Homeroom with Sal & Dr. Jennifer Doudna - Wednesday, January 13

Hi everyone, Sal Khan here. Welcome to the Homeroom with Sal livestream. We have a very, very exciting conversation today with Jennifer Doudna, the 2020 Nobel Prize winner in Chemistry for what has often been described as one of the most important discoveries in the history of biology or maybe in the history of science. And we'll talk about why that is. It could actually forever change what it even means to be human.

But before we go into that, I will give my standard announcements. Reminder that we are a not-for-profit, Khan Academy. So if you're in a position to do so, please think about going to khanacademy.org/donate. Donations of all sizes make a huge difference.

Also want to give a special shout-out to several organizations that stepped up, especially during COVID when they realized more people were depending on us and we were running at a deficit. Special thanks to Bank of America, AT&T, Google.org, Novartis, Fastly, and it was just announced yesterday, General Motors, for their very, very generous support to allow us to help millions of y'all keep learning in this year and last year.

Also want to remind you that there's a podcast version of this livestream wherever you get your podcast, "Homeroom with Sal," the podcast. With that, I'm very, very excited to introduce Jennifer, who is the Lee Kashing Chancellor's Chair Professor at the Department of Chemistry and Department of Molecular and Cell Biology, and you have a very long title—Department of Solid Molecular Logic at the University of California, Berkeley. You got the 2020 Nobel Prize in Chemistry for your work with CRISPR.

Thank you so much for joining us.

Jennifer Doudna: Thanks for inviting me, Sal. Great to be here!

So for those of you watching who have not heard of CRISPR, this will be, I predict, 100 years in the future, all of the other craziness of 2020 will kind of not be remembered as much as the work that Jennifer and her colleagues have done over the last several years in CRISPR. Jennifer, you know, for those who are unfamiliar with it, what’s kind of the headline or the cliff notes version of what CRISPR is and why it's important?

Jennifer Doudna: Well, I guess I would start by saying it's a technology for genome editing. What does that mean? Well, it’s a tool that scientists are using to make precise changes to the DNA in a cell or a whole organism that can lead to alterations in the genetic makeup of the cell or the resulting organism.

So we—ah, you got the video here—we're seeing the CRISPR system in action. So it’s a protein, that purple blob with a little zip code molecule in it, a piece of RNA that allows binding to a 20-letter sequence in the DNA of a cell. And so you can see the guide RNA marking the site and then DNA getting cut. That's the key activity of CRISPR. And what that does is induce a DNA repair pathway in cells that allows cells to alter the DNA sequence at that precise position. In the example we just saw in the video, there was insertion of a new piece of DNA that could allow cells to acquire a new gene or even a new set of genes. This is all now being controlled by scientists, so we can manipulate genes in ways that were previously very difficult or impossible.

Yeah, and for those watching who didn't fully appreciate how powerful some of what you just said is, you know, obviously our—I mean we're living systems—everything else is, you know, all living systems have DNA. And you know, you have these long sequences of DNA—parts of them, those are individual genes that can code for proteins or sets of proteins—and now using CRISPR, you all have introduced a technology that can help us edit DNA.

You know, before I go into all of the implications—positive and potentially, you know, ones that we have to wonder about—I’m curious about how your pathway to discovering this was. When did it first dawn on you that something like this could happen, and how hard or easy was it to get to the place that you got to?

Jennifer Doudna: Well, you know, Sal, what I love about CRISPR, one of the things, is the origin story. Because this is really a technology that came out of a fundamental curiosity-driven project. It was small science, not big science; it was science being done by a handful of laboratories.

And in our own lab at the University of California, Berkeley, we were investigating CRISPR, which was originally discovered to be a bacterial immune system—a way that bacteria can detect and destroy viruses. When I heard about this from my colleague, Jillian Banfield at Berkeley, probably a dozen years ago now, I was fascinated. I wondered, well, how does that work? And so we began investigating it.

People have known about CRISPR for some time—if this, you know, it stands for clustered regularly interspaced short palindromic repeats—but really what that is is these bacteria would have these sequences of what would be DNA or RNA, and it would have pieces of kind of ancient other viruses in it. And so it would use those as kind of that tagging location sequence the way that you just described in that previous visual to kind of cut viral DNA. Is that what it was doing?

