Sarah
Hello to a new episode of our STEMterview series. Today we have with us Professor Simon Conn from Flinders University in Adelaide. And he’s also the boss of our STEMcognito, my STEMcognito boss, basically, Marta. And it’s a real pleasure to have you with us today. Thanks for taking the time.

Simon
It’s lovely to be with you. And very nice of Marta, just to say that I’m the boss. I think in reality, it’s the other way around.

Sarah
I can’t wait to talk about that and hear more about this. Nice. Okay. But before we go deep into that topic, maybe we should start talking about your research. Can you summarize the research project for us, please?

Simon
Sure. So my area of research is in human disease, in particular cancer, and the fundamental initiation of it, which is, in many cases, driven by RNA molecules, small genetic anomalies that we call circular RNAs. These are molecules that are quite abundant, but they’re also cell specific and stage and developmental and region specific molecules. And in the case of cancer, they’re often expressed in specific cancers only. And the real advantage of circular RNAs is that they’re incredibly stable, meaning that we can use them as reliable biomarkers for disease, but they also play important roles in the development of the disease and the progression of cancer, which is a very important area of research and something very close to my heart.

Sarah
Okay, that is extremely interesting. So can you maybe just explain to our audience what exactly are circular RNAs.

Simon
Absolutely. So, I like to start as complicated as possible, and then try and refine things. So, an RNA is basically a messenger. So it’s the sort of conduit between our instruction manual, which is the DNA and most people know what DNA is, and the functional endpoints, which we call proteins. So in between that, to convert the DNA textbook into the functional protein, we have an RNA molecule.

Now, in a perfect world, we have 20 plus thousands coding sequences in our DNA, but we have more than 200,000 different RNA molecules that can be made. Circular RNAs are a sort of a byproduct of the processing of the RNA molecules. And they are, as the name suggests, circle, and meaning they don’t have any loose ends. And so they are very resistant to any sort of ability to break down. And so, we’ve been able to detect these circular RNAs in infant heel pricks, which would have been stored on paper for over 20 years. So you know, as opposed to DNA, which is normally really the most stable molecule, these circular RNAs are right up there.

Sarah
Okay, that’s interesting. So what kind of cell use the circular RNA for because we kind of know that there’s messenger RNA, there’s tRNA, they all have different functions for the cells. What is circular RNA actually doing?

Simon
Well, the more and more labs that research, the diverse the functions become, and also, I suppose, how they achieve these functions. And really, as with any functional molecule in the cell, it’s what it binds to. We sort of picture DNA or when we were at high school, or even earlier, if you’re in a very smart country, or smart school, it’s often drawn as sort of this free floating strand. And it couldn’t really be further from the truth. Everything is packed in adjacent to or binding to different molecules, proteins, fats, other storage components. And so really, the way a circular RNA works is through its interactions with other RNA molecules, other protein molecules and even DNA. And so these things were long thought to really bind to small RNAs called microRNAs and sort of altered their function. But the more and more we look at these, the broader capacity there is for them to play a role from. As I was saying, my first area of research into molecular biology was in plants. And so we identified a circular RNA that could regulate the formation of the flowers, in plants and sort of. When we misregulate them, change their expression level, it forms these Franken flowers with extra parts and missing petals and this kind of thing. In one sense, you can see a visual effect of that circular RNA and the deeper you dig, you can find out why it’s doing that. And that’s all the way through to how it can affect certain diseases. So cancer, hypertension, very important, and deadly diseases and small contributions that individual molecules can really be amplified into a disease. And that’s why we research what we do.

Sarah
Yeah. Okay. So how, how does it actually work? So, from what I understand, a circular RNA is mainly a regulator for cell functions, right?

Simon
Yes.

Sarah
So how can you regulate cancer or other human diseases?

Simon
So one common way it happens is a circular RNA has the ability to bind to certain proteins. So there are proteins known as tumor suppressor proteins. And so when they’re functional in the cell, it maintains the cell and a happy, non cancerous state. Now when they’re mutated, as we know, things like smoking, ultraviolet light, things that can damage the DNA and change the proteins, we know that can lead to cancer. But another way that they can be changed in the cell is by finding things that inhibit their function. And so circular RNAs are quite sticky in that sense. And they will bind in a specific manner to certain proteins, such as tumor suppressor proteins, inactivate them, and that can change the cell to now become sort of a precancerous cell. And over time, as it accumulates other mutations, it can actually lead from a healthy cell into a deadly cell.

