UNSW Centre for Ideas: UNSW Centre for Ideas

The conversation you're about to hear is between Deputy Vice Chancellor Merlin Crossley and scientific pioneer Jennifer Doudna. Jennifer's revolutionary CRISPR discovery earned her the 2020 Nobel Prize in Chemistry and forever transformed genetic research.

Enjoy the conversation. And if you haven't already, be sure to follow the UNSW Centre for Ideas podcast wherever you listen.

Merlin Crossley: Now, Jennifer, I've told you about you and how proud I am of the work we do here. How proud I am of the work that Martin Green did on and he's doing on solar panels. We think, 90% of the panels, solar panels in the world have used this technology. We're very proud of quantum computing. Michelle Simmons was Australian of the Year.

It's great to have a scientist as Australia of the Year a couple of years ago, and I'm also very proud of the fact that as well as having great academics, we have some of the smartest professional staff in HR, IT governance, in media and events. People like Ione Davis and Alice Marklew who organised this event. And I want to call out my friends in the finance division that I understand like to come to these lectures.

So, thanks everyone. All the staff at you and all the students, academics and professional staff who are with us today because, we aim to be a university where both the academic community and the professional staff come together and with the students to celebrate great, science. So let me introduce Jennifer.

Jennifer Doudna is the Li Ka Shing Chancellor's Chair and a Professor in the Departments of Chemistry and of Molecular and Cell Biology at the University of California, Berkeley.

Her groundbreaking development of CRISPR/Cas9 as a genome engineering technology, with collaborator Emmanuelle Charpentier, earned them the 2020 Nobel Prize in Chemistry and forever changed the course of human and agricultural genomics research. This powerful technology enabled scientists to change DNA, the code of life, with a precision previously only dreamed of just a few years ago. Labs worldwide, including mine, have redirected the course of their research programs to incorporate this new tool, creating a CRISPR revolution with huge implications across biology and medicine.

In addition to her scientific achievements, Jennifer is a leader in public discussion of the ethical implications of genome editing for human biology and societies, and advocates for thoughtful approaches to the development of policies around the safe use of CRISPR technology. She has written an excellent book, which I have here, A Crack in Creation by Jennifer Doudna and Samuel Sternberg, The New Power to Control Evolution.

So I recommend that book. Now let me begin. Jennifer, thank you for coming. It's great to have you here. Now, I was looking at your book and your name, and I looked at the last three letters of your name. I don't if anyone else noticed this, but that the last three letters are DNA. But I read the book, and you actually didn't begin by working on DNA.

You studied DNA’s cousin RNA. So clearly that was a bit of rebellion against nominative determinism. So RNA is like, if DNA is the written word, RNA is like the spoken word, it's a messenger. It doesn't last. But I think the first question I have to ask you, CRISPR/Cas9, that uses RNA to change DNA. Can you, in your own words, tell us what CRISPR/Cas9 is and why it's such a powerful thing?

Jennifer Doudna: Well, I'll just start by saying thank you so much for inviting me here. It's awesome to be here today. Hi, everybody. It's been a really interesting journey for me. I started my career in science in, you know, I don't know, the 1980s - seems like a long time ago now. And I was interested in RNA, actually, and, I why was I interested in this? Well, as you said, it's, it's a molecule is kind of a chemical cousin of DNA.

That is a transient molecule. It's only around for a short time in cells. And yet we know now that it's plays an incredible role in biology and probably was responsible for the origin of life on the planet. And that's what I researched when I was in graduate school.

And, it actually is the path that took me to CRISPR, because it is the molecule that allows bacteria to detect and, basically recognise invading viruses when they first enter the cell and, then recruit a protein which is called CRISPR/Cas9, to cut that viral DNA. And that was the process that we began investigating back in, you know, the mid 2000s after a Australian scientist, Joe Banfield, who's a colleague of mine at UC Berkeley, told me about her discovery of these signature RNAs in bacteria and wondered what they were doing.

So fast forwarding. That was kind of the original research. But what was exciting was that once we started studying this bacterial immune system called CRISPR, we realised that it could be harnessed as a technology to introduce targeted changes in DNA and other cell types. And that's really how the technology is being used today. It's actually used to make precision changes in the DNA, of essentially any kind of cell, in a way that is much easier than earlier technologies and has allowed scientists to do all kinds of interesting things that I'm sure we'll get into in this discussion.

Merlin Crossley: Yeah. So that's right. It is. It's transformed science completely. Now, can we go back in time to when you were growing up in… so you grew up in America, but you grew up in a very special part of America; Hawaii. Can you tell us about some of your childhood and your decision to study science and how you succeeded in getting your own lab?

Jennifer Doudna: The 50th state - Hawaii. So my family moved there in the early 70s, and I was a young girl. I was seven years old at the time, and I was captivated by that island environment. And as you see here in Australia, you know, there's just extraordinary diversity of life on our planet. And certainly in isolated environments where life has a chance to evolve as separate from other, you know, relative related species.

So I didn't know anything about any of that, of course, at the time. But I noticed that there were all kinds of very interesting plants and animals that had clearly adapted to the unique island environment. And I think that was the first, my first sort of indication that I might like to, in fact, understand, you know, the scientific basis for that.

And then I had a wonderful high school chemistry teacher who taught us kids that science is not about memorising facts in a textbook. It's actually about puzzles. It's about answering questions and figuring out how to answer those questions. And I found that so, so interesting. And I think that was the first time I started to think maybe I could, you know, I wonder if I could be a scientist.

Well, it turns out nobody in my family was a scientist. I like to say my family was a bunch of preachers and teachers. Yeah, but no scientists and few lawyers thrown in there. But, but yeah. So, it felt a little bit, you know, a little bit rebellious to kind of be going in that direction. And, and I just, I was very lucky that along the way I had a number of teachers and other mentors who encouraged my interest and helped me kind of make my path. And it was not a straight path at all. But, you know, I just I always kind of pursued what I found to be interesting. And I tried to work with people that were smarter than me.

Merlin Crossley: I want to ask you about what lab life is like. So a lot of people think of scientists as bent over a microscope, which is a very individual thing. You’re concentrating on one topic. And there is part of that. But it's not just long hours of, you know, plating out bacteria, looking at microscopes, growing cells. There's a lot more to it isn’t there? Can you try to describe what's it like being a graduate student postdoc in labs is like?

Jennifer Doudna: Well, when I first started working in the lab, I think it was back... It was when I was in college. And, you know, I felt so lucky that my professor, when I was a, I was a third year college student, allowed me to work in her love for the summer. And it was the you know, this was my first kind of discovery of what it was like to do real research, not cookbook…You know, you're following instructions in a lab manual or something, but it was really, you know, we had to invent the experiments because they had literally never been done. And we're answering questions that nobody knew the answer to.

And it was that that summer where I think I really caught the bug, you know, this joy of getting up in the morning and being excited to get to the lab because I wanted to see if you know what the results were of my previous day experiments.

