing. The issue with hepatitis B is people have a chronic infection for decades, meaning that they're just incurring damage in their liver over decades. But in this case, guess what? You could silence that.

Saloni Dattani:
Whenever you talk about hepatitis B, I always find it really scary to imagine this little piece of viral DNA that's just hanging around, years and years. And then eventually it's just like, "You know what? I'm going to give this person cancer." That freaks me out.

Jacob Trefethen:
I know it's very unfair. If it's any consolation, though, much of our DNA is millennia-old viruses. We've been infected all the way through.

Saloni Dattani:
But those don't do anything anymore. Or most of those don't.

Jacob Trefethen:
Well, you're right, but I mean, we all do die. So there's probably some that do something related to our death.

Saloni Dattani:
Oh no. I guess I just think of the literal thousands of rare diseases where, for a lot of them, you do actually know that this is caused by this particular gene. If you could develop an siRNA that targeted that specific gene and treat them, cool! We can do like loads of rare diseases with the same pathway, with the same like technology. That, I think, would be very cool. One statistic that I learned recently that I thought was very surprising was that, with rare diseases, about 95% of them have no approved drug that treats them at all.

Jacob Trefethen:
Gosh.

Saloni Dattani:
So we can do a lot with that, I think.

Jacob Trefethen:
What kind of rare diseases come to mind for you, if any?

Saloni Dattani:
I think it has to be ones where you've figured out which gene is involved, and sometimes that's not the case. With a bunch of autoimmune diseases, it's hard to tell exactly what's causing the disease, genetically.

With a lot of others, like Huntington's disease and things like that, we actually do have a pretty good idea of, this is the gene that's involved. And if we could silence them, that would be great. There are a bunch of drugs in the pipeline today or are approved for some of these, like hemophilia, there is a new siRNA drug for that, and I think it lasts a few months per dose, which is very cool.

Jacob Trefethen:
I'm also cautiously optimistic for diseases that affect broad populations. I'm going to name a couple, but I want to emphasize the caution, because I think there's still some work that needs to be done on this. We talked about how you can deliver to the liver. Deliver, if you will, sorry.

Saloni Dattani:
Ooh, I like that. Deliver to the liver.

Jacob Trefethen:
You can deliver to the liver quickly - not quickly, but effectively already. So there's then a question, well, what about diseases in other organs? I mean, you can definitely get to the heart pretty quickly, but can you deliver well in the medical sense? Can you get to the brain and deliver there?

Saloni Dattani:
What do you mean you can get to the heart pretty quickly? Like if you stab someone or like what are you thinking of?

Jacob Trefethen:
I was thinking that the blood gets there like once every second. Oh, I see. Yeah, you could also stab someone in the chest. The diseases I'm going to name are broad bucket, cardiovascular heart disease, and then secondly... Alzheimer's. Shall we start with..?

Saloni Dattani:
Let's go for Alzheimer's first.

Jacob Trefethen:
Let me start with the reason it's going to be hard. Delivering any drugs to the brain is hard, because the brain has various mechanisms to ensure that not everything that goes in your body gets to the brain; it's a sterile place up there, you really don't want bugs going up there. You don't want nonsense that could harm your brain.

There's a blood-brain barrier that exists that makes it hard to get in. That means that, for example, the first disease-modifying treatments for Alzheimer's that are antibodies, antibodies are pretty big proteins and you have to do a big dose, so that only a small proportion gets in and can help up in that.

Saloni Dattani:
Most of it just gets blocked, basically.

Jacob Trefethen:
Exactly. And siRNA, you know, it's smaller than an antibody, that's for sure. But you actually need a transport pathway of, how are you going to intentionally get in there? And once you're in there, does it matter which cell types you get delivered to? So the neurons, the microglia, whatever.

Saloni Dattani:
You don't want to silence that gene everywhere. Sometimes the gene might be actually doing something important.

