Science Show Summer - Merlin meets Dr Crispy
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ABC Listen. Podcasts, radio, news, music and more. Time for the science show and something really special today. If you recall my top 100 scientists, they were all defined as, yes, being terrific at research, but also fine human beings doing work for the public good. And American star Jennifer Doudna is a splendid example of both.

Her work on CRISPR has in recent weeks been shown to have promise in treating cystic fibrosis and now reducing methane emissions in cattle. Professor Doudna is introduced by University of New South Wales Deputy Vice-Chancellor Merlin Crossley and the hall is standing room only.

Now, Jennifer, I've told you about UNSW, how proud I am of the RNA work we do here, the work that Martin Green did on solar panels. We think 90% of the solar panels in the world have UNSW technology. We're very proud of quantum computing. Michelle Simmons was Australian of the year. And so let me introduce Jennifer.

Jennifer Doudna is the professor in the Department 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 enables 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, A Crack in Creation, by Jennifer Doudna and Samuel Sternberg, The New Power to Control Evolution. So I recommend that book.

Now, Jennifer, thank you for coming. Now, I was looking at your book and your name, and I looked at the last three letters of your name. I don't know if anyone else noticed this, but 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. If DNA is the written word, RNA is like the spoken word. It's a messenger. It doesn't last. But 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. Well, I'll just start by saying thank you so much for inviting me here. It's awesome to be here today. It's been a really interesting journey for me. I started my career in science in the 1980s, and I was interested in RNA.

actually. As you said, it's a molecule, it's 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 plays an incredible role in biology and probably was responsible for the origin of life on the planet. It actually is the path that took me to CRISPR because it is the molecule that allows bacteria to detect and

basically recognize 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 the mid-2000s after an Australian scientist, Joel 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. And that was kind of the original research. But what was exciting was that once we started studying this bacterial immune system called CRISPR, we realized 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.

Yes, it's transformed science completely. Now, can we go back in time to when you were growing up? So you grew up in America, but you grew up in a very special part of America, Hawaii. Can you tell us about your decision to study science and how you succeeded in getting your own lab? 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, there's just extraordinary diversity of life on our planet and certainly in isolated environments where life has a chance to evolve separate from other 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. I think that was my first sort of indication that I might like to, in fact, understand the scientific basis for that. And then I had a wonderful high school chemistry teacher who taught us kids that science is not about memorizing 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 interesting. And I think that was the first time I started to think, gee, 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, but no scientists. So it felt a little bit rebellious to be going in that direction. I was very lucky that along the way, I had a number of teachers and other mentors who encouraged my interests and helped me make my path. And it was not a straight path at all, but I always kind of pursued what I found to be interesting, and I tried to work with people that were smarter than me.

I want to ask you about what lab life is like. 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 plating out bacteria, looking at microscopes, growing cells, being a graduate student, postdoc in labs. What's that sort of life like?

Well, when I first started working in the lab, I think it was when I was in college, and I felt so lucky that my professor allowed me to work in her lab for the summer. And this was my first discovery of what it was like to do real research, not cookbook, you know, you're following instructions in a lab manual or something. 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 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 what the results were of my previous day experiment. And even if things didn't work, it was always like, okay, it didn't work, but why didn't it work? And 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. All these years later, it's still like that. I don't actually myself, sadly, work with my own hands in the laboratory. But when I'm back at Berkeley with my students, I'm usually every day spending time with them and trying to think through how they're doing experiments and what the results mean.

And we get that shared joy together of that process of discovery or so, you know, there's frustrations trying to figure things out, but 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. It's a very tiny little thing. It feels very exciting to have those kinds of discoveries happening all the time.

And it is this addiction to curiosity and discovery. And it is nice. Each day, the results are quite small. But yes, they're big to me as well, because you want to know what happens next. So some people see science as a very competitive industry.

endeavor because there are a lot of people in it. There are limited resources. There's limited time. And we do race to get things published. And we talk to each other about the scarcity of research grants because it's something we have in common. But we also collaborate and form very deep friendships. And in reading your book, your book emanates this sort of feeling of collaboration with Jill Banfield, with Emmanuel Charpentier, and with your co-author, 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? It's a great question. You know, when I was starting out in science, I didn't

didn't appreciate this. For me, at least, when I was learning about what do scientists do, they don't talk about that in textbooks, right? People often you get an image of scientists kind of working alone. But the reality is 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 a really integral part of everything that I've done in science is working with other people, sharing ideas, making discoveries together, struggling through things together and trying to figure them out. And as far as competition, for me, it's always been about competing with myself. In other words, I want to be the best competitor.

that I can be and I try to learn from other people and 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 figure out how to be better myself. 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. And 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 spent a lot of money on trials and things and it was very hidden myths, but now you make a change and it is like genetic surgery.