Jennifer Doudna: Yes, that’s right. And by the way, not necessarily ancient pieces of virus either. This is a system that works in real time. So during an infection, a bacterial cell could acquire a DNA sequence from a virus and then use it as the template to make a guide RNA molecule that allows this kind of searching that you're seeing going on here by the Cas9 protein. So this is a system that started as a fundamental biology project, but once Emmanuelle Charpentier—our collaborator and our lab—figured out how the Cas9 protein works as a DNA cleaver, we could see how it could be harnessed as a genome editing technology. And that’s really what's taken off over the last eight years.

When did you first learn about CRISPR and that these bacteria were using it in order to be a viral defense mechanism? And it dawned on you that, hey, maybe that could be used to edit DNA. When was this, and how long before you started making some significant progress on that?

Jennifer Doudna: I think I first heard about CRISPR in the mid-2000s from Jillian Banfield at Berkeley, who was researching this in bacteria. She was looking at DNA sequences in bacteria. She was one of the first laboratories to realize that bacteria were acquiring DNA and storing it in their own genetic material in real time in response to viral infections—a fascinating observation. At that time, it was a hypothesis that this might be some kind of immune system, and that's really where we got involved.

Initially, you know, were you like this is like a five percent chance of this actually leading to anything? Did people think that you were kind of, you know, going down a wild goose chase, or was it apparent pretty early that, no, this is a big idea?

Jennifer Doudna: A little of both, I guess. You know, I certainly felt like it was a very interesting biological phenomenon that I wanted to pursue. At the same time, I was a little bit nervous about, you know, using biomedical research funding to work on this because it wasn't entirely clear where it was headed in terms of ultimate outcomes. I can remember getting a few strange looks at scientific meetings when I first began talking about our work on CRISPR because at that time, almost nobody had heard of it, and it sounded like a real niche area of biology.

What was the moment when you said, "Oh my God, this works"? I'm sure you know one of my favorite papers, which I'm sure you're very familiar with, is Watson and Crick's paper where they found the structure of the double helix structure of DNA. It's a one-and-a-half page paper. At the end they say, I think they say something like, “It has not passed our attention the implications of this work.” When was that moment for you? When did it happen, and what did it just feel like, and how did you know that you'd kind of gotten to something?

Jennifer Doudna: Well, it was somewhat of a continuum, I would say. You know, towards the end of the 2000s, we were working on various different aspects of the CRISPR system in bacteria, mostly doing biochemical experiments in the lab—meaning working with purified proteins and RNAs and DNA molecules to figure out the chemistry of how they work together. And then, you know, that work really culminated in the work that we published in 2012, where we described the way that the Cas9 protein works as an RNA-guided molecular scissors that can cut DNA at a desired place. Importantly, we as scientists could control where the cutting happens by programming it with these molecules of RNA. I think for us, that was really the publication where we were able to point out that this could be used as a gene editing tool.

And I just want to make sure I understand that. Actually, could you move over a little bit? I think to the right—your camera’s much better, much, much better. You know, just to make sure I understand what makes the science so—it makes sense to me that you have this kind of protein-enzyme complex that has a strand of RNA on it, and that RNA can find the complementary part of DNA and then this protein is able to cut there and maybe in another place as well, maybe based on another RNA strand. How do you insert? Is that—I mean, in that visual we saw, there was that step where—does the DNA just kind of float in? If you put the right enzymes, it'll attach? How does that insertion work, or was that part easy? Did people already know how to do that?

Jennifer Doudna: No, that part is not easy, and in fact, that's a great question, Sal, because it really gets to the heart of this technology. Because importantly, CRISPR is a cutter; it’s a cutting technology. And the actual genome editing happens in the cell when the cell uses its repair proteins to fix the broken DNA. So in that example that we saw, that illustrates how in a cell, a broken piece of DNA could be repaired by inserting a new section of DNA. There are whole sets of proteins in cells that are responsible for that kind of chemistry, and in truth, we don’t fully understand, you know, how to control that reaction in the cells. But we know that cells are very good at detecting broken DNA and fixing it. And there are different ways to kind of try to, you know, encourage cells to do the DNA repair in a particular way, such as inserting a section of DNA to make that kind of desired genome edit.

You know, the thing we always like to emphasize, you know, whenever I make a video on chemistry or biology at Khan Academy, you know, in textbooks they kind of make you believe that these proteins have brains of their own and they know exactly where to zero in on. But these are these, you know, thermodynamic chemical systems where things are just constantly vibrating and colliding with each other, and some of those collisions stick if the right kind of things can get close enough with not too much energy to the right things, and enough energy too sometimes. And so it’s all this random stuff happening.