Jacob Trefethen:
Well, exactly. So think of Alzheimer's as the APP gene that's implicated in Alzheimer's and amyloid production.

Saloni Dattani:
A peepee?

Jacob Trefethen:
APP. And you know, APP is pretty useful around your body in plenty of ways, and so you don't want to silence it everywhere. The question is, can you knock it down in the brain and specifically in particular cells in the brain? So that is not something that has an affirmative answer yet.

The recent results from an Alnylam trial show you can reduce APP-related biomarkers with a drug injected into the spinal fluid. However, the reason that siRNA could be so exciting there is that you have this, the pitch is not only can you go after a particular gene that you know is implicated in the pathway of many cases of Alzheimer's - so say APP - but you can tune how much - we haven't talked about this aspect that much of it - you can tune how much you're knocking down the production of something.

You often don't want to knock it down 100%, you want to knock it down maybe 50%. We know that there are certain proteins we want to steer the cells away from overproducing, but sometimes you want to just knock it down 50%, and let the siRNA hang out in these endosomes in the cell and just slowly every day, it's knocked down. That's a pretty interesting application to me. That said, plenty of dementia has other causes, so it's not a monogenic disease in the same way as some of the other diseases we just talked about.

Saloni Dattani:
Yeah. I mean, I think what's interesting about many of these diseases is they're not necessarily caused by a single gene. But there are various genes that have some critical importance in part of the disease.

Cholesterol is one example, where it's caused by many different things, but there's one particular gene, PCSK9, that is kind of a bottleneck, in some way, to how much cholesterol you have in your blood. There are new siRNA drugs like inclisiran, which you mentioned, that target that PCSK9 specifically, that means that it reduces the levels of cholesterol in your blood.

Even though cholesterol is very complicated and there's lots of different things going on, you can sometimes find a specific protein that a lot of other things depend on.

Jacob Trefethen:
Which is both a positive for the way that many different diseases siRNA could end up helping with, it also imposes some limitations, in the following respect. You know, when I talk to an siRNA friend about, okay, so are we going to have siRNA drugs for everything?

One perspective is yes and you're going to get limited on the quality of the targets, the genetic targets. PCSK9 is an incredible target. How many targets do you have that have that level of evidence behind them, in relation to causation of these big diseases? Not so many.

One perspective is for the ones who have good evidence, there's already tens of companies, mostly in China, who are going massively after it with siRNAs.

So the question is actually, in addition to that, can you solve these delivery problems, which is a current limitation on organs, and can you actually generate better genetic evidence about other of the 20,000 genes in the human body that are implicated in disease? Because without that, the joys and wonders of siRNA won't get you very far.

Saloni Dattani:
I think that hypothesis thing is also relevant in Alzheimer's, right? There are some siRNAs that people are developing that target amyloid precursor protein, like you mentioned, and then there's some that are targeting tau. Depending on what hypothesis you have, you might think some of them might work better than others.

Jacob Trefethen:
Yeah.

Saloni Dattani:
Something that I find interesting is that you can also potentially use this for cancers. A lot of cancers are driven by what are called oncogenes, that basically drive cancer growth. Maybe they increase how fast cancer cells divide, or how much cancer cells metabolize, or how much they resist drugs and things like that.

If you can manage to silence those genes in a cancer, that could actually slow down the cancer quite a lot. What I find kind of confusing is that, sometimes you're trying to silence a gene that's kind of naturally in the body, and it might be like PCSK9 whereit's there, you can turn it off, you won't actually be harmed that much by having it switched off.

But then there are other genes where you only want to target the mutated version of that gene, not the gene normally. So there are some versions of siRNA drugs that could work potentially for large groups of people, and there are other versions where you have to figure out which specific mutation that person has, and then develop the siRNA that targets that.

Jacob Trefethen:
Right. And presumably the good news is that once you see the genome of that person, it's actually not that hard to do that because these are programmable drugs. You have to draw something that will high five, and that drawing can be quite simple.

