Berkeley Talks: Nobel laureate Jennifer Doudna on CRISPR and the future of gene editing

(Music: “No One Is Perfect” by HoliznaCC0)

Anne Brice (intro): This is Berkeley Talks, a UC Berkeley News podcast from the Office of Communications and Public Affairs that features lectures and conversations at Berkeley. You can follow Berkeley Talks wherever you listen to your podcasts. We’re also on YouTube @BerkeleyNews. New episodes come out every other Friday. You can find all of our podcast episodes, with transcripts and photos, on UC Berkeley News at news.berkeley.edu/podcasts.

(Music fades out)

Gustav Steinhardt (moderator): We have the immense privilege this week to welcome Dr. Jennifer Doudna. Dr. Doudna is the Lee Ka Shing Chancellor’s chair and professor in the departments of Chemistry and of Molecular and Cell Biology. She’s best known for her role in developing the CRISPR-Cas9 gene editing technology. Which since its discovery in 2012, has led to a revolution, as we all know in the biological sciences.

In addition to her role in discovering the technology, Dr. Doudna has also been an active voice in discussion around the ethical and social implications and how it can be used responsibly. She received her BS in biochemistry from Pomona College, and a Ph.D. in biological chemistry and molecular pharmacology from Harvard University. Then served as a postdoctoral fellow at the University of Colorado and a professor at Yale University before coming to Berkeley.

If I were to try to list all of Dr. Doudna’s honors and awards and accomplishments, there would be no time left for her talk, so I’ll just limit myself to a few highlights. She’s a member of the National Academy of Sciences. A fellow of the American Association for the Advancement of Science. And a nobel laureate in chemistry, actually the first woman from our campus to receive that prize.

In her talk today, Dr. Doudna discusses the path that led her from a general interest in RNA and the strategies that bacteria use to defend themselves from viruses to the groundbreaking discovery of CRISPR-Cas9. Please join me in welcoming Dr. Jennifer Doudna.

Jennifer Doudna: Hi everybody. Thank you so much for that warm introduction. And I’ll just say about the Nobel, hopefully the first of many here at Berkeley, right? Yes. Some of you here maybe. Well, it’s a great honor to be here. I’m delighted to have an opportunity to kind of update you about CRISPR-Cas. I did this talk. I forget exactly when it was. It was sometime in the last few years, but boy, things have changed a lot in the world since then in many ways. And what I want to do today is tell you a bit about how I came to this field of science, where I see it going, and the impact that it’s already having on people’s lives in very exciting ways.

This is kind of a quintessential story about Berkeley though. Because really the research that I’ll talk about today wouldn’t have happened I don’t think, certainly not for me if I had been working anywhere else. And that’s because we have a really collaborative environment on our campus. It’s an interdisciplinary campus with people that work in all kinds of fields. But importantly, they talk to each other. So that’s really fundamental to what I’ll tell you about today.

So I’m going to talk about CRISPR and genome editing. I’ll give you just a short introduction to what that is and how it works and how we came to it. I want to talk about CRISPR’s impact in human health. And I want to give you one specific example that’s already an FDA approved therapy for patients. And where I see the field developing from here. And then I want to talk at the end about new things that are happening in the world of CRISPR and things that we’re doing here at Berkeley in the Innovative Genomics Institute to make this possible.

So let’s talk about CRISPR. So back in, probably this is now maybe 15, 16 years ago, I was a relatively new faculty member at Berkeley at the time. And a colleague of ours, Jill Banfield here in the College of Natural Resources, someone I didn’t know, picked up the phone and called me one day. And said, “Jennifer, I understand that you work on RNA and I think I have a phenomenon that I’ve discovered, a phenomenon in bacteria that is RNA-centric and I want to tell you about it. And she proceeded, we met at the Free Speech Movement Cafe, of course, and she proceeded to tell me about a possible adaptive immune system in bacteria that helps bacteria fight off viral infection, like you’re seeing in action right here. Where bacterial cells are being injected with viral genetic material. They don’t have very long to defend themselves against it.

And Jill Banfield’s lab was one of the first around the world to come across signature sequences in bacterial DNA, suggesting that bacteria could acquire DNA sequences from viruses that were infecting them, kind of during this infectious process. Store them in their DNA in their genome in a location known as the CRISPR locus. And then make molecules of RNA from those DNA sequences that could guide proteins to find and destroy those viral DNAs if they showed up in the cell.