And even if things didn't work, it was always like, 'Okay, it didn't work, but why didn't it work?' And I, 'Okay, next time I'm going to do it differently or better.' And I love that process. And that's still how it is in the lab, you know, all these years later, it's still like that.

I don't actually myself, sadly, still work with my own hands in the laboratory, but I when I'm back at Berkeley with my students, I'm usually every day spending time with them and with their experiments and trying to think through how they're doing experiments and what the results mean. And we get that that shared joy together of, you know, that process of discovery or so you know, there's frustrations trying to figure things out.

But it's a, you know, it's a struggle that's really worth it, because at the end of the day, you feel like you've uncovered a new truth about nature that maybe nobody on the planet has ever understood. And it's a very tiny little thing. It's feels very exciting to have those kinds of discoveries happening all the time.

Merlin Crossley: It's true. I saw on the screen, in the video Curiosity and Discovery, and it is this addiction to curiosity and discovery and it is nice because each day /

Jennifer Doudna: Yeah.

Merlin Crossley: / the results are quite small but they're. Yes, they're big to me as well because you want to know what happens next.

Jennifer Doudna: Right.

Merlin Crossley: So some people see science is a very competitive endeavour because there are a lot of people in it. There are limited resources, there's limited time, and there's and we do race to get things published. And we do. We all talk to each other about the scarcity of research grants, because it's something we have in common and we know how it works, but we also collaborate and form very deep friendships.

And in reading your book, you know, you eat your book, emphasize this sort of feeling of, collaborate with Jill Banfield, with Emmanuelle Charpentier, and with your coauthor, Samuel Sternberg. So can you speak to us about the importance not of competition in science that we know about, but of friendship and collaboration?

Jennifer Doudna: It's a great question. You know, when I was starting out in science, I didn't appreciate this about science because I think, you know, for me at least, when I was learning about, you know, what do scientists do? They don't talk about that in textbooks, right? They talk about the hunched over the microscope. And, you know, people are often you get an image of scientists kind of working alone.

But the reality is, at least in, I would say in our fields, right, that it's very much a collaborative process and we're always working with other people, whether it's in one laboratory or collaborations between different labs. And that's something that I've found to be wonderful in science. I love this and, it's been really an integral part of everything that I've done in science is working with other people, sharing ideas, you know, making discoveries together, you know, struggling through things together and trying to figure them out.

And as far as competition, you know, I've always I, for me, it's always been about competing with myself. I always tell myself, you know, I'm competing with myself. In other words, I want to be the best that I can be and the best scientists that I can be. And I try to learn from other people. And, you know, if somebody else is doing something really well, you try to learn from that.

It's like, well, that's something to be admired. And let's try to take a leaf out of their book and, you know, figure out how to be better myself.

Merlin Crossley: Terrific. So now let's go back to CRISPR itself. So one of the papers that I saw was, making cows that don't have horns. And this is good, actually, it's good for the cows. They don't hurt each other. It's good for the farmers. It's, you know, it's an extraordinary thing that we can do that it's also I think it's accelerated the pace of medical research hugely.

And gene therapy, which is something which was talked about when I was a student. It's actually feasible now. I mean, people spend a lot of money on trials and things. And it was very in terms of its efficacy. It was very hidden messages. The cassettes always got turned off. But now you make a change and it is like genetic surgery.

So I think we're really getting things there. But can I ask you to reflect on what some of the bigger - the big advances have been in the CRISPR world of the applications? And then we'll get on more to what else might happen. But I'll ask you some of those.

Jennifer Doudna: Yeah. Well, the first, application that of course comes to mind is, is actually closely related to your own background, to your own research. And that is the approval in December of the of just this last year of, of a drug called Casgevy, that is a CRISPR therapy for people that have sickle cell disease. And this was really, I would say, a watershed moment in the field.

Many of us in the field felt a real sense of joy. And not only that, but of opportunity with that approval, because we can see what's coming, say, over the next 5 to 10 years. We're going to see, I think, a broad expansion of CRISPR and gene editing as a real therapy for people that have, not only rare genetic diseases, but I think in the future, perhaps even, you know, more common diseases that could potentially be prevented by making targeted, you know, tweaks to our genomes.

Maybe we'll get into some of that. But, I think that's certainly an area where there's a lot of opportunity right now. But, but let's talk about the hornless cattle. I mean, I think that's a that's an interesting example of, again, an credibly exciting branch of research right now that is, exploring how genome editing can make changes in animals and in crops and other types of plants that are going to be, I think, really important as we deal with the challenges of climate change and the growth of our population on the planet. It's now possible to do the kind of thing that you mentioned quickly, much, much faster than, you know, if you had to breed hornless cattle, you know. Yeah, that would be tough, right? And or if you had to, you know, saw the horns off, as they've done, which is, you know, very, very hard on animals and it's really not good.

So I think there is there's a lot of opportunity there. We have an institute at the University of California, Berkeley called the Innovative Genomics Institute, and one of the major focuses of that institute is actually looking for ways that CRISPR Cas9 will have an impact on our planet in a positive way by mitigating the effects of climate change.

We're actually working in cattle not to make hornless cattle, but actually to make cattle that don't release methane, which is one of the, you know, very powerful greenhouse gases. So that's an opportunity that I think is now, you know, in our hands with this kind of tool.

Merlin Crossley: Yeah. Another positive one I read an article about I don't know where it's up to, but it's about, chickens, hens. So I didn't know... So all baby chickens, the females they keep obviously for laying eggs, but also the ones in the supermarket that you eat are also female. So they're all female, and all the males just get sex, the baby chick and then put into a grinder straight away.

And there's some CRISPR people who, what they're doing is introducing, fluorescent mark so that you can tell before the egg hatches whether it's male or female, and it will only be on the chromosome that's for the males. So the females won't be genetically modified. The males will. And they can all go into an omelette before you have to have a chicken being born, which is, you know, which will be much kinder

So I think it I think these sort of things are impressive now going to genetic diseases again. So sickle cell disease is a disease that affects about 10 million people, lifelong debilitating disease. And it was about November in the UK and December in the US the therapy was approved. The trick with that though is you have to take the bone marrow out, kill the resident bone marrow, get it back in.

So it's very tricky. But I think some things you'll just be able to inject it and do it in vivo in the liver and things. Do you know any examples of that?

Jennifer Doudna: Yeah. That's very exciting. I think that's you put your finger on something that we think about every day at our institute and I yeah, I'm it's very much on my radar, which is how do we get to a place where we can deliver CRISPR/Cas9 without having to use a marrow transplant? In other words, doing it directly in the body.

And that's going to require some new technology. But many people are working on this. Many academic groups and companies are aware of the opportunities. And one of the things that's happened recently is that a company that has been working on a different disease that involves the liver has shown that they can actually use the same technology that was used for the Covid vaccine, which is an mRNA - if you had the Covid vaccine, you would have had this this type of, vehicle delivered as a vaccine. But the idea here is to use it as a way to take the CRISPR gene editor molecules into the liver cells, where it can make a targeted change to a gene there that can, you know, prevent liver disease.