Saloni Dattani:
I feel like that's the most amazing, interesting thing about siRNA, that you don't have to kind of develop it from scratch every time, but you just have to switch out the specific sequence. You just tell it, this is the RNA that I want you to destroy, and it goes out there and destroys it.

Jacob Trefethen:
Which maybe is a good time to talk about pandemics and infectious disease.

Saloni Dattani:
Ooh.

Jacob Trefethen:
You know, the reason that mRNA was so interesting and useful as a pandemic vaccine tool is the programmability, in that you can basically write a different string of nucleic acids for a different infectious disease, so you can be responsive quickly to new outbreaks.

I think siRNA shares that property in the case of pandemics, but has not got as far in terms of proving whether it's helpful. But you can visualize that, whereas mRNA is this kind of big molecule that's floppy and crazy, and so you need to encapsulate it in a lipid nanoparticle, siRNA is this double-stranded RNA, it's more stable and a bit smaller.

I think there's totally a future you could imagine where for some viruses or other infections, you are inhaling some siRNA that is, not a vaccine necessarily, it's actually interfering with something that the virus is using. And that is a potentially much more rapidly responsive platform, in the same way that mRNA is, because you can really just back-fit it to a new problem, a new virus.

Saloni Dattani:
It reminds me of, with HIV, there are these people who are just naturally immune to HIV infections because they have like a mutation in this specific gene - people just don't have a functioning version of that, of those proteins. The HIV virus uses those proteins to enter cells, so if it's dysfunctional in some way, the virus can't attach to it and enter your cells. So this is the kind of thing that you were thinking about, right?

Jacob Trefethen:
Yeah, that's analogous, I think.

Saloni Dattani:
Very cool.

Jacob Trefethen:
The programmability is a really interesting property. We've also talked about how some targets where they're not druggable - in the sense of the protein is hard to target - become druggable, if you can target the RNA that codes for protein. Those are two really interesting properties of siRNA. Are there other properties that you think are beneficial?

Saloni Dattani:
I think the best one is how long it lasts. With a lot of drugs, you have to take them every day. They very quickly get excreted, or not a lot of them is absorbed by the body, so you have to take them very frequently.

What's different about siRNA is that often lasts weeks or months, or sometimes like half a year, with just a single dose of an injection with an siRNA drug.

And I think the specific reason that happens is not clear yet, but the broader reason is basically that when you have siRNA, it gets trapped in this tiny bubble inside your cells, and occasionally some of the siRNA escapes that little bubble and it has its effect. And even at very small quantities - that tiny amount that slips out of these little bubbles - is enough to have its effect. Because it's slipping out every once in a while over a long period of time, that means that it can have its effect for months. And that I think is really cool. The fact that it's just kind of trickling out. Occasionally, it's like, "hey, you know what? I'm going to silence this gene for a while." And then another one comes out, and it's like, "me too!"

Jacob Trefethen:
Yeah, that is awesome. And so instead of visualizing taking a daily pill like a statin, say, you might be able to visualize taking a monthly shot like a futuristic GLP-1 in your thigh or something like that. And that is honestly, does sound way better than daily pills to me for a lot of things, that would be amazing.

Saloni Dattani:
Back when we did our first episode on HIV drugs and lenacapavir, which is also one of these drugs that lasts a very long time. We talked about how there are different ways to get drugs to last very long in the body. Like some of them are, what was it? Some of them are injected into fat and they slowly sleep out into the bloodstream. Some of them are in this crystallized form and they slowly dissolve. But I like this version where it's in a tiny bubble and occasionally it's just like, "I'm going to get out of here!"

Jacob Trefethen:
Yeah. So with lenacapavir, the depot - which we learned was not pronounced de-pot, but depot, that was one of the big updates from that episode - forms in this, you know, collective in your fat tissues, as you just said. In this case, it's in the cell itself. So you've got, take the liver targeting, you've got this siRNA attached to a sugar, it meets a liver cell. The sugar acts as a tag and the siRNA gets internalized into the cell and it's in this little bubble in the cell for months, it's crazy.