And so what happened next was that we started to research this in our lab. We’re biochemists, we study the way molecules work. Where we’re also chemists and we study the chemistry of life. And so by investigating the molecules that are responsible for this adaptive immune system, we came across a pathway that was really, truly remarkable. Nobody knew that bacteria had the ability to learn about viruses that are infecting them. Store that information in what’s effectively a genetic vaccination card, and then use that information for protection.

And I want to show you just kind of the summary of all of this. So once we had that info, we’d figured this out how it works, we realized that these same molecules that are used in bacteria for immunity for protection against infection could actually be deployed very differently in plant or animal or human cells to trigger DNA repair. And in doing so, we could induce targeted changes into genomes in a way that allows scientists to rewrite the code of life. So let me show you a short video that illustrates how this works.

So here we are zooming into a eukaryotic cell, like a plant or animal or human cell where the DNA is packaged inside the nucleus. And what CRISPR-Cas9, the protein here in purple and its RNA guide, the green molecule, are doing, are searching through the genome to find a 20-letter sequence in the DNA, that matches the sequence of the RNA molecule. And when that match occurs, this protein is able to unwind the DNA. It forms a duplex with the RNA guide. That’s what triggers DNA cutting. And once that double-stranded break occurs in the DNA, the broken ends of the DNA are passed off to repair enzymes that can detect the break and fix it. And in the process of fixing it, introduce a small or sometimes a larger change in the DNA sequence.

Now, this is quite interesting because it’s different from what happens in bacteria. In bacteria, double-stranded DNA breaks like this trigger DNA degradation because the cells are growing very fast and they have to copy their DNA very quickly. They don’t have time most of the time to fix it. But in our cells and in plants and animals that grow much slower, there is time to fix double-stranded breaks in DNA. And as many other people in the field before us had realized, if you could introduce double-stranded breaks to DNA, you could trigger targeted repair. And that’s really where CRISPR comes in. It’s that tool that makes the breaks.

And really importantly, what makes this a powerful technology is that it’s programmable. That’s what bacteria do. They program Cas9 to find different RNA, to find different DNA sequences in viruses. Once we understood how that programming works with these RNA molecules, we could change the RNA sequence to match any DNA sequence that we might want to target in any type of cell. And so we published that research in the summer of 2012, and our lives changed forever at that point. Because we now have a tool that empowers science and clinicians to make targeted changes in DNA that allow all kinds of interesting research. But also various applications that I’m going to tell you about.

So there’s wide-ranging potential, not only in fundamental science in terms of understanding the function of genes, but also making changes to genes that cause disease. So for medical applications. Also changing genes that are controlling all kinds of the properties of plants and bacteria that are important in our environment. And again, I’ll talk to you a little bit about some of the applications that are already happening with CRISPR, and some that are coming in the future with this. And I just want to point out here that if anyone is curious about the details of how these enzymes work and how people are already deploying them, I would refer you to a website that the Innovative Genomics Institute put up recently called CASpedia that tries to collect all of this information.

There now are dozens of papers that are published every week about CRISPR and using it, and finding new types of CRISPR enzymes and testing them. And so we try to capture a lot of that information here. And we do it with a large cohort of students and post-docs that volunteer their time to read the literature and update this site. And we’d love your feedback. So if you use it, please let us know if it’s useful or if there are other features that you would like to see.

And as you heard it briefly in the introduction, one of the things about CRISPR, and frankly really about any powerful technology, is that along with incredible benefits and opportunities comes potential risk. And that was something that we recognized very early on in the field. We organized the first meeting in early 2015 here. We organized the meeting at Berkeley. We held the meeting in the northern California area. We brought in 20 scientists from around the world who could appreciate the potential risk of using CRISPR, especially in the human germline. Meaning for editing embryos. And that has led to a now longstanding tradition of global meetings about the safety and responsibility that we have with CRISPR.

This is a report that was produced a few years ago by the National Academies of Science in the US, in the UK, and in China. And these meetings now are held every other year to address the ongoing challenges of handling and managing such an important and powerful technology as genome editing. But I want to now turn to an actual use of CRISPR that I think is really exciting because it illustrates the power of the technology and the potential of the technology to transform people’s lives. And also as I’ll show you some of the challenges that still lie ahead.