And they are already in a phase three clinical trial with that work. So that means that they're already, they've shown it's safe and effective and they're now just adjusting the dose. So I expect that'll be maybe the next type of approval that we'll see coming along for CRISPR therapy. And but the reason it's relevant to the discussion of sickle cell disease is that it sort of shows what's, I think coming in the future, as you said, which is that it won't be necessary to take cells out and do the editing in the laboratory and replant them, replace them into the body. You can do that all in probably a one and done type of treatment directly into the body them.

Merlin Crossley: And that will be terrific if people can do that. So I want to ask you about what is a controversial area when you talk about in your book, which isn't about, just treating the cells of the body, let the blood cells of the liver cells, but treating the whole organism so that it's what we call germline gene therapy, so that the progeny also carry the disease.

And there's a recent paper, there's a ApoE4 variant that people have discovered. If you have, it's I think 2% of the population will have two copies of this variant. And the population genetics was very confusing. But now that we know we have many more genotypes, you can tell this really does give you a very high risk of Alzheimer's.

So there will be people who get their genome sequence and say, ‘Yikes, I've got Alzheimer's. I'm going to get Alzheimer's. My partner is going to get this Alzheimer's. I don't really want my kids to get Alzheimer's. Is there anything I can do?’ Now some people would say that's playing God. Other people would say, we should do everything to help people.

If we can change it, we can't. We might. It's a very delicate topic. It's illegal in Australia. If I were to do that, it's ten years in prison. It's. It's illegal and seriously illegal. I know I wouldn't know where to begin with germline gene therapy, but. So there's none of it happening in Australia. But in some countries people are exploring this and people are making the case that for some conditions, I mean, even with most things, you can select an embryo, pre-implantation screening. But if there were two people who had sickle cell who were partnered up and wanted to have kids, and you might think that's rare, but people with sickle cell spend a lot of time in waiting rooms in clinics, and they often meet other people with sickle cells in their own communities. So it's not actually as well as it sounds.

And if you had two people with sickle cell and they wanted to have a kid who didn't have sickle cell, you know, germline is the only way. Now it's illegal at the moment. It's really illegal because I think the technology hasn't reached a stage where people are comfortable with it. But in the future, if it were to reach a stage that we knew from all the work on plants and animals, it was safe. Do you think that a case could be made that if two people came to you with sickle cell and said, look, I'd like to have a child, can you do CRISPR on the eggs? Do you think that's something that people would contemplate?

Jennifer Doudna: I mean, I think, I think you're absolutely right that the first criterion has to be, you know, is a technology safe. And is it is it effective? Right. And then we're not there yet, that's for sure. With germline editing, which is what you're talking about making heritable changes in eggs or sperm or embryos. but we can already, I think, see on the horizon a day when we will be at that point.

Right? Because as you said, in some countries, people are working on this. And I think it's very likely that at some point in maybe the not too distant future, it will be shown that, you know, you can do that type of editing safely. And then the question will be, you know, should we do it and when and where and you know, who should decide who should pay for it?

And I think that the scenario you described is an example of a case where you might conclude, you know, many people might say, ‘Yeah, that makes a there's a good case for that’. But I think, I do think those, those cases are probably going to be relatively rare. And so we need to be thinking now about, you know, how to how to, you know, how do we think about this, how do we feel about that as a society?

And I don't I also don't think that it can be there's there can be sort of a global, regulation of it. I think it'll end up being, you know, probably country by country, because there are different cultural norms, different, you know, different, expectations and different countries. And, the thing that I think about a lot to be honest, is the whole equity, angle, you know, making sure that I wouldn't like to see the technology used in a way that increases inequities, you know, that that we already see in the world. So, I do think we have to be very thoughtful about how we use technologies of any kind, and certainly CRISPR.

Merlin Crossley: Yeah. And I think if it does happen, I think it will be used for correcting defects first. I mean, I always think of the genome is like, a city, you can use this technology to fix up a blocked road or a bridge that's fallen down or a pothole, but you can't, you know - designed cities are always the worst ones and designed humans…

I'm not actually, I don't I'm not concerned that much about genetic enhancement because I think it's to people wouldn't know where to begin. But I don't know. What do you think? Are you worried about genetic enhancements, super people, that sort of thing?

Jennifer Doudna: Well, I don't know if I'm worried about super people. There's a few tweaks I'd like myself. I'll just say that. But I guess I do think that already, you know, we know of certain genes that can be altered that have, you know, change things about, say, our physical appearance. Like, for example, eye colour is already something that, you know, can be, detected and perhaps selected for in in vitro fertilisation clinics and with CRISPR, in principle, you could, you know, you could make the tweak yourself.

And there are other things of that nature. So, you know, that's a question, right? Should CRISPR be used in that way? I personally think it shouldn't. Right? I think it's a trivial use that would not be appropriate, given the, you know, potential risk of the technology, for one thing. But I think you're right, about super humans in the sense that I think, you know, in most cases, the traits that we see in ourselves are complex.

You know, they involve many genes, and they probably involve many things that don't have to do directly with the gene sequence, but have to do with, you know, you again, we were talking about this before the session today that, you know, that involve, chemical changes to DNA that, don't affect the actual DNA sequence, but affect the way that the sequence is read.

And so I think there, you know, it's going to be a long time before we have enough knowledge about our own genome that we could use a technology like CRISPR to, you know, to make, changes in our, you know, our physical or emotional or intellectual properties.

Merlin Crossley: Yeah. It is that thing about what makes us human is interactions of many genes. And you don't know. And that's why I make the analogy to cities. Sydney is a beautiful city because it's grown up organically. Canberra was a planned city, but it's getting better. It's getting a lot better. So now I, I wanted to change track - this an interesting-  because we can now modify DNA.

And when I was actually a postdoc, I went to see Jurassic Park, which was about bringing back dinosaurs. And I walked out and thought - I was different from other people - horrified. But I just thought if only it were true. But it's not true and it's not true. The DNA from dinosaurs is all gone, and so you can't do that.

But the wooly mammoths, there is a company that's interested in the wooly mammoths. There's. They're interested in the dodo. And in Australia, they're interested in the thylacine. Other. But when I was very young, my parents gave me a book about, the Tasmanian tiger, the thylacine, and it had a map of all the sightings in Tasmania on one page.

And there were many. And I was thinking, oh, it's it could be true. The thylacine still exists. And then on the next page, all over Tasmania, there's black dots. And then it had on the next page the, sightings of the thylacine in the rest of Australia. It was covered with black dots as well. And Thylacines hadn't lived in mainland Australia for 20,000 years, but people saw them.

And the point was that people wanted to believe it. But it is extinct. But there are people who want to bring that back. And the idea is if you have, is embryonic stem cells from these organisms, you can start with, you know, getting elephant DNA. And then you can, little by little, change it into a wooly mammoth.