That's so helpful that it happens to just form a depot down there, you know, and it's slowly released because the RNA that is doing the coding of bad proteins is in the cytoplasm of the cell, so you get to interfere in that. It's awesome. Okay.

So we have the programmability. We can 'hit new targets that were harder when you were trying to hit proteins than when you're hitting RNA'. And we have long-lasting. I mean, that is a pretty powerful combination, I have to be honest! And then, so what are the drawbacks? Why have we not seen siRNA just absolutely crush all these diseases already?

Saloni Dattani:
That is a good question. I think there's several reasons. I think the main one is this, do you actually know what the correct biological reason behind this drug is? I think that's actually going to be a challenge over and over, we're going to occasionally see some of these drugs fail, and it's not going to be because of siRNA technology necessarily, but it's going to be because we actually just got the theory wrong. It turned out that this gene that we thought was critical and this pathway was a confounder or something, it just happened to change or something like that, or it's a by-product in some way. I think that's the big one. Does anything come to mind for you?

Jacob Trefethen:
I think that's a big one for sure, actually understanding drivers of disease. I think the second big one for me is delivery. It took a long time to solve the problems that now mean that the liver deliver is possible, and I expect it will take a lot of time to solve problems when you're trying to deliver the other organs around the body.

Those won't all be the same problems, you know, and when it comes to delivering to the brain, you might be talking about transferrin receptors and other things that help you shuttle into the brain across the blood-brain barrier. That kind of chemistry, that kind of biology, is quite different too when you're talking about the heart, when you're talking about the kidneys, and all of that. So I think delivery will remain a big bottleneck for a while.

Saloni Dattani:
What other downsides can you think of?

Jacob Trefethen:
You know, listeners of this podcast will probably be wondering, is this going to be deliverable at scale? Because we are always interested in the actual health impact, and not just cool technology.

I would say for this one, we have not yet reached a scale of siRNA usage that is anywhere like the usage of small molecule drugs. So small molecule drugs, the production of them is very commoditized and there are hundreds of companies around the world that can make small molecule drugs, actually, maybe thousands, I don't know.

siRNA, if you think about the fundamentals of it, I'm somewhat optimistic about the underlying cost structure; it shouldn't be fundamentally that expensive to produce double-stranded RNA that you conjugate to something.

When you compare that to something that is more complicated, like CAR-T therapy - that's a cellular therapy individualized to a patient, requires a lot of fancy machines, a lot of fancy work, and a lot of monitoring.

In this case, once we get further with siRNA, I think the underlying cost structure looks pretty good. Now, it's not going to be as cheap as small molecules in the next decade, but I don't see why it couldn't be that you're creating doses of things for say tens of dollars instead of dollars.

Of course, as with any new medicine, the price and the cost may differ a lot, because companies that hold the patent rights may charge high prices to try and make back money for the R&D that they did to get to the finish line. But the thing that long-term matters a lot is the cost, the underlying cost is low enough that you can produce things at scale, not just in the US and the UK, but in countries that have lower public health budgets in total and less built out private insurance too.

So I'm cautiously optimistic, even though I don't think we're going to get to small molecules soon. I'm curious what you think about that.

Saloni Dattani:
When you mentioned scale, I was actually thinking about how the drugs are taken. What you said makes total sense to me. The other difference between most drugs and siRNA drugs is that a lot of drugs are taken as pills, whereas siRNA is typically injected, and you need more skills to do that, and it's harder to do that at scale than it is to just give people pills, basically. I don't think that there are siRNA drugs yet that are taken orally. Maybe there will be in the future, if someone figures out how to do that. But for now, I think that also limits how much you can scale them up.