But can I ask you to reflect on what some of the big advances have been in the CRISPR world, the applications? Yeah. Well, the first application that, of course, comes to mind is actually closely related to your own research. And that is the approval in December of just this last year of a drug called Casgevi that is a CRISPR therapy for people that have sickle cell disease.

And this was really a watershed moment in the field. Many of us 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 five 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, they're

perhaps even more common diseases that could potentially be prevented by making targeted tweaks to our genomes. I think that's certainly an area where there's a lot of opportunity right now. But let's talk about the hornless cattle. I mean, I think that's an interesting example of an incredibly exciting branch of research right now that is exploring how genome editing can make changes in animals and in crops.

that are going to be, I think, really important as we deal with the challenges of climate change.

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, that would be tough. Or if you had to, you know, saw the horns off as they've done, which is very hard on animals and it's really not good. So I think 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 is actually looking for ways that CRISPR-Cas9 will have an impact on

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 very powerful greenhouse gases. So that's an opportunity that I think is now in our hands with this kind of tool.

Yeah, another positive one I read an article about, I don't know where it's up to, but it's about chickens, hens, 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, what they're doing is introducing a fluorescent mark that

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 much kinder. So I think these sort of things are interesting.

Now going to genetic diseases again, so sickle cell disease is a disease that affects about 10 million people, lifelong debilitating disease. And 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? Yeah, that's very exciting. You put your finger on something that we think about every day at our institute, and 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 bone marrow transplant? In other words, doing it directly in the body. And that's going to require some new technology, right?

But many people are working on this. 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 vehicle delivered as a vaccine and

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 prevent liver disease. And they are already in a phase three clinical trial with that work. So that means that 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. But the reason it's relevant to the discussion of sickle cell disease is that it 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.

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, 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. 2% of the population will have two copies of this variant. And 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'm going to get Alzheimer's. My partner's going to get 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 might. It's a very delicate topic.

It's illegal in Australia. If I were to do that, it's 10 years in prison. It's illegal and seriously illegal. 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 cell from their own community. So it's not actually as rare 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, do you

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? I think you're absolutely right. The first criterion has to be, you know, is a technology safe and is it effective? 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. 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, 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, yeah, there's a good case for that. But I do think those cases are probably going to be relatively rare.

And so we need to be thinking now about how do we feel about that as a society? I also don't think that there can be sort of a global regulation of it. I think it'll end up being probably country by country because there are different cultural norms, different expectations in different countries.

And the thing that I think about a lot, to be honest, is the whole equity angle, making sure that I wouldn't like to see the technology used in a way that increases inequities 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. If it does happen, I think it will be used for correcting defects, right?

First, I mean, I always think of the genome is like a city. You can use this technology to fix a blocked road or a bridge that's fallen down or a pothole, but you can't design cities are always the worst ones and design humans. I'm not concerned that much about genetic enhancement because I think people wouldn't know where to begin. But I don't know. What do you think? Are you worried about genetic enhancement, super people, that sort of thing?

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 we know of certain genes that can be altered that have changed things about, say, our physical appearance. Like, for example, eye color is already something that can be detected and perhaps selected for in vitro fertilization clinics. And with CRISPR, in principle, you can make the tweak yourself. And there are other things of that nature. So 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 potential risk of the technology for one thing. But I think you're right about superhumans in the sense that in most cases, the traits that we see in ourselves are complex. 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 chemical changes to DNA that don't affect the actual DNA sequence, but affect the way that the sequence is read.

So I think there 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 make changes in our physical or emotional or intellectual properties. 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 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 only what were true, but it's not true. And it's not true. The DNA from dinosaurs is all gone. So you can't do that. But the woolly mammoth, there is a company that's interested in the woolly mammoth, the Dodo company.