Now I'm sort of skeptical about this because to me, it's there's a lot of steps. It's like stacking up ladders to reach the moon. And it's really hard to fit an elephant into a petri dish. And I think these groups have got very good, very, keen PR departments. But I don't want you to say anything.. this is probably being recorded… Anything libelous against the actual companies. But do you think we'll see a wooly mammoth, a dodo and a thylacine in ten years?

Jennifer Doudna: No. I don't, but I do think the idea of, of, you know, resurrecting extinct species is captivating, isn't it? It's kind of fascinating. I think it's something we're all we're all sort of intrigued by, I think in different ways. no, I don't think any of those are likely. But I do think that, there might be some interesting opportunities.

I have a colleague, Beth Shapiro, who up until recently has been a professor at the University of California, Santa Cruz. And, you know, she works on she studies, you know, the evolution of large animals, like she's looked at, polar bears, for example. And you know, how they’ve evolved - and she's also looked at lots of species of birds.

And of course, you know, there have been many extinctions along the way when you start studying the evolution of these animals. And of course, she's gotten very interested in the genetics of this. And so she and I have had some very interesting conversations about, you know, what CRISPR might be useful for in terms of perhaps bringing back, animals like the passenger pigeon or, you know, animals that haven't been extinct for that long and that maybe don't differ that much genetically from animals that are, that we find in, you know, our world today.

I think - I think this is true. I think I heard that Beth Shapiro has actually gone to that company called Colossal, that is, trying to resurrect wooly mammoths. So I'm actually very eager to talk to her and find out what her view of this is. I'd love to know how she would answer your question.

Merlin Crossley: Yeah, that's it is good. I think some will be easier than others. I agree the polar bear and the brown bear are quite similar. I think.

Jennifer Doudna: Indeed.

Merlin Crossley: Quite similar. Yeah, I think with the others the lack of a good reference genome is going to be a problem for them because they won't. They won't because you've got to get everything right. You can't get you jnow, you can't get it 98% right. Yeah.

Jennifer Doudna: Yeah yeah.

Merlin Crossley: And I think that's very hot. So there's a another interesting idea. So shortly after you published, the CRISPR work, there was a paper in PNAS about things called gene drives. So gene drives, and, you know, none of this could be done before you, one could properly write DNA, but you can get a gene so that it jumps basically in normal Mendelian genetics, if it's on one chromosome, it'll go into some of the babies, not others.

But you can get a gene drive. So it goes to every single one, and you can drive a particular characteristic across every, all of the offspring. Now, if you drive something like male, this being a male, that will send the species to extinction and gene drives, touted as a mechanism, one might want to get rid of the mosquito that carries malaria.

Actually, people have said we might want to get rid of, the rat Rattus Rattus and Rattus Norwegian, because they're essentially - it's not clear they live in the wild. They're essentially an organism which is parasitic on humans and called.

Jennifer Doudna: The cane toad.

Merlin Crossley: Right. It’s the cane toad that we might want to get rid of the cane toad in Australia. We might want to get rid of the rabbit. I think there are groups working on getting rid of the rabbit with gene drives, and there's certain breeds of dog I don't like very much, but mostly they're unpopular anyway, and they are sort of becoming out of fashion.

But there is a lot of controversy about gene drives, because it is an awesome power to drive a species like the rat to extinction. And to me, actually, I think that in a way... So the New Zealanders, we gave them the gift of brushtail possums and they want to drive the brushtail possum to extinction this way, but we're a bit worried that it could cross over to us, where we love… I think everyone here loves brushtail possums. So what do you think about gene drives?

Jennifer Doudna: Well, let's start with what is a gene drive? So, you know, people might be wondering what this is, and, and it's, it's an interesting phenomenon because and it's possible when you have a technology like CRISPR, which makes, you know, a targeted change to DNA. And so what people have shown in the laboratory is possible with CRISPR, is that you can put it onto a, some kind of a vehicle that is able to get into cells and get into, you know, germ cells in a type of animal, like, could be a mosquito or, you know, it could be a rat.

And, when it gets in there, it's able to make a cut in the genome that inserts more of the CRISPR machinery into the genome so then it makes more. And it essentially is able to quickly change all the cells in that organism to have some particular genetic trait, you know, using CRISPR. So it's essentially a way of bypassing normal Mendelian genetics of inheritance by allowing a trait to be transferred, as we say, horizontally among, you know, animals that are, you know, all sort of in a, in a particular generation, rather than waiting for them to reproduce and pass along a trait as we normally are, you know, observe.

And so, this is possible in the lab, and people have done it with animals like, you know, fruit flies and mosquitoes. I don't think they've done it with other animals, that I'm aware of. You know, I think it'd be a lot harder to do it in a in a rat, but it's more of a theoretical thing, you know?

What would happen if we did this and, and as you said, you know, I think the interest in this initially stemmed from the idea that, you know, you could potentially use that type of technology to eliminate a species, like eliminate the Anopheles mosquito that can spread malaria. The challenge there, I think,  or a challenge is certainly the potential for that to get out of control or to go in ways that are unexpected.

And I think probably everyone here, you know, is familiar with the idea that, you know, as humans, we try to do things sometimes that, you know, go in a direction that we don't intend, or that are  negative. And we certainly saw this in Hawaii many times. Right? Where a species would be brought in, or would people would try to eliminate it.

And by doing so, they created more problems that they weren't, you know, maybe predicting that would happen. And I think that's the danger with gene drives. So I think we really have to be very careful with that type of use of CRISPR. Fortunately, it's hard enough to do it that it's not something that can happen sort of accidentally or trivially.

Nonetheless, the people that I know that are working on gene drives in the US, work under very restricted conditions where they, you know… if they have a gene drive with with fruit flies, those flies have to be in a, you know, very secure enclosure where they can't get out.

Merlin Crossley: Yeah, I think that's the right way to go. I think it's interesting, I, I remember talking to ecologists about the Anopheles mosquito and I said, you know, could it, you know, perhaps it fertilise something important. And so, you know, it's pollinates something. But there are many different the biologists working on this, about 100 different mosquitoes and things.

So hopefully, I mean, I think we've got rid of smallpox. You know, I think probably getting rid of the Anopheles mosquito is a good idea. Some people have pet rats, but you could probably make them immune to the gene drive. You probably have some pet ones. So you know, so… but I think that there is a case for them.

Now we've got about 35 minutes left. I'm going to, I think, call upon the people, who are going to, ask questions. We've got about 5 or 6 of them and then I've got some questions online. So we'll go to the floor. The lights are coming up now. So people sense that we are moving this stage in.

The first question is from our very own Palli Thordarson, the director of the RNA Institute here at UNSW over to you.

Palli Thordarson: Thank you Merlin. And thanks Jennifer. And actually, you kind of touched on the, sort of twofold question here. Two points I had. And I guess the first one, because you touched on this, is to drive this whole field further. And what is going to be more important to modify and improve the gene editing methods themselves or improve the delivery methods, because there's sort of two slightly different frontiers of your technology.