Sarah
Okay, so you have this tumor suppressor protein that is there to keep the cell healthy. And the circular RNA is basically helping it. But when the tumor suppressor protein is mutated through different environmental factors like smoking, the RNA is not binding anymore. So it cannot really function properly. Is that how I understand?

Simon
Well, it’s normally the other way. Yeah, in the absence of mutations in those tumor suppressor genes, different RNA molecules can bind to them and inactivate their function. So it converts a healthy protein, which isn’t changed into an inactive form or something that can’t produce its function. So it’s sort of a double negative, which we don’t really like to talk about. It’s quite confusing, but if something is in its healthy state will suppress the change towards cancer, if you suppress the suppressor, which is what the circular RNA has the ability to do in many cases, then it can promote cancer formation of that cell.

Circular RNAs can also act by binding other small RNAs such as microRNAs. And the impact of that is quite diverse. And so, a microRNA can potentially regulate expression of hundreds to thousands of downstream genes. And surface circular RNA is abundant enough and combined on or activate enough of these little microRNAs, then potentially can regulate thousands of genes and really change how that cell behaves. All the cells in our body have the same DNA. It’s really what parts of that DNA are copied, and so how much of that RNA is there and so, if you can change 15% of that, by the change in expression of one circular RNA, small things can have big consequences.

Sarah
I see. And you said that plants have circular RNA but also humans and what about other species? What about unicellular organisms like bacteria, fungi? Do they have circular RNA? I never heard of it.

Simon
No, they are. And so that they are present in all, we say, all eukaryotic forms of life. From yeast, protists, there’s also encoded on viruses as well. And within the virus itself, it doesn’t make the circular RNA, but once it invades its host, the circular RNAs can be made from their genome. So yeah, they really are something that crosses all species.

Sarah
And how come they have only been discovered now? Because I understand until I met Marta, I’d never even heard of circular RNA. I had to study everything about mRNA, tRNA, and rRNA. And I think they’re single strand RNA as well. But circular, that’s to me completely new.

Simon
Well, yes. It sounds like you’ve been working hard on that. Hopefully, I haven’t made you sweat too much. But you’re not alone, really. Circular RNAs have been ignored largely for decades. There are single examples of how circular RNA has been presented back to the 1990s. But they were really dismissed as sort of artifacts of what we call RNA splicing. So, as the immature RNAs converted into a mature RNA, it undergoes some changes to it. And that’s what we call splicing. So the reason it’s been ignored is because initially, because the way these are made, are actually formed, they can read a linear RNA into a circular RNA. Even with high throughput sequencing, the reads that cover that back splice junction, which is unique to circular RNAs, were dismissed as junk. They couldn’t really be explained. They thought it was a splicing event between two molecules. And so they would dismiss them because it would askew the reads. Or ascribing those reads to a linear RNA. So I suppose it’s a combination of people weren’t really looking. And that was made worse by the fact that the reads were just initially being dismissed through the standard pipelines. Was really only in about 2012, when they started to actually look for these reeds. And they could actually detect thousands of these circular RNA molecules that since turned into hundreds of thousands of circular RNA molecules in a space of less than 10 years. So, we’ve gotten better at recognizing them. And we can also use particular enzymes, which act a little bit like Pac Man. They act on the ends of linear RNAs, integrate RNAs that aren’t circularized. And so if we can treat an RNA extraction with this enzyme, it destroys most of the linear and enriches these circular RNA molecules. So a combination of those factors can help us detect them. And yeah.

Sarah
I was actually just thinking, How are circular RNA being produced? Because they are still probably being produced as one single strand, but then somehow something makes them circular, right?

Simon
That’s right.

Sarah
The splicing event you were talking about right?