And so yeah, I definitely can conceptualize how the enzyme and the RNA—they're part of this complex. You know, at some point they're going to run into the right part of the DNA, they cut, and then yeah, how do we get that right DNA sequence in there? It sounds like it is a little bit stochastic; you could have some of the DNA might just repair but if you are able to kind of have those DNA fragments around in the presence of the right enzymes, some of that will get stuck in as well?

Jennifer Doudna: Yes, exactly. And so because of that, you know, scientists are trying to manipulate the conditions of these gene editing experiments so that we get the desired outcome—whether it's insertion of a new section of DNA or disruption of a small sequence, such as a single base pair.

And there are already a lot of questions coming in. I think a lot of people are able to extrapolate what this could do for better or for worse, maybe in certain circumstances. So from Facebook, Michelle Fury is asking, can this be done to adults? Can the DNA editing be done to adults or only to embryos? Which goes to this—can it be done for somatic cells, which we have trillions of, or do you have to kind of get something at the embryonic stage?

Jennifer Doudna: Great question, Michelle. So, you know, the answer is that the vast majority of genome editing for people is going to be, in my opinion, certainly for the foreseeable future, will be in adults or kids, but certainly not in embryos. And you might wonder, well, how does that work? And typically, it would be a treatment where cells that can regenerate or even create a new tissue would be the ones being edited.

So I’ll give you an example—sickle cell disease is a well-known genetic disorder of the blood that results from a single mutation in a gene that encodes one of these essential proteins for carrying oxygen in our red blood cells. And so with sickle cell disease, CRISPR can be used to make correcting mutations just in those cells that give rise to new red blood cells. And so that’s a way that this therapy can be used in patients in a way where it impacts the patient, but not anybody else.

And how is that done? Is that done by introducing the enzyme directly into the cell somehow, or does it have, like, a vector—a kind of a harmless virus that can kind of take it in? How do you introduce it into the somatic cells—the body cells, these potentially trillions of cells that might be involved here?

Jennifer Doudna: Yeah, well, right now, the way it’s being done is by taking those blood precursor cells, we call them blood stem cells, out of a patient and doing the genome editing in the laboratory. So it can—and the CRISPR protein and its guiding RNA can be introduced in different ways. It can be put in as a directly assembled molecular complex of the protein and the RNA, or it can be put in, as you mentioned, by using what we call a vector, for example, a virus that can encode those materials.

Oh, so y'all will take the stem cells out, and I mean, when you're able to do it, like, you're not doing one cell at a time; you're able to do, like, blobs of it, I guess? I think that’s a technical term—blobs—by either with a virus or introducing it. And, you know, I am curious because I know I've—you could tell people I hang out with—I’ve had debates with my friends overnight about, you know, when you do it the way you just described, it affects that one individual and hopefully it cures them of sickle cell, which could be a very bad disease, so that's huge.

There’s the other possibility of you're going to the germ line; you’re either going directly to an embryo or you're going to the cells that produce the sperm and the eggs, and then that, in theory, you're affecting the gene pool. And so one question is, you know, is that doable? And then what are your thoughts on that? Because there’s a possibility of removing sickle cell from the gene pool entirely, but where do you see the puts and takes there?

Jennifer Doudna: Right, so this is what we call germline or germ cell editing. And we call them germ cells because they're literally able to give rise to many more cells that are of a particular type so, you know, you can create a whole organism, like a whole human being. And the reason that that is, in my view, a much more profound use of CRISPR is that it creates what we call a heritable change in the DNA. So it affects not just the individual, but all of their kids and their kids' kids.

Now, you know, if you could remove a harmful gene from the human population—and that would obviously take time—but, you know, you could, in principle, do this using genome editing, and it could be argued that, you know, there might be cases where that would be desirable. But I think right now, for many reasons—some of them are technical, and of course, there are many ethical implications—I think most scientists feel that that is not an appropriate use of CRISPR in humans right now and that we should focus on somatic cell editing.

And this is already leading to—if I remember being at a conference, and someone was talking about this—there are already people being treated for sickle cell because of—

Jennifer Doudna: Yes, right! It’s extraordinary! It's very exciting for all of us working in the field to see this work already benefiting patients, and we know there will be many more to benefit in the future.