Jennifer Doudna: Yeah. Well, I think first of all, thank you for the question. I think that we're seeing both happening right now. So the, you know, for anyone that's, you know, reading the literature in this area or reading, you know, X, formerly Twitter, you know, that there are articles coming out daily, often at the level of, you know, tens, if not more of labs around the world that are making tweaks, changes, improvements, etc. to the CRISPR technology.

So we now have a large toolbox that all is all kind of based on CRISPR molecules that allow scientists to do all kinds of manipulations to genomes; making changes to DNA directly, making changes to the output of the DNA. And, also doing things like imaging DNA. So there's lots of, you know, ways that the technology is being advanced and that's going to continue, I think, for quite a while.

And, you know, there are new enzymes being discovered. And, you know, it's just like a whole industry now of people doing that type of work, including... we do some of that do. but the other half of your question is incredibly important, which is, you know, if we want to use these editors in organisms, which, you know, we do, then how do we get them into the cells where they can have an impact?

And this is a challenge, whether we're talking about making changes in a person for a therapeutic benefit or whether we're talking about making a change in a cow, like to make horn less cattle, which was an example that we talked about. Or whether you're talking about making drought resistant rice, you know, another application of CRISPR, these are all interesting applications that could be very useful.

But, we need to figure out how to get the editors into the right cell type. And so that's really I think about this every day now, because I think this is really, in a way, the, the, the gating factor now with genome editing is not so much the editors, because we've got a lot of good ones, but we need to be able to figure out how to deliver them.

Palli Thordarson: Thank you. That's great to hear. It's one of our main challenges and our, target areas. And my commercialisation chief who couldn't be here, he’s sick. He was interested sort of a follow up on that: RNA technology in general, and CRISPR is really RNA technology. But we've got I'm mRNA vaccines, we've got oligons and whatnot. Do you think these technologies, are (indecipherable) so we'll end up competing? Or what do you see this there are two parallel technologies with gene editing and all the RNA futures developing?

Jennifer Doudna: Yeah, it's an interesting point because before CRISPR came along there was a wonderful, you know, whole sort of area of research that focused on using RNA molecules to make changes to the output of cells. Right? A technology called RNAi or RNA interference, a Nobel Prize winning discovery, that we talked about a little bit about the Covid vaccine, which is based on delivering mRNA into people as a, you know, as a therapeutic.

And, I think what I've noticed and I think is very interesting is that a lot of times in science, you see interesting intersections of fields. And I think that's what's happened with CRISPR and with these kinds of RNA based technologies is that, you know, because CRISPR does rely fundamentally on RNA as the as the targeting agent in these gene editors, we've been able to benefit from a lot of the research that's gone into studying RNA, understanding its structure and how to chemically modify it so it stabilise, how to deliver it.

All of those discoveries with RNA are now kind of being ported over to the world of CRISPR. And there's a lot of intersection there.

Merlin Crossley: Yeah. It's terrific. I mean, we should say that, yeah, it's human… The human body, of course, made out of millions and trillions of cells. And each one of them actually has evolved to not live packages of DNA and RNA in, because packages of DNA and RNA are viruses and you don't actually, you know, it's that's why it is the hardest thing, getting it into every single cell.

And you have to get it into all the cells if you want to trade certain things, sometimes you don't, but often so terrific. So the next question, is from Ramon Varcoe.

Ramon Varcoe: Thank you Merlin. And, thank you, Jennifer for visiting us here in Sydney. I'm a vascular surgeon from across the road, but I have a keen interest in genetics of disease. And I'm going to ask you a question that you've already kind of touched on, but, I'm keen to hear more in detailed discussion around what you think are the greatest ethical risks that we're likely to face in the immediate future with CRISPR gene editing technology.

Jennifer Doudna: Yeah, the ethical risks. Well, I think one of them we did already touch on, which is maybe not top of mind to everyone, but certainly something that has really emerged for me as one of the major risks, and that is equity, you know. Right? So and let's take the sickle cell therapy as an example. Right now, I mean, it's very exciting that we have an approved therapy with CRISPR. That's amazing. And it's great for patients. I've met some of the people that have gotten this therapy, and they tell me that it totally changed their life, right? Completely to be essentially cured of this genetic disease. It's amazing. However, that therapy right now costs $2 million US for each person.

And as you pointed out, it requires effectively a bone marrow transplant. So somebody has to go through all of the procedure to have their own bone marrow destroyed with chemicals. And then they have to be hospitalised more often for weeks to have a bone marrow transplant. And then they have to go through the recovery from that process. So it's a, you know, very long, very involved process.

And the end result could be great. But if it's expensive and hard to administer, then I think that's going to prevent it from getting to most of the people that could benefit from it. And so that's something that again, you know, back to the question about delivery. You know, I think this is where if we - what if we had a way to deliver the therapeutic CRISPR into patients without, you know, maybe it was like a single injection or maybe someday it's a pill that they could take? And it could be done in a small community hospital, maybe even a doctor's office.

I mean, that would be completely transformative, right? So.. and I, that's where I like to set my sights, because I think companies will do a lot of the work that's going to kind of be in the immediate future with the field. But I think as academics, our role is really to be thinking way ahead of that.

Right? We should be thinking about the future, the, you know, longer term, where can we see the real impacts if we solve this problem, what's going to be possible? That's the way I like to think about the field. So that's one area I think some of the other challenges, you know, we did talk about germline editing. To be honest, I that's kind of gone a little bit down on my priority list of challenges.

And why? Well, because I think after the 2018 announcement of CRISPR babies that some people here might be aware of, where it's a scientist actually did use CRISPR in human embryos that were then implanted to create a pregnancy that created the birth of, you know, twin girls that had CRISPR modified genomes. And we don't know their their fate, by the way, at this point.

But, you know, since then, there was really an international outcry against that type of use of CRISPR, at least for now. And we haven't seen repeat incidents like that. So I think this has been good. And there is a you know, there isn't a really strong international community now that kind of pays attention to what's happening in that type of research and how it should be regulated.

And then I think the third thing I would say so, so we talked about germline editing equity. And then I think the third piece is really, you know, how do we decide where CRISPR should be applied. So you, I think you said you're in cardioversion ocular research and clinical work right? So, you know, I think there's a lot of opportunities actually in, in cardiovascular applications with CRISPR.

And one of them is the idea that we could prevent cardiovascular disease possibly, by making a change to a single gene that is known to be protective in the human population, in those people that have this particular form of the gene. And, and so… but again, it gets to this question of, you know, is that where should we really be putting our focus on that type of application when there already are drugs available to treat, you know, this type of, situation for people?

Maybe it is. Maybe it isn't. You know, I don't know. And if we, you know, if we focus in that area, then it means that we can't put resources in other areas. So I think that's a challenge as well with this technology is we have to figure out what are the priorities and where should we be focusing our resources.

Ramon Varcoe: That’s wonderful. Thank you very much.

Merlin Crossley: Terrific. Thank you. So the next question is from Jess Cheung.