And in Australia, they're interested in the thylacine. But there are people who want to bring that back. And the idea is,

If you have embryonic stem cells from these organisms, you can start with getting elephant DNA and little by little change it into a woolly mammoth. Now, I'm sort of skeptical about this because 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. Do you think we'll see a woolly mammoth, a dodo and a thylacine in 10 years?

No. I don't. But I do think the idea of resurrecting extinct species is captivating, isn't it? 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...

until recently has been a professor at the University of California, Santa Cruz. And she studies evolution of large animals, like she's looked at polar bears, for example, and how they evolved. And she's also looked at lots of species of birds. And of course, there've 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 what CRISPR might be useful for in terms of perhaps bringing back animals like the passenger pigeon, animals that haven't been extinct for that long and that maybe don't differ that much genetically from animals that we find in our world today.

I think I heard that Beth Shapiro has actually gone to that company called Colossal that is trying to resurrect woolly 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. I think some will be easier than others. I agree. The polar bear and the brown bear are quite similar, I think. Yeah. I think with the others, the lack of a good reference genome is going to be a problem for them because you've got to get everything right. You can't get, you know... You can't get it 98% right. Yeah. And I think that's very hard. Another interesting idea. So shortly after you published the CRISPR work,

There was a paper in PNAS about things called gene drives. You can get a gene so that it jumps 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 all of the offspring. Now, if you drive something like

maleness, being a male, that will send the species to extinction. And gene drives are 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 norwegicus, because it's not clear they live in the wild. They're essentially an organism which is parasitic on humans. Or the cane toad, right, is another one to talk about. 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. But there is a lot of controversy about gene drives because...

because it is an awesome power to drive a species like the rat to extinction. So the New Zealanders, we gave them the gift of brush-tailed possums and they want to drive the brush-tailed 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 brush-tailed possums. So what do you think about gene drives?

Well, let's start with what is a gene drive? People might be wondering what this is. And it's possible when you have a technology like CRISPR, which makes 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 some kind of a vehicle that is able to get into cells and get into germ cells in a type of animal, like it could be a mosquito or 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. It's essentially a way of bypassing normal Mendelian genetics of inheritance and

by allowing a trait to be transferred, as we say, horizontally among animals that are in a particular generation rather than waiting for them to reproduce and pass along a trait as we normally observe. And this is possible in the lab, and people have done it with animals like fruit flies and mosquitoes. I don't think they've done it with other animals that I'm aware of. I think it'd be a lot harder to do it in a rat, but it's more of a theoretical thing. You know, what would happen if we did this?

And as you said, I think the interest in this initially stemmed from the idea that 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 is familiar with the idea that as humans, we try to do things sometimes that go in a direction that we don't intend, that are negative. And we certainly saw this in Hawaii many times, right? Where a species would be brought in,

People would try to eliminate it. And by doing so, they created more problems that they weren't 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. 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 U.S.,

work under very restricted conditions. If they have a gene drive with fruit flies, those flies have to be in a very secure enclosure where they can't get out.

Yeah, I think that's the right way to go. I remember talking to ecologists about the Anopheles mosquito and I said, could it, perhaps it fertilizes something important. But there are many different, there are biologists working on this, about 100 different mosquitoes and things. We've got rid of smallpox. You know, I think probably getting rid of the Anopheles mosquito is a good idea.

A good idea indeed. Merlin Crossley, Deputy Vice-Chancellor of the University of New South Wales, with Nobel laureate Dr Jennifer Doudna. This is The Science Show, and time for questions from the audience. The first question is from our very own Pally Thordarson, the Director of the RNA Institute at UNSW. Over to you, Pally. To drive this whole field further, 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. Well, I think we're seeing both happening right now. So 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 to the CRISPR technology. So we now have a large toolbox.

that 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 ways that 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 it too.

The other half of your question is incredibly important, which is 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

or whether you're talking about making drought-resistant rice, 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. Because I think this is really, in a way, 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.

Yeah, it's terrific. I mean, we should say that the human body, of course, made out of millions and trillions of cells. And each one of them actually has evolved to not let packages of DNA and RNA in because packages of DNA and RNA are viruses. And 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 treat certain things. Sometimes you don't. So the next question is from Raymond Varko. 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. I'm keen to hear what you think are the greatest ethical risks that we're likely to face in the immediate future with CRISPR gene editing technology. 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 it's certainly something that has really emerged for me as one of the major risks, and that is equity.