Absolutely! And on the ethics of this, a question from Facebook: Jeffrey Kritzberg is asking, who should decide the ethics of the science? Just because we can, should we? The butterfly effect may not be a strong enough analogy, and I think what he's referring to is you could edit one gene; it seems to do one thing—but you know these are complex systems. And obviously, there was that—I don't know if folks know—there was that case in China where a scientist, you know, kind of went rogue, used this technology to edit an embryo to have a more resistance towards AIDS. And actually, I read that that scientist was put in prison because of the questionable ethics of this.

So one, how do you—you know, it seems like the cat's out of the bag—this is something that can be done by scientists anywhere; you don't need billions of dollars of capital to do CRISPR. Who do you think should decide it? What do you think is going to happen as you know if there's countries or jurisdictions where people don't care? How can we regulate this type of thing?

Jennifer Doudna: I think so, first of all, thanks for the question, Jeffrey. I think the situation with CRISPR is, in a way, analogous to what we see for a number of types of technologies—whether they’re in the biological sciences or technology or computing—you know, with, for example, artificial intelligence—where the question is the technology is powerful, there are many opportunities to use it to do things that will be beneficial to humanity, but there also are risks. How do we control those risks, and who decides about uses?

And I guess, you know, for me with CRISPR, I feel strongly that those decisions really do need to be made by all the stakeholders that are involved. So in the end, that kind of means all of us. And that will require scientists to engage and discuss the science itself and the kind of way the technology works, and also to work closely with regulators and all sorts of groups that are thinking about, in this case, how genome editing could impact people in the future so that we can make responsible decisions.

And that sounds, you know, hard—and it is—but I think a way to start is by engaging the scientific community globally to think about this and work on it together. And I've been actually very pleased over the last few years that in discussions that I started with my colleagues back in, I think, it was 2015, we've been able to engage with now the World Health Organization, with UNESCO, and with many of the scientific societies around the world to come together.

There have been many conferences and committees that have been convened to look into this, and we now have, I think, a very good framework for using CRISPR in different settings going forward.

And tons of questions are coming in because this is such a fascinating topic. You know, I’m curious, and there are several questions along this line: well, one, beyond sickle cell, where do you think is the next obvious—I mean, sickle cell seems, it is very compelling because it's one mutation, as you mentioned; it seems to have a clear negative. If you can fix it, clear positive. What are the next things that you think CRISPR will be able to influence?

And I am also curious—I think everyone watching is curious—what's the next frontier for you? Where do you think this can go next? What's your research now on?

Jennifer Doudna: Well, I’ll start with the first question. So, you know, there are a few thousand human diseases that are well-known to be caused by a single genetic mutation—a single gene whose correction could lead to a therapeutic benefit. So those are our, I think, obvious initial targets for CRISPR. The big challenge is the challenge of delivery, which means how do we get the CRISPR molecules into the cells that need editing?

So the example of sickle cell is a good one because it provides a way to do the editing outside of the patient because of the need to edit the cells of the blood, which can be easily found and then taken into the laboratory and edited and then replaced. But what if we wanted to edit a gene in brain cells or in heart cells or muscle cells? You know, it’s a lot harder to do that in the patient.

So that’s, I think, in many ways where the bottleneck is right now in the genome editing field. So in terms of, you know, the next maybe near-term targets for CRISPR, I certainly think other blood disorders will be addressed as well as diseases of the eye because this is, again, a tissue where potentially one can deliver the CRISPR molecules locally by injection.

And maybe in the not-too-distant future, maybe a few years from now, we’ll see therapies for muscular dystrophy coming along. There are a number of groups and companies that are working very actively on muscular dystrophy because of the potential to deliver CRISPR molecules into muscle cells—doing that using viruses that specifically go into muscle cells.

But in terms of my own research, I’m continuing to work on the fundamentals of CRISPR and understanding how it works, but we’re also engaging increasingly in this challenge of delivery because I think that for me as a scientist, I really want to see this technology be affordable and available to everybody around the world that needs it. That’s a tall order, but I think one step towards doing that is making sure that we can deliver it into a cell type where it can be beneficial.