Jess Cheung: Hi Merlin. Thanks. So I'm Jess - I'm actually an honour student at UNSW right now. So I actually majored in biotechnology, but I ended up jumping ship to earth in environmental sciences because I was interested in conservation. What was the best piece of advice you've ever received, and what kind of advice would you have for anyone looking to follow in your footsteps?

Jennifer Doudna: Gosh, the best advice I've received, that's a tough one. I've received lots of advice. I've only paid attention to some of it. For better or worse, I think I think my advice currently, I'll just tell you what I say to my own students, and that is that I tell them that I think the best thing that they can do at an early stage of their career is to really discover what they're passionate about and what they're good at, you know?

And that's what I try to do in my research lab, is I have, you know, I have a lot of students that I've worked with over the years, and I've you my job… is really to help them become the scientist they can be in the future, you know, if they want to go in that direction or really whatever they want to do professionally and to do that, they really have to get in touch with what they're passionate about personally.

And for each of us, it's a little bit different. And we also have to figure out what we're good at and what we like to do. And, you know, kind of try to look at the intersection of those things. So I definitely think that is very important. And that means not… it kind of means tuning out, you know, what might be popular right now, what you might, you know, be hearing that you should do or what people think you, you know, could do to make your resume look better or, you know, things like that. Right?

I don't think that's a good way to pursue science, in my opinion, or to say, oh, I want to win a Nobel Prize. You know, I by the way, I never thought that I would go in that direction. Right? That wasn't something that was on my radar at all, and that wasn't why I was doing my science.

So I think it's very, very important to really identify what you're personally passionate about doing and then try to do more of it.

Merlin Crossly: So next question is from Michael O'Dea.

Michael O'Dea: Thanks Jennifer and Merlin for the lovely talk. Mine has a bit of overlap with the previous one here, but essentially my question is about like time and focus. I always find it interesting in the CRISPR story, there was a bit left field of what you're working on normally. And so what I want to know is if you had any advice for young scientists on, like, picking the right questions to ask, like, there's so many interesting things to study at the beginning, but time for just a few. How do you choose?

Jennifer Doudna: Yeah, this is a really good question. And I don't I don't have a great answer to it, to be honest. I get asked this question a lot and I ask myself this question like, you know, how do I choose things? And for me, the honest truth, you know, the honest answer to that is that it's somewhat serendipitous, you know, in the sense that, again, like the answer to the previous question, I always try to figure out what am I excited about?

What am I passionate about understanding. And then what are my opportunities? Right? And, you know, because at some level, you have to do things that you can do or that you have resources to do. And for me, it often also involves who's around, you know, who, who's coming into my lab or what are their interests.

And, where do they intersect with mine or what collaborators might be available. And in the case of CRISPR, the story there is kind of really interesting because not only did it come about for me because of this, you know, interaction with Joe Banfield at Berkeley who told me about CRISPR, I wouldn't have… guaranteed I wouldn't have been aware of it otherwise.

It was, you know, there are only maybe five papers published at the time. And they were in very obscure journals. They weren't journals I was reading. And so, you know, I just wouldn't have ever heard it. But, furthermore, what happened was a guy, you know, right after I’d sort of had that conversation with Joe, and that's very interesting, but I don't really have any money to work on it, and I don't really have anybody in my lab to work on it.

And then what happened was a guy walked into my office named Blake Wiedenheft and Blake Wiedenheft was, a graduate student who was just finishing his work in Montana, where he had been working at Yellowstone National Park, which is a, you know, big park in the US. that has a lot of volcanic activity and hot springs that have interesting bacteria growing in them.

And he was probably one of the very rare people that at that time, you know, was aware of CRISPR because they're found in a lot of these Yellowstone bacteria. And so he walked into my office and they said, you know, I want to come to Berkeley and I'm looking for a lab to do my postdoctoral work in.

And I said, oh, that's great, what do you want to work on? And he said, well, have you ever heard of CRISPR? And I had, you know, right? Most people have said all the time. And so that's how we got started on it, was that he came to my lab and started working on, you know, kind of the very early kind of investigations of CRISPR.

And because he had a very infectious personality, he was one of these work hard, play hard kind of guys. When new students came to my lab and I'd say, you know, what projects look interesting to you? The first two students that came after Blake joined my lab said, I want to work with that guy because he looks like he's having fun, right?

And so they built up a little team. And so pretty soon we had a really a core group that was working on this project that I kind of thought was a, you know, kind of a little niche area of biology. It was kind of almost like a little hobby of mine. And I felt very guilty using my research dollars to work on it because it was just fun, you know?

But that's how it got started. And I think that's when I look back on my career, that's often how we've gone into, you know, various things that we've worked on over the years is that kind of, you know, intersection of opportunity and the right people in the right place at the right time to do science.

Merlin Crossley: Yeah. The hot springs is very interesting. We had, Francisco Mojica, we gave him an award for his work and he’s a beautiful guy. He works at Alicante in Spain, and he was working in the salt marshes. And these things where people are working on something that is a little bit out of the mainstream, not doing the me too, everyone else, bandwagon science, but a little bit out on and that's where some of the big discoveries are made.

But it takes it takes a bit of courage to be doing unique work. So let's do the next question. Now, the first question is interesting actually, I'll just read it out because this is quite pertinent to Australia where we believe in societal impact and we believe in translation of research. But this question says, Can you take it too far?

‘Grants require the linking of basic research to medical outcomes. Does this help or hinder long term research\ How can we better support long term scientific projects?’ So Francis Mojica wouldn't have got a grant for his salt marshes, I guess.

Jennifer Doudna: Yeah, this is a very, very important question. It's something I do think about a lot. And that is that, as you just heard in my little anecdote, you know, I was lucky that I had a little bit of money that I could carve out to pay Blake so that he could get started working on CRISPR. And like you said, it was not a popular topic at all, like nobody had heard of it.

And so, you know, but it was very important that we got going on that because it did lead into a very interesting direction that I don't think anybody at the time could have, you know, anticipated. And so we want to make sure that scientists have enough of those kinds of opportunities, I think, to do truly curiosity driven research. Work that they're doing simply because they're curious.

They want to know how the world works. And you know, what's the truth about nature? So but I think that has to be balanced with, the fact that, you know, there's a lot of problems out there to solve. Right? And we got a lot of big problems that we're all facing, whether they're in health care, whether they're in our climate, or other areas.

And, we need to have science that actually addresses those problems. And so I do think there's an opportunity to continue to, you know, figure out how to better bring those two kinds of science together. And I don't have a one size fits all solution, but I'll just tell you what we're doing at our institute. This is one reason we founded the Innovative Genomics Institute.

And I noticed on my way in here today that, that your university is building a new building in the health sector that kind of does the same kind of thing, it looks like, which is very interesting, which is that it tries to bring together people that are doing academic science that's really just truly curiosity driven with folks that are working on, you know, trying to solve a particular problem, whether it's in cardiovascular disease or anything else.