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 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. Then they have to be hospitalized, often for weeks. And then they have to go through the recovery from that process. So it's a 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, back to the question about delivery, what if we had a way to deliver the therapeutic CRISPR into patients with 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. That's where I like to set my sights because I think companies will do a lot of the work that's gonna be in the immediate future with the field, but I think as academics,

our role is really to be thinking way ahead of that. 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, that's 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 a scientist actually did use CRISPR in human embryos that were then implanted to create a pregnancy that created the birth of twin girls that had CRISPR modified genomes and

And we don't know their fate, by the way, at this point. But 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 really strong international community now that pays attention to what's happening in that type of research and how it should be regulated. And then I think the third piece is really, how do we decide where CRISPR should be applied?

You know, I think there's a lot of opportunities actually 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 and those people that have this particular form of a gene.

But again, it gets to this question of, you know, should we really be putting our focus on that type of application when there already are drugs available to treat this type of situation for people? And 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.

So the next question is from Jess Chong. Hi Marilyn, thanks. So I'm Jess. I'm actually an honors student at UNSW right now. So I actually majored in biotechnology, but I ended up jumping ship to earth and 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?

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. 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.

And that's what I try to do in my research lab is I have a lot of students that I've worked with over the years. And I view my job is really to help them become the scientist that they can be in the future. 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 try to look at the intersection of those things.

So, I definitely think that is very important. And that means tuning out what might be popular right now, what you might be hearing that you should do, or what people think you could do to make your resume look better, or things like that. 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." By the way, I never thought that I would go

in that direction. 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. So next question is from Michael O'Day. Michael.

Thanks, Jennifer and Mel. My question is about time and focus. I always found 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 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? This is a really good question. I asked myself this question, how do I choose things? For me, the honest answer to that is that it's somewhat serendipitous.

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's coming into my lab and what are their interests and where do they intersect with mine? And in the case of CRISPR, the story there is really interesting because not only did it come about for me because of this interaction with Jill Banfield at Berkeley who told me about CRISPR, I wouldn't have

guaranteed I wouldn't have been aware of it otherwise. It may be 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 Jill, I thought, well, 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

was a graduate student who was just finishing his work in Montana, working at Yellowstone National Park, which is a big park in the U.S. 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 was aware of CRISPR because they're found in a lot of these Yellowstone bacteria.

And so he walked into my office and he said, 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, so.

And so that's how we got started on it was that he came to my lab and started working on 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. And so they built up a little team. And so pretty soon we had a core group that was working on this project that I thought was 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. But that's how it got started. When I look back on my career, that's often how we've gone into various things that we've worked on over the years is that intersection of opportunity and the right people in the right place at the right time to do science.

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. That's where often the big discoveries are made. But it takes a bit of courage to be doing unique work. So the next question, 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?

This is a very, very important question. It's something I do think about a lot. And that is, as you just heard in my little anecdote, 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.

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 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 what's the truth about nature.

But I think that has to be balanced with the fact that there's a lot of problems out there to solve. And we've 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.

This is one reason we founded the Innovative Genomics Institute. And I noticed on my way in here today that your university is 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 trying to solve a particular problem.

You know, sort of allowing those people to kind of bump elbows and potentially come up with solutions that they might not otherwise identify if they were working 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 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 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 scientists actually literally 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. That's true. So the next question, it would be great to know

how, and this is in uppercase, negative scientific results impacted your science journey. So negative results, I think that's probably from a PhD student because they suffer terribly from negative results. I tell my students, they're hard 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.

Well, I think there's, isn't there a journal of irreproducible results? Yeah. And 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 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 I think failed experiments and things that don't pan out are actually incredibly important, aren't they? Because they shape how we think about what we're doing. And for me, it's often been the case that you have what you think is a great idea and then you do the experiment and it doesn't work and you struggle with it for a while.

you realize that you have to make a change. You have to redirect things and it makes you reevaluate. At least this is what I do. You know, it makes me think, okay, was my idea wrong? Or is there a technical challenge here? Do I just simply not have the right technology? Sometimes I realize, 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 reevaluate. I wonder what you think about this, because 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 road to go down? Or is it a sign that 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. It's an emotional roller coaster, 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. You know, a lot of endurance sportsmen say this, their ability to endure pain is what makes them champions. But it has its highs, roller coasters. Indeed. A great run. What are your thoughts on the potential weaponization of CRISPR? For instance, increasing the pathogenicity or lethality of a microorganism such as tuberculosis. A lot of people are worried about that sort of thing.