And you know, it’s important to note we’ve talked a lot about the implications for CRISPR to kind of change and maybe, you know, quote, improve. But maybe sometimes people could go rogue; it also allows us to understand, you know, one of the main things where we’re so afraid to edit genetics is because it’s such a complex system, but obviously outside of humans, you could do it in other models and in other animals or in bacteria—you could now edit and kind of run, you know, kind of A/B testing the way that you do in software—like what if I change this, how does that happen? What if I change this? What if I change this?

Are you seeing that type of research accelerate dramatically because of CRISPR?

Jennifer Doudna: Hugely! Hugely! I mean, this is something that over the last eight years we’ve just seen research taking off at an extraordinary pace, doing exactly what you just said, Sal, because now that we have this technology for precise manipulation of one or even many genes in cells in the laboratory, it’s an incredible tool. It means that we can now manipulate genes and understand gene functions in ways that previously would have been very difficult or, in some cases, impossible really to figure out.

Yeah, and you know, in the time we have, we have a lot of young people watching and a lot of parents of young people have this question from Facebook: Carol Smith Capper—a paraphrase—they have a son who works who wants to do… actually, I just lost the question… um, who—well, I’ll paraphrase—who has—who wants to go into this type of field. What would you say to a young person who’s fascinated by this? You know, I've heard people say what computing has been the last two or three decades, the next two or three decades is going to be all about genetic technology. What do you recommend to someone in high school? What should they focus on? What should they study? What are good majors to be in, and what do you think the careers will be like, you know, as you go in the decades ahead?

Jennifer Doudna: Thanks for the question, Carol. I—there are so many opportunities for young folks who are getting into science right now or thinking about that, you know, is this science the right career for me? And like you said, Sal, I think, you know, it’s just—I think many of us that are working in this field feel that there are just exploding opportunities. There are many, many things that were difficult to do even a year or two ago that we’re now able to do as scientists, you know, in terms of our research.

So for students, I would say, you know, pursue your— I always tell my own students, my own son, you know, pursue your passions. And if it’s if it’s biology that that you get really excited about, you know, pursue that. If it’s chemistry—for me it was—it was chemistry in those early days, you know, and wanting to understand how molecules work. And I’ve always found for myself that, you know, by really following my own kind of gut feelings about things, you know, what I felt really passionately excited about studying, that has always led me in interesting directions—not always directions that I could have predicted either, which kind of makes science fun!

Absolutely! And maybe my last question—I am curious, you know, I mean how does it feel? I mean, do you ever sit there and, you know, look in the mirror and say, "Yeah, I just changed humanity forever"?

Jennifer Doudna: Well, I have to say that, you know, when we were first doing this research in the laboratory, there were a number of moments for me where I was kind of pinching myself and saying, you know, is this really happening? I mean, you know, this is— it seemed kind of fantastical to think that bacteria had evolved a system for detecting viruses that we could then figure out how it worked in the laboratory and that that insight would allow us to harness it as a powerful technology.

So, you know, it was really an incredible experience to be involved in that. And yeah, again, I—to me, I would just again, getting back to why I’m a scientist and why I think it’s such a wonderful career for students that are thinking about this—it’s, you know, it's a way to continue to have the kind of curiosity-driven passions that you have when you’re growing up, you know, and you get to as a scientist, you know, people still pay me to, you know, ask questions and try to figure out how things work. So it’s really a fun career!

No, well, you can feel the energy, and I mean, I think it makes sense because you are literally changing the world. And you know, people speak in hyperbolic terms about a lot of things. About what you have done—I do think in 100 or 200 years, a lot of what we’re doing in our current time might be forgotten, but this is going to be one of these things that will change, I hopefully believe, forever positively humanity. So thank you so much for your work, and thank you for joining us and inspiring us.

Jennifer Doudna: Thanks for inviting me, Sal! Great to be here!

So thanks everyone for joining! If you couldn’t tell, I was a little bit star-struck. For anyone who has followed what's been going on in biology and chemistry over the last several years, what Jennifer's work with her colleagues is really—it's a—it's going to be a big deal, and you're only going to hear more and more about it.

So, look, I encourage you, if any of what we said is confusing, definitely you can review the foundations on Khan Academy about your chemistry and your biology. But I encourage you to look into that because I have a feeling in many fields, especially if you’re going into biotech or medicine, the work Jennifer's work and CRISPR is going to be a central element. So it’s a good thing to get smart on.

So with that, thanks so much for joining, and I will see all of y'all, I believe, next week. I live day to day; I don’t know what I'm doing tomorrow. But I will see y'all! Have a good day!