Simon
Exactly, right. So we like to simplify what RNA splicing is, We’re basically calling it cutting and pasting. So if you can imagine a long piece of string and you cut it up into a hundred pieces, and then you remove bits that don’t look right, or they’re frayed, or they’re the wrong color, and you stick all the like pieces back together, in a perfect world with your eyes open, you could make another linear strand. But if you can imagine, as I was saying before, these RNA molecules are not straight lines. They’re actually, really quite dynamic three dimensional structures, and when you have a molecule that might start here, loop back on itself, when the scissors come along to cut it up, and then the paste comes along to stick it back together, pieces that are closer will stick together more frequently. So circular RNA can be formed that way, because pieces which are perhaps if you stretched it out, would be very far apart. And if they’re very close together, they get stuck back at higher frequencies. And my lab looks at factors which promote that circularization and there are a number of those which include proteins that basically act as magnets to stick regions together, sequences in the DNA which are also very sticky, such as repetitive regions. And these enzymes called the spliceosome, they’re just like any other kinetic protein and that they’ll act on things which are in close proximity. So, whether correctly or not, we call them non canonical, or sort of non common RNAs, but in fact, they are made quite reproducibly. And so we actually do think that they’re meant to be made, we just need to find out what it is they’re doing in the cell. And why are they being made.

Sarah
Okay, that is super interesting. So my thought that is coming to mind now is because I was just reading and writing about the new mRNA vaccine against COVID-19. And I remember that the researchers had to find different ways to stabilize the mRNA so that it’s not being degraded in our body immediately when it comes. So they stuck this poly-A tail, and they substituted the uridine with a pseudouridine. But what about circular RNA? Could that be an approach that could be used for future RNA based vaccines? Because you said it would be or circular RNA is more stable? Is that also true in our body?

Simon
Yes, absolutely. So yeah, I’m glad you did draw that conclusion, because it absolutely does feel like RNAs, even more than linear RNAs can do two things, we can make them great targets or great models for vaccination. As naked RNA, they stimulate a really high immune response by themselves. And we’re still really learning about how that works. But by itself, in theory, this circular RNA molecule could act as an adjuvant to sort of boost an immune response. And then they can actually be used to encode for proteins. So some circular RNAs, while we call them noncoding, do actually have what we call an internal ribosomal entry site, which is encoded in them. And that allows these molecules which lack sort of the characteristics of an mRNA, which is translated, they lack a five prime cap, they lack this poly-A tail, but they have enough ability to bind to the ribosomes and make a protein. So yes, making a circular RNA, which encodes for in this case, let’s say a spike protein from SARS-Cov-2 might actually be a very efficient way to produce the protein for a longer amount of time and invoke a higher immune response initially. So really, it may be that holy grail of immune treatment that is waiting to be developed. So it’s not something we’re developing, but I think it’s something that we’ve talked to colleagues about, and I really do hope it can be used in the future. They just need to make enough of it, I think.

Sarah
Okay, nice. Interesting. I mean, there’s still enough infectious diseases that we are lacking vaccines for. I mean, just today is World AIDS Day. So I think it’s worth mentioning that. Good.

Simon
Absolutely. I mean, there’s a good reason why viruses are often made of RNA, are often circular, they actually do have a stability. The downside of it is if it’s an infectious disease carrying virus, then it’s terrible for humans, but as a virus, it’s a very efficient way to send its message around, and hopefully we can turn that around and use it against some of these viruses to help humanity in that way.

Sarah
Yeah, good point. And then you also mentioned that you’re actually a plant scientist or you started as a plant scientist. Now you’re, in fact, you’re in human diseases and specializing in cancer. Can you talk to me about this journey? I think it’s super interesting to come from plants and then go to humans and now specializing in cancer.

Simon
I’d love to answer that question. And I’ll do it by telling a story. My wife is a postdoc as well. So she works with me in my current laboratory. We were both actually plant scientists when we started in our PhDs and first postdoc positions. We were looking both at molecular biology. She was studying the microbiome of plants, and I was studying how individual cells express different transcripts. And we knew this was intimately able to be translated to any system we liked. So we wanted to learn as much as we could from plants. I think the real eureka moment for why we wanted to change came when she was getting a haircut. And there was a lady who was cutting her hair and explaining how she hated genetically modified organisms, how they were there to kill everybody and would hate to meet somebody who worked in that area. Both of us obviously were working in that area. She didn’t feel like she had the ability with her long hair in the hands of somebody with scissors around it to actually express the fact and defend the research that she was doing.