Jacob Trefethen:
Yeah, I think that before GLP-1s went mainstream, I would have been quite concerned about that limitation, and now so many people seem comfortable with these tiny needles, so I don't know. I guess that brings me to a question for you, which is fast forward 10 years, do you expect that you will be on at least one siRNA drug?

Saloni Dattani:
Oh, oh, that's fun. You know, when we did our cholesterol statins episode, we said we should definitely get tested for cholesterol. And I was like, if I get a cholesterol level above a certain threshold, I'll start taking statins because I could get them prescribed. But I didn't make it to the threshold. So I actually can't.

Jacob Trefethen:
No, I'm so sorry.

Saloni Dattani:
It's so sad. But if I had, then definitely yes. Unfortunately, it's hard to predict what diseases I might have in 10 years. I feel like that's the question here. And then it's, will I have a disease that can be treated with siRNA drugs? I don't know. I think the chances are sort of low for now.

Jacob Trefethen:
Okay.

Saloni Dattani:
Thankfully, but I don't know.

Jacob Trefethen:
Loser...

Saloni Dattani:
Yeah, it sucks. But actually, there's a way out of this because in the UK, there are some statins that you can take over the counter. So maybe I will, anyway.

Jacob Trefethen:
Your doctor is like, I don't recommend this. Screw you, man.

Saloni Dattani:
Who cares? I'm going to take them anyway.

Jacob Trefethen:
Well, I think I will be on one.

Saloni Dattani:
For what?

Jacob Trefethen:
And I think that the reason for that is that my cholesterol is higher than yours.

Saloni Dattani:
Lucky you.

Jacob Trefethen:
I think that in 10 years time, there will be these siRNAs that are designed to, you know, you don't have to take them every day and you can, they have seemingly little side effects and they can knock you right down on LDL cholesterol. I just think I'll be on one if I'm sort of being realistic about it. And that's, quite calming, actually, if I'm honest, because I'm like, oh, gosh, I don't have to think about cholesterol as much, because, you know, if I'm being completely honest, I am not actually yet on statins. I'm sorry, even though I… because it's just like such a faff. Whereas here I'll be like, OK, great. I can just do that one and done.

Saloni Dattani:
Yeah. I guess the other thing that I think about is maybe diabetes that I have, you know, family members who have diabetes. I don't have it myself yet, but I love sugar, I love desserts, and so I'm just like, if there's one disease I get in the next 10 years, maybe it'll be that, and maybe there will be some siRNA drugs for it.

Jacob Trefethen:
You've got GalNAc receptors on your tongue.

Saloni Dattani:
I had a viral tweet about a cake that I ate.

Jacob Trefethen:
I saw this tweet.

Saloni Dattani:
It was so funny to me that one of my most popular tweets ever in history was just this dessert that I ate and really enjoyed. It was on the menu, it just said it was a baklava sandwich. And I was like, what is that? Is it baklava or is it baklava?

Jacob Trefethen:
Listeners, in the comments, adjudicate.

Saloni Dattani:
Well, whatever it was, it just said baklava sandwich. And I was like, I don't know what that is, but I want that. It was two layers of baklava, and in the middle, there was pistachio ice cream, and it was so-

Jacob Trefethen:
Oh my God. Did you finish the whole thing?

Saloni Dattani:
If I had to get siRNA drugs after eating a lot of these cakes, that's fine!

Jacob Trefethen:
That is beau- they should serve siRNA drugs on the side of the baklava.

Saloni Dattani:
I couldn't actually eat the whole thing, but I fortunately had skipped main course and I just had starters.

Jacob Trefethen:
Oh, thank goodness.

Saloni Dattani:
Good. I can eat more of it.

Jacob Trefethen:
Well, I'm glad that your most important work is getting the most attention. I feel that that is a common phenomenon. In fact, my dad is a mathematician, and the thing that- he's worked on linear algebra and numerical algorithms, all these important topics that he got famous for - and the thing that got him most famous was one time he said a random thing about how to calculate BMI, ad then all over the news, it was, "Professor says BMI is calculated wrong!" when it was an offhand comment.