And, you know, sort of allowing those people to kind of bump elbows and, you know, potentially come up with solutions that they might not otherwise identify if they were working, you know, apart. And so that's really what we do at our institute. And in fact, I insisted that we have our lab set up so that people that are doing agricultural research and, you know, working with plants are literally right next door to a lab that is doing clinical research and is taking samples from people that are in clinical trials that are, you know, where they're being treated with, CRISPR.

And we have an active trial right now, for example, at our institute that is, focused on sickle cell disease to try to figure out better ways of doing this delivery. And those people, those scientists, actually, literally, you know, run into each other every day. They meet for coffee. And it turns out that, surprisingly, maybe or maybe not, they have, things that they find in common and they end up trading ideas, especially on the way the technology is being deployed. So I think we need to do more of that and find venues like, it sounds like you're doing here that allow that to happen.

Merlin Crossley: Yeah. Terrific. That's true. So the next question is quite a nice question. I'll read it out. It would be great to know how, and this is in uppercase ‘negative scientific results’ and then it goes back, impacted your science journey. So negative results I think that's probably from a PhD student because they suffer terribly from negative results. So I tell my students they had to publish negative results because you can't say I went to Scotland and didn't see the Loch Ness Monster.

Therefore it doesn't exist because no one will accept that publication. But it's a valid publication. What about negative results? Did you suffer from negative results?

Jennifer Doudna: Well, I think there's - isn't there a journal of irreproducible results? Yeah. And you know, when I was in graduate school, we used to read that journal, because, you know, we were, all of us, me included, had lots of failed experiments, lots of things that were in irreproducible. And so, you know, it was kind of gratifying to see that, oh, people are actually publishing papers on that type of data.

But, you know, I would say that, yeah, I think failed experiments and, you know, things that don't pan out are actually incredibly important. Aren’t they? Because they help us, they shape how we think about what we're doing. And for me, it's often been the case that, you know, when I have, failed experiments or, you know, things that, you know, you have a, you have what you think is a great idea, and then you do the experiment and, you know, it doesn't work in that you struggle with it for a while.

You realise that you have to make a change. You have to redirect things, and it makes you kind of reevaluate – and this is what I do. You know, it makes me think, okay, maybe my it was my idea wrong. Or is there a technical challenge here? Do I just simply not have the right technology to answer this question right now?

Or, you know, maybe sometimes I realise, actually, that question wasn't so interesting after all, and maybe I should just be doing something else. So it often is an opportunity to kind of reevaluate. But I will say also that - and I wonder what you think about this because, you know, you have run a research lab also for some time -

And I think science is struggle. You know, it is. And sometimes and this is one of the real challenges, is that you have to figure out, if you have a failed experiment, is it just a bump in the road. And you should keep struggling because it's a really important, you know, road to go down? Or is it a sign that, you know, maybe I should really change course? And I find that is one of the hardest decisions to make in science, even now, is to figure out which path I'm on. You know.

Merlin Crossley: It's an emotional rollercoaster. Science is an absolute emotional roller coaster, and you don't know when - whether you should keep banging your head against the wall because you're about to break through. Or you should say, this is not the way I'll go a different way. And I know in the students that I've mentored over the years, it's often about temperament rather than, you know - a lot of endurance sportsmen say this - their ability to endure pain is what makes them champions. And science is an emotional rollercoaster because as you know so. But it has its highs, rollercoasters.

Jennifer Doudna: Indeed.

Merlin Crossley: So this, I think we've got to do this question. What are your thoughts on the potential weaponisation of CRISPR, for instance, increasing the pathogenicity or lethality of a micro organism such as tuberculosis? A lot of people are worried about that sort of thing.

Jennifer Doudna: Well, yeah, it's a concern. I would I would just say, though, that I think that capability exists even without CRISPR. you know, recently in the US, there's been a lot of discussion about and I think we even had to legislation that was passed recently about, you know, is it okay to for people to be able to order from a company that synthesises DNA, should you be able to just order any DNA that you want, like so?

Suppose somebody places in order for the DNA sequence of the smallpox virus, should that be okay? You know, and of course, I think we would all say ‘No’. And, but how do you regulate that? How do you how do you make sure you know? And it is a concern, but that's completely independent of CRISPR. You don't need CRISPR to do that.

And so I think that, you know, CRISPR is yet another technology that comes along with, you know, the good and the bad. But I don't think it is a technology that is providing particularly unique capabilities, that are, you know, easy enough to deploy that I would worry about it in a kind of a general sense.

Merlin Crossley: I agree completely. I worry a lot more about nuclear weapons, actually, because, you know, they're demonstrated to be destructive. So this is a good question, too. And I think this explains something about how science is done. How did CRISPR go from being first discovered to becoming easily accessible in labs globally? I think this is important because of how much we do share in things like Addgene.

You know, people do share don’t they?

Jennifer Doudna: They do and, you know, CRISPR and this is a this is a great question because it really kind of gets to the heart of, you know, why - why did this technology take off the way it did? Because it took off very quickly. Right? We published a paper in the summer of 2012, and by the end of that year, there were already multiple labs that had, you know, work in progress or, you know, being published in journals showing that CRISPR could be used for genome editing in different systems, including in an entire organism.

A lab had already shown that you could use it in zebrafish to make, you know, changes in zebrafish and why was that? Well, it's because it's just easy, you know, it's easy to use. It's a programable system. This is how bacteria use CRISPR. They use it as a programable way to program cells to protect the cell against a viral infection.

And they do it in a in, kind of in real time. And so once we understood that molecular mechanism, it was easy to harness it as a genome editor. And because it, you know, it works on any kind of DNA - it didn't matter if you were doing it in bacterial cells or human brain cells or, you know, the, you know, rice cells or wheat or anything else -anything with DNA could be manipulated with CRISPR.

And so it just, you know, it just meant that it could be adapted very, very quickly. And really within, I would say the first maybe two years after that 2012 publication, there was just a rapid adoption of CRISPR by labs, you know, increasingly, you know, globally who were saying, ‘Oh, that looks like a cool tool. I'm going to use that in butterflies, or I'm going to use that in, you know, mole rats’ or whatever they were working on.

And so, you know, the more that happened, the more other scientists saw, ‘Oh, that looks useful. I'm going to try that widget’. And so it just took off very quickly. And what helped was that there's a nonprofit organization called Addgene that will distribute research reagents like CRISPR very inexpensively to people who are working in academic labs anywhere around the world.

And so that made it possible very easily for labs to get access to the, you know, the fundamental molecules they needed. And from there they could just change them as they needed to program them for their system and start working with them.

Merlin Crossley: Yeah. It's fantastic. It just you put it on a piece of paper, send it to the post, and everyone has it. It's absolutely… and it does work. You know, we haven't talked, but previously you could modify DNA, but you'd set up, plates with 96 wells. You'd have ten of them. You'd search through one at a time and you get two modifications.

It would take you a year. But this, I mean, everyone was astonished. It just works first time and everyone couldn't do it. Except there was an article where someone from the journal Science said, anyone can do it, and the journalist gave it a try and he couldn't do it. He hadn't been trained properly in a lab, but it is…it does work. So I have to ask you this one. We haven't touched on this one, but what were the good things and the bad changes in your life after you became a Nobel laureate?