So I want to talk in particular about the use of CRISPR to correct a disease-causing mutation. In this case, a mutation that causes sickle cell disease. So sickle cell disease is one of the best understood of the human genetic diseases. It’s a disease caused by a single base pair change in one gene of the human genome. And when that base pair mutation occurs, it’s in a gene encoding a protein important for carrying oxygen in our blood. It’s the fetal hemoglobin… It’s the adult form of hemoglobin. When that base pair change occurs, it causes a disruption, the structure of that hemoglobin protein. And as a result, it produces cells that are sickled in shape, and they tend to block blood vessels. They tend to lead to organ damage over time in patients that have this affliction. And those people, although they can be a diagnosed up until CRISPR came along, there was no way to cure them of their disease. They had to experience blood transfusions typically every few weeks, with hospitalizations incredibly disruptive to their lives.

And I just want to also mention that you might ask, well, why has a mutation like that been maintained in the human population? And we think it’s because in people that inherit one copy of the sickle cell gene, they don’t have sickle cell disease, they actually have protection from malaria. And so we find that if you look globally at where the sickle cell mutation occurs and what human populations, it tends to be more abundant in areas of the world where malaria is an endemic disease.

Unfortunately, when somebody inherits two copies of the sickle cell gene from mom and dad, then they do have sickle cell disease and they suffer from this disorder. So one of the really interesting things about CRISPR is that, this is my own personal experience with this. Is that this technology has really brought together a lot of different threads of research that we’re going on in lots of labs around the world, initially completely independently. And I want to just use a couple of slides to talk about the backstory to understanding sickle cell disease. And that quest to understand the disease really led to the question of, how is hemoglobin protein production regulated in humans? And how does it change over time between the time that we’re a fetus, a developing fetus to when we’re born and we’re growing up into an adult?

And so this is a chart that just shows that something that’s very interesting. I actually teach this in the Bio IA course that I teach here at Berkeley. Is we talk about the fact that hemoglobin is made of two different types of proteins. And when we’re fetuses, those two proteins are called alpha and gamma. Gamma globin is fetal hemoglobin. It has a higher affinity for oxygen because it needs to pull oxygen from the mother’s blood and help feed the tissues in the fetus. But after birth, the production of fetal hemoglobin drops off, as you can see in this chart here in the blue curve. And instead, we get activation of a gene encoding the beta globin protein, which is part of adult hemoglobin. And so I’ll just refer that to that as adult hemoglobin. And so that’s the normal process.

Now, if this happens in somebody that has sickle cell, when they start producing beta globin, they’re making a sickle form of this protein. And that’s when they start to experience the symptoms of sickle cell disease, typically not too long after birth. And so that’s what’s shown here. And the other thing that’s very interesting is that scientists like Stuart Orkin, who is a professor at Harvard Medical School, years ago, asked the question, how does that regulation work? And he started investigating what is it that controls the production of fetal hemoglobin? What turns it off when we’re born? And interestingly, what maintains fetal hemoglobin production in a very small number of people in the population who naturally produce fetal hemoglobin as adults.

And what he found is that there’s a protein called a transcription factor known as BCL-11A, complicated name. This is a protein whose job is to turn off the production of fetal hemoglobin. So normally this transcription factor is binding to DNA, it’s binding to the gene that’s responsible, that encodes fetal hemoglobin turning off production of that protein right around the time of birth. And so this knowledge then, imagine sort of that backdrop to the emergence of CRISPR genome editing. This was sort of the light bulb going off saying, “Aha, if we know how fetal hemoglobin is turned off. Suppose we could disrupt the production of this transcription factor and turn back on the production of fetal hemoglobin? That could be a way to override the effects of adult hemoglobin that’s in the sickled form.”

And so that was exactly the strategy that a group of scientists, some at a company and some in academic labs teamed up to do. And they designed a version of CRISPR-Cas9, which is shown here. And I sort of have to laugh when I see this cartoon because it’s almost exactly what we had drawn up on our whiteboard here in the lab at Berkeley many years ago, when we were thinking about how this actually works. And what was done is to design a form of the guide RNA for Cas9 that recognizes a sequence in the human genome corresponding to the binding site for factors that allow expression of BCL-11A.

And so when we make Cas9 as a complex that can recognize this part of the DNA, it makes a disruptive change to the DNA. That’s the editing that occurs. It turns off production of this transcription factor. And as a result, fetal hemoglobin is reactivated in cells that receive that type of editing. And this is just showing you the details over here. Really, again, emphasizing that by understanding the details of how this protein works, how to design guide RNAs that would trigger the kind DNA cutting that could induce a change like this was critical, to being able to deploy it for a very specific application in the clinic.