So it turns out that the most popular way to get famous does relate to food and diet, and that is probably something about our species.

Saloni Dattani:
Okay, so both of us expect that we might be on siRNA drugs in 10 years. How excited are you about them more broadly than that? Do you think we'll be able to use them across many different diseases or will it just be a small number of them?

Jacob Trefethen:
I am excited. I'm actually very excited. I think that there are problems left to solve, but it is an unusually promising modality and that is because of the properties we discussed today. It's the fact that it's programmable. It's the fact that it might open up new targets where it's hard to hit a protein but easier to hit the RNA. And it's the fact that it's long lasting. I think that if you pair that with enough genetic evidence about the drivers of different diseases, I think you might be able to really help with many diseases.

Saloni Dattani:
I find that the first one, being able to target these diseases, or these proteins, that people previously thought were undruggable - and there are various estimates around there, but people estimate that 80 or 90% of proteins in the body are undruggable. They are too round or too smooth or they change shape a lot, and it's hard to know exactly what structure they have, and what structure you should be targeting, and how to target it. Even if you do develop drugs, they might not attach to them properly.

So the fact that you can kind of take a step back and say, let's not target the protein at all, but let's just prevent this protein from being produced. That, I think, is really exciting and circumvents that big problem.

I am also kind of excited because it seems like it's better than a bunch of the other genetic medicines out there. So there's CRISPR and there's gene therapies, all of these seem very important for some diseases, but siRNA seems like it's more off-the-shelf. You don't have to extract cells in your body and then put siRNA into them and then put them back in the body, and that's currently what happens with CRISPR and gene editing that happens that way. They're ex vivo, so you have to extract someone's cells, maybe their cancer cells or their blood cells, you then get rid of the other stem cells that produce that type of cell in their body, you edit the cells that you've extracted, and then you put them back.

That makes it very hard to scale that kind of medicine up. Whereas with an siRNA drug, it's just an injection. And many people will be able to have the same siRNA drug to silence their genes instead of doing this outside the body. People are trying to figure out how to do gene editing in the body, but it's still kind of difficult, and it might take a while, whereas this has already succeeded. So that's one thing I'm excited about.

Jacob Trefethen:
Awesome.

Saloni Dattani:
So we are almost at the end of the episode, but before we end, what are the things that you'll take away from this episode?

Jacob Trefethen:
One of my big takeaways is around the long-lasting nature of siRNA versus a daily small molecule drug, say. It's kind of full circle for our podcast, because we started our podcast with an episode on lenacapavir, this HIV drug that sticks around for six months, twelve months.

But the way siRNAs stick around is different. They make it into a cell, say your liver cells, and then they're in these little endosome bubbles inside the cell, and they slowly trickle out over a period of weeks or months. That can be really useful when there's something in that cell that you want to stop making so much protein. So I think that's an interesting property of the biology and chemistry of siRNAs, which, for drug development purposes, can be quite useful.

Saloni Dattani:
I think that one's very interesting because often when people think of RNA, the main difference that they know between RNA and DNA is that RNA is less stable and our RNA is more a temporary thing. But in this case, it turns out that you can- it just gets trapped in this bubble, and because of that, it has this long lasting effect.

For me, the thing that I found really interesting is just how many different types of diseases it could potentially be used for, so: infectious diseases where you have a viral infection and you can use siRNA to silence the genes that those viruses use and prevent them from multiplying or maintaining themselves in their cells or whatever. Like hepatitis B, you can prevent it from sticking around for years or decades.

But then you can also hopefully prevent infections by silencing genes in your own body that those viruses depend on, which I think is cool. It's like if you were a rock climbing wall and the virus was climbing the rocks and... this is the worst analogy.

Jacob Trefethen:
I'm still listening...