Well, yeah, it's a concern. I would just say, though, that I think that capability exists even without CRISPR. Recently in the U.S., there's been a lot of discussion about, and I think we even had legislation that was passed recently about, is it okay for people to be able to order from a company that synthesizes DNA? Should you be able to just order any DNA that you want? Suppose somebody places an order for the DNA sequence of the smallpox virus. Yeah.

Should that be okay? Of course, I think we would all say no. But how do you regulate that? How do you make sure? But that's completely independent of CRISPR. You don't need CRISPR to do that. And so I think that CRISPR is yet another technology that comes along with the good and the bad. But I don't think it is a technology that is providing particularly unique capabilities to

that are easy enough to deploy that I would worry about it in a kind of a general sense. I agree completely. I worry a lot more about nuclear weapons, actually, because 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 and things like ad gene. People do share, don't they? They do. This is a great question because it really kind of gets to the heart of 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 work in progress or 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.

And why was that? Well, it's because it's just easy. It's easy to use. It's a programmable system. This is how bacteria use CRISPR. They use it as a programmable way to program cells to protect the cell against a viral infection, and they do it in real time. And so once we understood that molecular mechanism,

It was easy to harness it as a genome editor and it works on any kind of DNA. It didn't matter if you were doing it in bacterial cells or human brain cells or rice cells or wheat or anything else. Anything with DNA could be manipulated.

CRISPR. And so 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 increasingly 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 mole rats," or whatever they were working on. And so the more that happened,

happened, the more other scientists saw, "Oh, that looks useful. I'm going to try that widget." 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 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. Yeah, it's fantastic. It's just you put it on a piece of paper, send it through the post and everyone has it and it does work. Previously, you could modify DNA, but you'd set up plates with 96 wells. You'd have 10 of them. You'd search through one at a time and you'd get two modifications. It would take you a year. But this, everyone was astonished. It just works first time.

I have to ask you this one. We haven't touched on this. What were the good things and the bad changes in your life after you became a Nobel laureate? Yeah.

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, your role now is really as an ambassador for science, that your role is really to communicate your joy of doing science and why students who are thinking about a career in science should pursue it.

And I've thought about that a lot because I do get invited to do a number of events of this type and I do enjoy it. It's a lot of fun. It does take time, though, and it does take time away from my research and from my own students experience.

So I've had to figure out how to balance that. But on balance, I would say it's been great. 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. It's also meant that I've had a lot of opportunities to interact with people that I might never have met otherwise that have come

to me because they've heard about CRISPR through the Nobel and they reach out in different capacities, whether they want to collaborate on a project or whether they want to 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? Yeah, yeah.

And so prioritizing is tricky. And people ask me, you know, how do I manage my time? And the answer is not very well. It's often a juggling act. 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 what I think is most important for me right now is really ensuring that science will go on, you know, that those of you that are at the start of your careers are going to have the opportunities that I feel like I had in science to make a difference.

I want to thank you so much for coming. It's interesting when Jess said, you know, what's the advice? My advice is 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 sets this culture of curiosity and science. And I think that does make the world a better place. So thank you for coming and sharing your story and your achievements with us.

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

Merlin Crossley, Deputy Vice-Chancellor, University of New South Wales, was in conversation with Professor Jennifer Doudna, Nobel Prize winner for chemistry and for producing CRISPR, the powerful gene editing technology. She was visiting Australia. Production by David Fisher. And my thanks to University of New South Wales for help with that recording. Next week, another female star of science. And this is a turn-up, or was, of Hollywood.

Hedy Lamarr, who hated being called the most beautiful woman in the world, and even said anyone could do that, just stand there looking stupid.

but she was far too clever to be trapped like that. Her genius was both using music to re-engineer communications and leading the way to Wi-Fi and much more, and also for duping the Nazis and helping to beat them in World War II. I'm Robin Williams. You've been listening to an ABC podcast. Discover more great ABC podcasts, live radio and exclusives on the ABC Listen app.