Now, flip the situation and explain to the person that you’re a cancer researcher, and you’re really there to try to help people. It’s interesting that similar kinds of investigations in different areas can invoke such a distinct response in the public. Now, I’m sure, she was very well informed about the area that she knew about. But often it’s what that message actually is. And we would say we evolved with our research, we went from plants to mice to humans, and now where we’re going to be forever is in cancer research. The journey seemed like a natural one, but it did take us all over the world to different institutions, and back to Australia where we started the journey. And I think maybe, as opposed to mouse testicles, which is one of the areas of research I did investigate, somebody you speak to will always know somebody who had cancer. Or, hopefully, it’s not the person you’re speaking to, because often you can underestimate people’s lives by what they want to share with you at the time. So I feel it’s the right progression for me, and many people like me to have made and really cut my teeth in plant science and learned a lot. Didn’t learn about the emotional impact that your research can have on people. And I think, you know, had I known that the transfer over to cancer research would have probably been a lot faster, because it is somewhere that I feel that we can make more of a difference.

Sarah
Okay, that’s really interesting, yeah, to rather work on the system as RNA and then just try to use that system or that approach to answer different questions.

Simon
If we can, we always say helping one person is enough. But we can hopefully use our research to help more people.

Sarah
That is really nice. Nice. Okay. And Marta actually also just told me that you won an award for a presentation last week for good communication.

Simon
I did. I hope it comes across today. I can communicate. I don’t know, I think all respect to you, Sarah, for making it such an engaging discussion. But yes, I was fortunate. I do feel there were some other very deserving presenters that should have received the award. But I’m very proud to have been given the mid career research award at the College of Medicine and Public Health at Flinders University. We had an emerging leader showcase, which Marta also spoke at I have to say, and some amazing feedback I got from colleagues about her efforts. So she should have won. But I’ll take it on behalf of the lab. I think that’s what’s been done. It’s been given to the lab. But look, we were talking about circular RNAs, myself and Marta, and the impact that has clearly reached the audience and I was very glad to be able to present that, and to use this opportunity to share our story and the research area more broadly.

Sarah
Maybe you can, because we are obviously a science communication platform, maybe you can just tell me a bit more of your motivation behind good science communication. Why do you think it’s important? What is your motivation behind all that effort?

Simon
This is a really good question, and one that’s not often asked. What, why do we need to communicate? It’s almost you assume it’s such an obvious answer, but I don’t think it really is.

Sarah
Unfortunately, especially for many scientists.

Simon
Yeah, we are. Most of us grew up as nerds at school, and we weren’t really very good at talking back then. So why should we be good at talking now? But it is part of the job, and what we want to do is not only to be heard, right, it’s to actually be able to spread the correct message and to not be misinterpreted. I think if nothing else, the COVID 19 pandemic and all the stories and reporting around it leaves so much opportunity for misinterpretation by the same person, not by different parties. The same person can often get conflicting messages. So I think communication is important not only to share the message, but to reiterate that message. And I like the feeling, especially when I get to present to people who haven’t heard the story before, that I’ve taught them something that they will then take away and talk to other people about, it may only be one degree of separation from there, but it may be two, maybe three, it may be seven. Kevin Bacon might hear it. Whatever happens, I think the message often does get back to you to say, ”my son, or my third cousin heard you at school and really loved it, and now they want to do science”. And I think it has that sort of ability to reach beyond just the message, and to see. As Marta does very well, it’s not a cookie cutter type of person who is a scientist. You can receive messages from a vast array of people and appreciate that you might be that person in 5 years or 10 years who will make the difference. So communication in science, really, it can’t be under appreciated. And so I really respect what you and Marta, and anybody in that area is doing to actively encourage us non driven, non naturally good communicators to get our message out there.

Sarah
So that’s also not true. I mean, thank you very much for the compliment, I appreciate it. But I also think there’s a lot of really good communicators in the scientific world. It’s just sometimes they don’t feel as if people are actually listening to them. I mean, communication can be anything from presenting, like giving really good presentations, but also writing, obviously, I mean. I also know very good, amazing artists or scientists, communication is everything basically. It’s not only talking.

Simon
That’s right. And, we do have that ability. Sometimes we often feel, even in our field, we see good people presenting or communicating to your class or to your entire field and marvel at what they can do. But it’s really achievable by everybody. You just need to be told that you do have a voice, and that can be heard.

Sarah
And get more support from the academic field, I guess. Unfortunately, that is just…yeah. Some universities or institutions don’t really appreciate the effort or don’t support it that much, unfortunately.