Saloni Dattani:
And if you just, you know, all the holds just fell off that rock climbing wall and the virus is like, "god damn it, I can't climb the wall anymore!" It's just like that.

Jacob Trefethen:
That is flawless, yeah. Simile. Yeah. Best simile of the episode. Keep going.

Saloni Dattani:
But also it's not just infectious diseases, it's loads of different rare diseases you could use it for. You just have to figure out what gene it's for, what gene causes that rare disease and can you manage to get the siRNA to the right cells in the body, that I think is very hard.

The fact that it can be used for such a wide variety of different diseases, I think is pretty cool.

And then also the common diseases, like Alzheimer's, and lots of different cancers, and heart disease, and cholesterol, where it's already been approved. Just the fact that it seems very versatile, it's a bit like if someone discovered antibodies for the first time or they discovered vaccines for the first time and they're like, "oh, wow, we can apply this to so many different places."

Jacob Trefethen:
Totally. Well, another thing I learned this episode is there's a type of RNA called snoRNA, and there are two types called saRNA. And our listeners should go out and find more types of RNA as quickly as they can, so that they can win Nobel Prizes too.

Saloni Dattani:
When you think of snoRNA, do you think of Snorlax or is that just me?

Jacob Trefethen:
That is just you.

Saloni Dattani:
Unfortunate.

Jacob Trefethen:
But now I will.

Saloni Dattani:
It's because it's snoring, right?

Jacob Trefethen:
Okay, I hear what you're saying. You're saying snorner is kind of...

Saloni Dattani:
It's not snoRNA, it's snor-na.

Jacob Trefethen:
Yes. Snorna. Okay.

Saloni Dattani:
I think the two things that I'm more cautious about are about the delivery, so how do you get siRNA to organs outside of the liver? How do you get it to the brain? How do you get it to the eyes? I don't know. How do you get it to your fingers? Well, maybe that one's easy.

But how you get it to places aside from the liver, is something that scientists still need to crack, and that hasn't happened yet. Or maybe it has, and maybe those drugs are actually in the pipeline right now. Who knows?

Then the other thing that I'm less confident about is how can we be sure that we're silencing the right gene? Like what if we actually silence a gene that's actually important? Or, less bad, something that's just irrelevant, and we've just wasted a lot of money trying to develop siRNA drugs for something that actually didn't affect the disease very much at all.

Jacob Trefethen:
Yeah, I think we're going to learn the hard way on some of these complex diseases that involve multiple genes. I think one positive note to end on is that you don't always need to use siRNA to silence a gene, you can use it to knock down a gene. So some of this will be tunable and different scientists will learn, as they go, in the lab and then once drugs are made in clinical trials too.

Saloni Dattani:
I feel like siRNA is kind of this ultimate test of, did we really understand this disease or not, you know?

Jacob Trefethen:
A lot of about faces are coming up. It's like, well, we knocked down the gene and they still look ugly. It's actually not a disease, that's not a disease.

Saloni Dattani:
And nothing happened. Yeah.

Jacob Trefethen:
Saloni, can we switch off disease?

Saloni Dattani:
Sometimes.

Jacob Trefethen:
Yes! That's much better than... What's that principle when you ask a question, the answer is no? In this case, the answer is sometimes. That's pretty cool. Okay, listeners, great to talk to you.

Saloni Dattani:
Silence.

Jacob Trefethen:
Time to knock down our listeners and maybe silence them.

Saloni Dattani:
Yeah, in a few seconds, you'll know what it's like when we go silent. That's right. Sorry, I shouldn't laugh at my own jokes.

Jacob Trefethen:
Call us a intermediary product in a liver cell because we're about to get silent.

Saloni Dattani:
All right, well, I hope you enjoyed this episode and ... [static noise] ... see you later!

Jacob Trefethen:
See you later!

Saloni Dattani:
Bye.

Jacob Trefethen:
Bye.