So how is this actually used in patients? And so this is a cartoon that shows how the sickle cell therapy is applied. And the idea is that patients who have sickle cell disease can have blood stem cells taken from their body. Those cells are cultured in a lab dish, where they can receive the CRISPR-Cas9 protein with its RNA guide targeting BCL-11A. And the editing occurs in these cells, reactivating production of fetal hemoglobin. And after those edits are checked, and we’re sure that the editing was done correctly. And fetal hemoglobin is being produced in these cells. These are stem cells, they can be put back into the patient where they repopulate the bone marrow and they start making cells that are now effective at carrying oxygen. And overriding the mutation that causes sickle cell disease.

Does this work? It sounds complicated maybe. The answer is it works incredibly well. So this is a picture of Victoria Gray, two pictures of her. She was the first US patient to receive this therapy now almost six years ago in a clinical trial. And this is a picture of her taken about a year and a half ago at a conference in London where she was a spokesperson for the patient community who are benefiting from this therapeutic. And what’s remarkable is that her sickle cell symptoms have not returned since she received a one-time treatment with this therapy. So it’s truly remarkable.

I’ve talked to her, she explained to me how her life completely changed for the better after receiving this therapy. And so she’s become a really active sort of patient advocate in the community, helping other people who might benefit from this therapy to understand what it’s all about, how it works, and whether it might be right for them.

So what happened next? Well, this was that research and the clinical trial that she was part of, concluded about maybe three years ago now. And it underwent a Food and Drug Administration review. And the FDA actually approved this therapeutic now in going back to December of 2023. And at the same time, there was an approval in the United Kingdom. So there’s now an actual clinical therapy, using exactly the same enzyme that many years ago we had started investigating here at Berkeley. So it’s really remarkable to see that almost direct line between very fundamental, curiosity-driven research leading directly to a clinical application in people. So super cool.

So are we done? We can all just say, “Oh, good, well, got that done. I’m going to go do something else now.” Not quite, because there are some very important challenges that lie ahead to ensuring that this type of therapy can be effective and accessible not only to anybody that wants to get it who has sickle cell disease. But also to people that might have any other type of rare disease where again, CRISPR could be incredibly helpful. And in the future, I think also to much more common diseases that we could potentially use CRISPR to help protect us from.

So what are the challenges? Well, two big ones that I’m listing here. One is cost. So right now the cost of that approved sickle cell therapy is about $2 million a patient. So it’s a lot of money, and it’s clearly going to mean that most people globally that could potentially benefit from this are not going to get access. Why is it so darn expensive? Well, one of the reasons is that it’s very hard right now to deliver CRISPR into these blood stem cells. So I described how it’s done currently where those cells are taken out of a patient, they’re edited in the lab, and then they’re transplanted back into the patient. Well, that transplant process involves a bone marrow transplant.

And if you know anybody that’s gone through a bone marrow transplant, and I do, it’s a very unpleasant procedure and it takes many weeks of hospitalization. It’s very expensive, very unpleasant. And so wouldn’t it be great if we had a way to deliver CRISPR molecules in a targeted fashion in the body? We call that in-vivo, without requiring such an arduous and very, very expensive procedure. So that’s something that we think about a lot right now. In both in my lab, but also with our collaborators and at our institute, the Innovative Genomics Institute.

And in just a few slides, I want to just tell you briefly about what we’re doing to address this challenge. Namely, how do we edit cells in vivo? How do we get these editing molecules where they need to go and get them to do the right thing to make changes to DNA that can be beneficial in a patient?

So back to this cartoon. So we sort of took a step back and said, “How would we imagine being able to do something like that? And are there any examples in biology where molecules are delivered in a targeted way in the body into specific kinds of cells or tissues?” And so if you’ve ever been infected with a virus, which probably everybody here has been at some point or another. You’ve had a cold or you’ve had the flu or you’ve had COVID, then you’ve been infected by a virus. And so that viruses are actually very good at doing that, right? That’s what they do. They target respiratory cells, they target cardiac cells, they target brain cells depending on the type of virus that we’re talking about.

And so we started thinking, what if we could learn from the machinery of viruses and harness that machinery to deliver not a viral genome for an infection, but deliver CRISPR molecules for gene editing? And this was the work of a wonderful former postdoctoral scholar in our lab, Jenny Hamilton, who came to my lab a few years ago with a background in virology. Who started to really work on this and ask these questions. So what I’m showing here are just two very general strategies for molecular delivery. And by the way, this is not just for CRISPR, but we could use this approach for delivering any kinds of molecules in the body.