Simon
I think so, until it’s too late.

Sarah
Until it’s too late

Simon
Yeah.I think a lot of, sort of work that we do can’t be backdated. You need to get your message out. And you need to have it supported now so that it can make that impact in future once it’s there. It can be listened to and learned from, fit for years to come. So we need to be able to plant that seed and have organizations ready and willing and driving that communication. So yeah, that’s absolutely true. Some are much better than others. That’s for sure.

Sarah
That was a really good concluding point, I guess. Thank you very much, Simon for your time and for this really amazing conversation. So at the end of our STEMterviews, we always have a bit of a random question game, which means I’m just going to ask you some random questions that more or less have to do with science or communication and I would just like to listen to what you think about those things.

Simon
Fantastic. Now I’m nervous. Is that normal? Does everybody feel at this point?

Sarah
I don’t know, ask the other people that I’ve interviewed. Yes, the first one should be easy, I think. What was your favorite subject at school?

Simon
Oh, I’ll say PE. Do you know what PE is? Physical education. Yes. So the time when I beat my state’s badminton champion, PE coach in. Badminton was one of my shining lights. I mean, science was great. Don’t get me wrong, but when I think back to that moment, yeah, it always gives me a smile.

Sarah
Nice. That’s a cool story. Okay, and one sentence, what are you truly passionate about?

Simon
I’m passionate about trying to help people who feel helpless. I guess a lot of that comes from losing people that I love, from a range of things, diseases, cancer, suicide, things like this. And I think I would consider my life cheap if I could help one person with some research that I can convert my intellect and the intellect of people I work with into an ability to save or extend somebody’s life. I can’t think of a better answer to that question.

Sarah
That is an amazing answer. That’s a great motivation for everything you do. Yes. Awesome. What do you do in your free time?

Simon
I injure myself is what I do.

Sarah
Playing Badminton?

Simon
Sorry?

Sarah
Playing Badminton?

Simon
No, not anymore. I wish, no. I have a small farm. And so I have a lot of animals around. And sometimes I can be more unpredictable than my children. And chasing them back into paddocks has caused me a number of injuries. So children and animals is what I do when I have free time and love doing it. Looking after.

Sarah
Nice, that’s cool. Okay, the next question, what would you do if you were donated $10 million to your project?

Simon
To my sorry?

Sarah
To your project. The research project.

Simon
Oh fantastic. So we would develop….so a lot of the research in my lab looks at brain cancer of a devastating disease that has a very short time between diagnosis and death. And however, if it’s picked up early enough, in many cases, it’s curable. So I would invest that money into a highly streamlined human biobank system with living organoids to allow us to capture enough material from patients to detect the most sensitive and specific biomarkers for this disease so that we could utilize a screening based method to detect this disease as early as possible. That would be good use of that money.

Sarah
That would be amazing. Again, it’s about helping people. That’s amazing. Yes.

Simon
Whatever it takes, I think. Right?

Sarah
Yeah, amazing. Okay. And the last question is, if you wrote a book, what will be the topic of the book?

Simon
Oh, wow. That’s really stumped me, actually. Wow, that’s a good question. I would call it “The Perfect Answer to Any Question Your Child Could Ask”. It might not have the perfect answer in it, but I think it would probably be the best selling book just because of the title. Something to get you out of any situation. Actually, Marta never seems flustered. She should probably write the book. And because she seems to always have an answer for every question that I have. So I’m basically a big child anyway.
Sarah
Aren’t we all a big child.

Simon
So yeah, it might be a very thin book. MIght only have a single sentence, might just be mum or dad loves you. That could be the answer to any question. But yeah, something again helping people. That’s what it’s about.

Sarah
Amazing. I love it. Cool. Awesome, Simon. Thank you so much again, for your time. It has been a real pleasure talking to you.

Simon
Please, Sarah, no need to thank me. It was a pleasure to talk to you. Thank you for your time. And yeah, I hope there’s enough there for you to get some interest. And, yeah, very happy to talk to anybody who’s got some more questions about the work that Marta and myself do in the lab here at Flinders in Adelaide, Australia.

Sarah
Awesome. I guess maybe we’ll get some more emails now, let’s see.

Simon
Absolutely

Sarah
Okay, thank you so much. Bye bye.

Simon
Thank you. Bye.

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