Jennifer Doudna: Oh, yeah, that's a great question. Well, let's start with the good. It's been amazing to.. you know, my husband, who's also a scientist and a professor at Berkeley, after I won the Nobel Prize, he said to me, ‘You know, he said, I think that your role now is really as an ambassador for science, that your role is really to communicate your joy of doing science and why, you know, students who are thinking about a career in science should, you know, should pursue it’.

And I've thought about that a lot because I, you know, I do get invited to do a number of, you know, events of this type. And I do enjoy it. It's a lot of fun. It does take time though, right? It does. And it does take time away from my research and from my own students. And so I've had to figure out how to how to balance that.

But on balance, I would say it's been great. You know, I it's really I enjoy it and I think it's very important. It's something that means a lot to me personally. And I do feel a lot of excitement when I look out, like in an audience like this and I see a lot of young people here, and probably many of you are, you know, you're all going to make the breakthroughs of the future.

And that's exciting to me to think about. So I love that. And, you know, and it's also meant that I've had a lot of opportunities to interact with people that I might never have met otherwise, you know, that have come to me because they've, you know, heard about CRISPR through the Nobel, and they reach out in different capacities - so whether they want to collaborate on a project or whether they want to, you know, write an article of some kind or other projects that they're working on.

So that's been all really very interesting. I guess the downside if there is one, it's kind of the flip side of that coin in a way. Right. It's just that I don't have enough time, you know, and yeah. Yeah. And so prioritising is tricky. And people ask me, you know, how do I manage my time? And the answer is not very well.

You know, it's often a juggling act and, and I think all of us professionally feel this at some level, right, is that, you know, you're always trying to figure out what your priorities should be. But on balance, I'm just incredibly grateful. And I like I said, I, you know, what I think is most important for me right now is really ensuring that science will go on.

That those of you that are at the start of your careers are going to have the opportunities that I feel like I had, you know, in science to make a difference.

Merlin Crossley: It's a good job. You are a good ambassador. I mean, some Nobel, most Nobel laureates, are but it's very good.

Jennifer Doudna: It's always a learning curve. I'm always on it.

Merlin Crossley: But that's that is part of your job now. So, this is going to be the last question, and it's it's a very simple one, actually, but I think it will give people an idea. Can you tell us what your lab is working on at the moment? So a couple of projects and I think give people an idea of what are you doing at the moment?

Jennifer Doudna: Yeah, sure. I'd love to tell you about that. I we could be here all day, but I'll keep it short because we're running down the clock here, but, but yeah, I'll tell you about a couple of things we're doing. So. And they kind of give you a sense of the flavour of my lab. And I would say very roughly, that my lab is kind of divided into two halves that very much intersect and interact a lot, but the two halves are applied and fundamental.

So I have a number of people that come to my lab now that really want to do very fundamental work. They're curious about how CRISPR works, which I still am. Of course, there's lots of unanswered questions there, and they want to investigate how these enzymes are able to seek out a target site in DNA in a genome. I mean, it's kind of .. it is a fascinating question.

How are they able to find a small sequence in the, you know, 3 or 6 billion, you know, 3 billion base pairs, let's say, in the human genome and do it quite accurately? You know, it's quite… and quickly I mean, it's astounding, right? How does that really work? So we're you know, investigating the mechanisms of this.

And we're also curious about finding new kinds of enzymes that are RNA guided. And I suspect there are a lot more out there that just have escaped attention up until now. And why do we want to find these? Well, we're just curious, you know, we want to know what's out there. And I think that there's a potentially very interesting evolutionary track that has selected for these types of programable proteins that do lots of other things that haven't been found yet, but that's a hypothesis that has to be tested.

And so one of my students recently was able to show that he could make a structural model of one of these proteins that's, well known to be a CRISPR, enzyme. And what does that mean? Well, he basically has a three dimensional shape of what this molecule looks like. That doesn't have to depend on the actual sequence of the protein.

It's just a, you know, it's a molecular architecture. And with modern techniques we can design a program, a computer program that will search through the AlphaFold database, if you know what that is, right? So using the sort of predicted three dimensional structures of all the proteins that are out there to identify proteins that look like this CRISPR protein, but maybe not at the sequence level.

And guess what? He found some things. Right. So we have these proteins that clearly fold up three dimensionally. They look identical to CRISPR enzymes, but they don't look anything like CRISPR proteins at the actual, amino acid sequence level. And so we're fascinated by this. And, you know, there were just the very beginning of this project. So we're just starting to now experiment with these and figure out what they do.

And, you know, do they have RNA guides? So it looks like some do. And so we're trying to figure out what they are. So that's been really fun. And it's just a you know it's just one of those Sherlock Holmes kind of things. You know, we're just kind of sleuthing, trying to figure out what these are and what they do.

The other project that I'll mention kind of represents what's happening on my more applied side of my lab, because there we appreciate that for CRISPR to have real global impact, and not just in a few niche areas and with a few people that can afford it, but, you know, really to have impact on maybe, eventually all of our lives in positive ways, we really have to solve this delivery problem.

And even though we know that, you know, we're not going to probably solve it ourselves, it's a big problem, but we want to at least contribute to that. And so recently, what we've been doing is taking advantage of viruses that are very good at delivering the viral genome into cells, except we gut them of their viral material, so they can't actually infect cells, but they still have the machinery to get into cells.

And so then we engineer them. So they're actually what are they putting into cells? Well, they're putting CRISPR in the cells. Right? And then we can program them to go into particular cells that we want them to go into. And that's been really exciting because now we can start to see a path - and we're doing this now in animal, you know, sort of mouse type experiments where we can show that we can get targeted genome editing in vivo using this type of delivery strategy.

And we imagine that one day we might be able to do that also in people, let's say. So it's been really interesting to see that kind of technology developing.

Merlin Crossley: Yeah, those are superbly smart experiments. I mean, looking for other RNA guided things with AlphaFold and delivery. It's just that's fantastic. So you've got your work set out for you. So look, I'll finish up now because we've got 17 seconds left. I want to thank you so much for coming. It's interesting when Jess said, you know, what's the advice?

My advice is, you know, if you're young, get a mentor like Jennifer, you know, having excellent people coming here and describing their work, it lifts us all up and it sets... If you can find smart people who care it, it sets this culture of curiosity and science. And I think this does make the world a better place. So thank you for coming and sharing your story and your achievements with us today.

And I also have to say to you, please do, subscribe to the UNSW Centre for Ideas newsletter, and, you can relive all of this on the podcast later if you need to relive it, if you missed anything at all. And I finished by thanking Alice and Ione and everyone for organising it. And, looking around at all my friends and colleagues and visitors to the university for coming to be in the audience today.

So let's all join to thank Jennifer. Thank you.

UNSW Centre for Ideas: Thanks for listening. For more information visit unswcentreforideas.com and don't forget to subscribe wherever you get your podcasts.