You probably know that viruses have been used for various kinds of therapeutic delivery. So we can deliver molecules that are encapsulated in an actual virus, which comes with pros and cons, right? Those viruses can be very effective at delivery, but they can also cause an actual infection. Sometimes they cause integration of genetic material into the genome. You might not want that. So that’s the situation with viral vectors. And then we can imagine, or we actually have access to various kinds of non-viral delivery methods that involve either direct chemical modification of molecules.

So they go to particular types of cells or using things like lipids. If you’ve heard of lipid nanoparticles, like if you’ve had the COVID vaccine, you would’ve had lipid nanoparticles that are delivering molecules into tissues. So these are non-viral types of strategies. And so Jenny’s question was, “Could we simply combine these and deliver pre-assembled CRISPR-Cas9 guide RNA molecules by using a package that looks a bit like a virus, but doesn’t have the downsides of using an actual virus for infection?”

And I’ll just very briefly describe the idea here. And I want to show you one piece of data that got us very excited. So the strategy that Jenny and her lab mates took, Connor Sushida was also involved in this project originally. Was to ask whether we could change the way that these viral particles are put together. And this is a cartoon that shows the way that these particles, which she started calling enveloped delivery vehicles, or EDVs, can be put together so that they are themselves programmable. So we can control which kinds of cells they get into.

And so the idea was to combine on the surface of these particles, two different kinds of molecules. We have molecules shown in gold that are called fusogens. So they’re capable of fusing these particles with cells. And again, that’s just exactly what viruses do. Except Jenny started using a, what we’re calling a mutant or mute form, mutated form of this fusogen derived from a virus that has the ability to fuse. But it doesn’t have the ability to bind to a particular type of cell.

And to provide that specificity, the second molecule shown on the surface here in blue are molecules that have on the surface a part of an antibody. So they provide the targeted recognition of molecules that we find on particular cell types in the body. And that means that by changing this antibody here in principle, we could direct these EDVs to lung cells, to blood cells, to immune cells, to brain cells simply by changing the identity of that single chain antibody.

That was the concept. And importantly, as I mentioned before, the interior of these particles was also redesigned by Jenny with knowledge of how viruses are put together to ensure that we could encapsulate the CRISPR-Cas9 protein and its guide RNA, rather than any kind of viral DNA or RNA molecules.

And I just want to show you one experiment. So this is now an experiment that Jenny did. We published this work last year. But it got us very excited about the potential of EDVs to allow in vivo editing. And I’ll just walk you briefly through the data, or let me just describe the experiment. So the idea here is to use what’s called a humanized mouse. So these are mice that have their own immune cells ablated, and they are transplanted with human immune cells. And those cells T and B cells populate the mouse. And that means that we can then target those cells with EDVs that are designed to target human immune cells. And in this case, targeting human T cells.

And then you may have heard of a therapeutic approach called CAR-T cells. This CAR stands for chimeric antigen receptor, long word acronym. Fundamentally, what it just means is that this is a T-cell whose T-cell receptor. The molecule that allows it to bind to a foreign cell and kill it off, for example, has been redesigned to recognize a particular type of receptor. And so, the question that Jenny was asking in this experiment was, could we actually generate these kinds of reprogrammed T-cells, CAR-T cells in this humanized mouse model using EDVs to deliver genome editors that would trigger that targeted change?

And these are control experiments over here. I really just want to draw your attention to one graph and one piece of data that drew our attention and got us very excited. And that was that when this experiment was conducted, EDVs with CRISPR-Cas9 were injected into these animals once. One-time injection. Targeting human T-cells that were in these animals. Jenny found that compared to a control reaction using a virus which goes randomly into random cells and integrates randomly into the human genome. She found that targeted precision genome editing editing happened only in the T-cells in these animals that had been treated with the Cas9-carrying EDVs.

And so even though the efficiency was modest, about 1.5% here of the cells had been modified. That was the piece of data that made us think we’re onto something here. We’re onto an exciting direction of how we can understand the way viruses target cells and harness that knowledge to allow targeting of other kinds of molecules like genome editors. And since then, this has led to a really a big effort now in our lab, in our institute, and in companies that are also building teams to focus on this type of strategy. To allow targeted editing in all kinds of different tissues of the human body, in ways that we think could really open up the accessibility and affordability of CRISPR technology in the long run.

And this is just, I wanted to just show you a couple of slides that illustrate where sort of in the bigger picture this is all going. So we imagine getting to a point where there’s a much shorter therapy duration. So, instead of CRISPR therapeutic taking a year of delivery when you count the time spent preparing and then going through the bone marrow transplants procedure and then recovering from it. Imagine that the duration was a week. And within a week a patient could receive a one-time treatment that was curative for their disease.

And furthermore, imagine the cost was $50,000. We’d love to get it down to $10,000, right? We’d like to reduce the cost of manufacturing the molecules that are necessary. Reduce the number of those molecules that we need to use. And make sure that the editing is done so precisely that we can be very confident that this type of editing will be effective for disease. And that’s, again, it might sound like a tall order, but amazing progress is being made on these goals. It’s incredibly exciting to see the momentum and the progress that’s been made.

So I wanted to point out a couple of things that I think are very interesting to folks. Especially thinking about how a university like Berkeley, which doesn’t have a medical school, is able to directly contribute and participate in applications in clinical medicine. And so what we did, and so the IGI stands for Innovative Genomics Institute. We teamed up with our colleagues and our at two other UC campuses, UCLA and UCSF. We had colleagues on both of these campuses, which both have medical schools that were working with sickle cell patients. They were very familiar with the disease phenotype, and they were also very excited about the potential to treat their patients with this new strategy.

And so we ended up getting an approved investigational new drug, or IND, from the FDA. Allowing us as academics to proceed with a clinical trial for sickle cell disease using our CRISPR-Cas9 therapeutic strategy. Why would we do this when there’s already an approved therapy that a company is making? Again, our goal is to reduce the cost and ultimately make this much more widely available. I fundamentally believe in this. It’s the right thing to do, and it’s what a public university should be doing. And so this is what we’re doing. And so we’re now enrolling our patients and working with this team to figure out how to advance sort of the next generation of CRISPR therapies that will ultimately be much more affordable.

And this is again, just showing that we’d love to reduce the amount of time and the cost, which is currently very high to something much more reasonable. Now, something I didn’t mention that is going to be incredibly important in all of this is thinking about how a therapy like this is regulated. So you probably know that the Food and Drug Administration in our country and equivalent organizations elsewhere in the world are responsible for ensuring that therapies are safe, first of all, and effective. And so we think that there’s a really interesting opportunity to work with the FDA in the United States on a way to turn CRISPR into what they would define as a platform.

And this means that we have a therapy that is based on the same protein. So you can imagine CRISPR-Cas9 that same protein, it’s used in bacteria. We can use it in plants, we can use it in sickle cell patients. We think we could use it in lots of other kinds of disease treatments. The very same protein. The only thing that would change is the RNA molecule that guides it to a particular place in the genome. So our strategy right now is to work with the FDA and including many other colleagues, to educate everybody about how this works and the safety of changing the guide RNA to a different guide.

And by the way, increasingly machine learning is helping to predict the guides that are going to be safe and effective. So that’s a technology that’s coming to play here as well. And defining CRISPR ultimately as a platform where a change in the RNA guide would be defined by regulators as the same therapy. It would have to go through a very streamlined clinical testing process, but not the current very arduous and very, very expensive process for each new iteration of CRISPR-Cas9.

So this is very exciting, and we’ve been working with folks at the FDA. That’s a little bit in flux at the moment because the FDA personnel have been changing. But fortunately with the Innovative Genomics Institute and our clinical partners, we have a lot of momentum. And there’s a lot of desire on the part of many people to see this come about. Because we can all see the potential of this technology if we can just make it easier to test it and ensure safety and effectiveness in patients.

And I’ll just sort of leave you with a couple of ideas. I want to point out that we constantly think about the number of people that ultimately could benefit from something like this. I still hear pretty much weekly from people around the world that are affected by genetic disease in their family. Often it’s their children who are affected. And I dream of the day when we can quickly and easily just reformulate CRISPR for that mutation and provide an effective therapeutic. It would be extraordinary. There’s no reason technically why we cannot do that. It’s simply now a question of making it happen.

And then I did tell you that I would highlight sort of where this is all going in the future, and I just want to leave you with one, I think very exciting possibility. And that is that we start to think about impacts of CRISPR elsewhere across the world in human health, but also in the health of our planet. One of the areas where we appreciate that CRISPR could be really impactful is in modifications to microbiomes. So microbiomes are the collections of bacteria that populate our bodies, our soil, our environment, and also the guts of animals like cows. And when they’re in cows, what they do is they make methane.

And methane is a very powerful greenhouse gas. It turns out that a lot of the greenhouse gas emitted around the world, about a third of the global methane emitted around the world comes from farmed animals like cattle. And so our current team at the Innovative Genomics Institute. And by the way, this is a really exciting partnership with UC Davis, who just became a formal partner of the IGI. Is to target CRISPR in the cow rumen microbiome to tune down the genes that are responsible for production of methane. And shift the energy balance from making methane to making more milk or more meat. And we know this is possible from our collaborators work. We just now need a sustainable way to do it, and we think that CRISPR will offer that opportunity. So please stay tuned. We have an incredible team of young investigators at IGI that are working on this, and we think that it’s going to be transformative.

So I’ll just conclude. I want to leave time for some questions, but I just want to point out that we’re really now in an era of programmable genome editing. It’s really exciting to see all the possible applications of this. We know that it can be safe and effective to treat and even to potentially cure human disease. And we need to continue to advance the technology so that it can be deployed more widely. And that’s going to require continual activity, not only on the science and technology front. But also thinking about the appropriate guidelines and regulation of this. And ensuring transparency, especially for things like applications in human embryos, which is coming, and we have to be ready for it. We have to ensure that those applications are moving forward responsibly.

So I’ll close there. I want to thank an incredible group of people here at Berkeley. It’s a joy to come in every day and work with these amazing students, post-docs, technicians who are doing the work that I talked about in my lab. And then of course, we have a great team at the Innovative Genomics Institute. We’re located right on the corner of Oxford and Hearst. So come visit us, and I’ll take questions. Thank you. I think there are mics coming around too, if people want to raise their hands.

Audience 01: What’s your opinion on scientific exploration into mirror life?

Jennifer Doudna: Yeah, so great question. Yeah, so he’s asking about something that is not CRISPR, but we’ll answer it anyway. So there was a paper that came out not too long ago from a group of scientists concerned about what’s called mirror life. So imagine that we could take DNA and proteins which have a handedness to them and flip it. And then you could have a kind of mirror form of life in which enzymes would be impervious to the kind of degradation and regulation that happens normally in biology. I think it’s a danger, and I think that I fully agree with the article that came out recently advising caution.

Audience 02: Hi, thanks for the talk. I wonder if there’s any current work being done on Huntington’s disease?

Jennifer Doudna: There is, yes. And that’s actually one of the projects that we’re working on currently at the Innovative Genomics Institute. It’s an NIH-funded project, so hopefully that will go forward. But you’re asking about a disease that is really devastating. For folks here that may not know about it, it’s a neurodegenerative disease. It has a single gene that causes the disease, so kind of analogous to sickle cell disease. And to treat it, we know we can do it in the lab, you know, treating Huntington’s-derived cells in the laboratory. But to treat a patient, we need to get the gene editors into the brain. So that’s the current focus is how to deliver to those cells in the brain. Hi.

Audience 03: Hi. Thank you for the talk. As CRISPR evolved as a form of adaptive immunity against viruses and bacteria, what possibility would CRISPR have as a therapeutic against infectious diseases in humans?

Jennifer Doudna: Yeah, great question. So in humans, I think that there’s a couple of possibilities. One is that you could imagine targeting bacterial infections in humans by delivering some form of CRISPR that would be destructive to those cells. One of the things that I didn’t tell you that’s also very interesting about CRISPR biology is that these are systems that adapt really rapidly. So I think that one of the challenges with directly targeting bacteria with CRISPR is that they could quickly adapt away from it, and sort of evade it.

So I think an alternative as actually to go back to the idea of programming human T cells, like I mentioned, right? So I think one of the things that’s very interesting to me is the possibility of programming human T cells to be ready for future pandemics. And that’s one of the things we’re working on with some partners at UC, San Francisco. Is to explore, again, using machine learning, predicting what kinds of viruses are potentially going to evolve in the future? And how do we proactively protect against them?

Audience 04: Hi.

Jennifer Doudna: Hi.

Audience 04: Thank you for the talk. And I’m really curious, where are the modifications that people have done to the CRISPR system to mitigate its risk and allow it to be helpful to so many people?

Jennifer Doudna: Right. So modifications, so a couple things. First of all, lots of research over the last decade has gone into understanding how accurate it is, right? And so some of the modifications now are in ways that make CRISPR even more precise than it was previously. The other thing that people are exploring is its immunogenicity, because it’s a foreign protein. So you could imagine that it might trigger an immune response, and we know that it can do that. And so there’s been a lot of efforts to try to mitigate that, or find ways around it. But I have to say that so far, neither of those things have been real bottlenecks in the application of CRISPR. I think it’s really more about delivery right now.

Audience 05: Yeah. Thank you. I’m just wondering, given the state of federal funding… I’m over here.

Jennifer Doudna: Oh, thank you. Oh, thank you. Sorry. Yeah.

Audience 05: How feasible is it for you to continue this work without cooperation or funding from the federal government or even interference?

Jennifer Doudna: Right. Well, I have a couple of comments there. First of all, we’re fortunate that we have a number of non-federal sources of funding, so that’s very important. And we’re incredibly grateful to donors that are supporting some of this work. Their vision and their commitment is truly remarkable and incredibly important.

That being said, I do encourage everyone here that cares about this and thinks about this to contact your members of Congress. And to just emphasize to them how important it is to each of us that taxpayer money is used for science. I mean, it can’t be said enough. It’s incredibly important.

Now, we had a visit recently from Congressman Liu and Congresswoman Simon recently at the Innovative Genomics Institute, who both came to talk to us about NIH-supported research. And what was amazing to me is that neither one of them… and I think they’re both in favor of supporting the NIH and the NSF and other federal sources of funding for this type of research. But they did not have awareness of all of the ways that those sources of funding support a campus like this, right? And so we helped to help them understand that.

We introduced them to students that are on training grants, for example, that are paid by federal funds. And it’s very, very important that I think each of one of us do our part to communicate that. If we don’t speak up, then no one thinks we care. Right? So we have to speak up.

Audience 06: Hi. Oh, hi. Thank you so much for the talk. As we know, accumulation of micro- and nano-plastics has been an issue, and is becoming an even larger issue for both humans and the environment. In terms of photosynthesis and gut microbiomes, for example. Can CRISPR help us? Are there any applications for us to become more resistant to these genomic disruptions that microplastics can cause?

Jennifer Doudna: Can CRISPR help with genomic disruptions coming from microplastics? I think is the summary of your question. The short answer is not in a direct way. But I think that what I’m seeing probably potentially more impactful there is work to design bugs that are capable of metabolizing plastics. I think that’s a very interesting area of biology. We’re not working on it at IGI because we have too many other things we’re doing. But it’s exciting to think about, and I think CRISPR could help with that. Yeah.

Audience 07: In sickle cell, when the treatment, the Cas9 treatment causes the reversion to producing fetal hemoglobin, is any malaria immunity maintained? And if not, would there be a way to have both/and?

Jennifer Doudna: It’s a really interesting question. I don’t know the answer to that. But it’s possible that with the way this therapy works, it would be maintained. Because the protection from malaria comes from the production of that sickle form of hemoglobin. And it could be that enough of that is maintained in those cells that you get protection. I don’t know if that’s true, but I think it’s a possibility. It’s not an easy thing necessarily to test, right? You certainly can’t really test it in humans. You could maybe do an epidemiological study over time about this.

But you bring up a really interesting point, and that is that in the broader applications of CRISPR, we do have to think about trade-offs, right? When you make a gene edit, you might be removing something you don’t want or turning something on that you do want, but that could have unintended consequences. So it’s just something that we have to keep in mind. Yeah.

Audience 08: Hi. Amazing work and very inspiring to see also all of the future applications that you are working on, other people are working on. We’ve seen the microbiomes, and we’ve seen agriculture delivery. If from any of the future applications, you choose one, or perhaps there’s one that you’re thinking of, but that’s not as realistic or in sight yet, maybe even a wild dream. What would you say is the future of CRISPR?

Jennifer Doudna: Well, I have to say that one thing I think about a lot, and it is farther off in the future, but it’s a really interesting possibility, is that eventually CRISPR is used for genetic vaccination. And what I mean by that is suppose that you can imagine a time in the future when all of us have our DNA sequences in hand. We know what’s in our genomes. Therefore, we know some of the diseases we might be more susceptible to, like Alzheimer’s or cardiovascular disease. And I imagine that we could tune genes that are making us susceptible to those kinds of things early in our lives so that we don’t have to worry about them in the future. I think this would be very exciting.

There actually is already a commercial approach to the cardiovascular side of things. Where they’re using CRISPR to reduce cells that are producing molecules responsible for high cholesterol in patients, or just in anybody, really. And so if that goes forward, that really could be potentially the first kind of protective or prophylactic use of CRISPR. But it might not be the only way to use it that way.

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Anne Brice (outro): You’ve been listening to Berkeley Talks, a UC Berkeley News podcast from the Office of Communications and Public Affairs that features lectures and conversations at Berkeley. Follow us wherever you listen to your podcasts. You can find all of our podcast episodes, with transcripts and photos, on UC Berkeley News at news.berkeley.edu/podcasts.

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