< Jennifer Doudna: What does CRISPR mean for the future of human evolution?

MANOUSH ZOMORODI, HOST:

It's the Ted Radio Hour from NPR. I'm Manoush Zomorodi. And I want to go back about 10 years to Berkeley, Calif., specifically to a lab on the UC Berkeley campus run by a woman named Jennifer Doudna.

JENNIFER DOUDNA: I've always investigated fundamental questions about the nature of modern biology, in particular on molecules of RNA. These are chemical cousins of DNA that do lots of interesting things in cells and viruses.

ZOMORODI: So Jennifer was studying RNA molecules, and that led her...

DOUDNA: To investigate a rumored bacterial immune system called CRISPR.

ZOMORODI: CRISPR, or clustered regularly interspaced short palindromic repeats.

DOUDNA: Wow. Impressive.

ZOMORODI: Did I get it?

DOUDNA: Yes.

ZOMORODI: OK, thank you.

DOUDNA: You did.

ZOMORODI: Thank you. I have been working on that. I'm really glad you came up with the acronym.

DOUDNA: (Laughter) Well, I didn't, but the field did. Yeah.

ZOMORODI: OK. So you've probably heard of CRISPR at some point, but you may not know the whole story. Around 2011, Jennifer started collaborating with a French professor named Emmanuelle Charpentier, and they began looking into CRISPR, this naturally occurring phenomenon in bacteria.

DOUDNA: Correct. It's an adaptive immune system that bacteria employ to protect themselves from viral infection. And we began studying an enzyme, a protein called CRISPR-Cas9, which could be incredibly useful for detecting RNA and DNA molecules and for cutting them up.

ZOMORODI: She and Emmanuelle found that this CRISPR-Cas9 molecule destroys viruses by cutting up their DNA and altering their genome. Their discovery was huge.

DOUDNA: And this led to a breakthrough, really a finding that this system could be harnessed as a tool, as a technology, for manipulating DNA sequences in a programmable fashion. And it was through that work that we realized that this system could in fact be deployed as a genome editing tool.

ZOMORODI: Meaning they could use CRISPR-Cas9 to target and alter specific genes.

DOUDNA: It was basically immediately clear that this was an extraordinary breakthrough technology.

ZOMORODI: OK. So we should be clear scientists have been working on gene editing for a long time, but there had never been a tool quite like this, right? The analogy I always hear is that it is basically - that you can cut and paste DNA. Is that right?

DOUDNA: I actually love that analogy for genome editing because it really is, in fact, what genome editing is all about. So we can think of the genome, which is the DNA found in a cell that has all of the instructions for making a cell or a whole organism, and we can think of that information like the information in a book or, maybe better, an encyclopedia. And what scientists have been trying to do now for decades, honestly, is to understand the information content of the genome, particularly the human genome. And what CRISPR does is to give scientists an incredibly precise and programmable tool for altering the code to identify and cut specific DNA sequences. And we can control which sequences it's cutting. We can decide how to program it and have it go to that place in the genome, just like you might thumb to a page in a book volume and, you know, change a word or a paragraph or move things around. And it actually is cutting and pasting information in the DNA.

ZOMORODI: Do you remember what it looked like when you sort of connected the dots? Were you like, whoa, I have to sit down or I need a whiskey? Like, what went through your mind on a non-scientific level, on a purely human emotional level?

DOUDNA: Well, a great little vignette that comes to mind was an evening in those days when I was - you know, I had just come home from the lab and, you know, we had just gotten the data that showed how this worked. And I was at home. I was - you know, I was cooking spaghetti in my kitchen for my young son, and I just suddenly burst out laughing because I thought, this is so crazy, you know, that we started working on this thing, didn't really know where it was going, and it certainly wasn't a popular area of science at the time. Most people had never heard of CRISPR. And yet we had uncovered this just absolutely extraordinary molecule whose chemistry was going to probably change the world.

ZOMORODI: Unlocking the mysteries of the genome has been a holy grail for scientists. And with CRISPR and other tools, humans have invented mechanisms to change evolution. But only recently have scientists begun to deploy these tools. And this next chapter is complex. There are so many questions. Will genetic treatments become everyday procedures? Should they be used to eradicate disease, revive extinct species, even help us live longer? And how can we make sure these tools work for the benefit of all humankind? And so today on the show - reshaping evolution because we are on the precipice of the next scientific revolution, one that could profoundly change humanity in exciting and frightening ways over the next century. Jennifer Doudna and Emmanuelle Charpentier's work earned them the Nobel Prize in chemistry in 2020. And now their development of the CRISPR-Cas9 molecule is being tested in over a dozen clinical trials.

DOUDNA: Everything from sickle cell disease, beta thalassemia, which is another blood disorder, disorders of the eye, liver disease, heart disease and muscular dystrophy. So it's just mind-boggling to think of a technology going from initial publication in an academic research journal to being widely deployed for so many different applications.

ZOMORODI: Can we go back to the blood disorder, sickle cell disease? My understanding is that a person's red blood cells are misshapen, and so that means they can't carry enough oxygen.

DOUDNA: That's right. And that's why it's referred to as sickle cell disease because when you look under a microscope, the cells have a classic sickled shape, and people with sickle cell disease make a form of the protein called hemoglobin that carries oxygen in the blood that is prone to aggregation, prone to sticking together and forming aggregates that lead to these sickled shape of the cells.

ZOMORODI: And so how does CRISPR work to fix it?

DOUDNA: To treat sickle cell disease at its source, what's done is to remove what are called blood stem cells from an affected individual. These come out of the bone marrow. And they are cells that have the potential to develop into new red blood cells. And to ensure that they don't have the sickle cell trait, CRISPR can be used to either change the DNA of the affected gene, or they can actually suppress the effects of the sickle cell gene mutation. And that's what's done. So the CRISPR is used to make those changes in blood stem cells, and then the edited cells are infused back into the patient where they can repopulate the bone marrow and effectively replace the red blood cells with corrected cells.

ZOMORODI: So just to be clear, you're saying that there could be a family that says, you know, we have passed down sickle cell to generation after generation, and we want it to end with us.

DOUDNA: Well, that's right. It could, you know, and it's extraordinary. And even today, you know, this is something that is already being used in patients in these trials. Victoria Gray, she was actually the first U.S. patient to receive a CRISPR-based therapy for her sickle cell disease. And, you know, she's showing that this type of approach can actually work quite well in terms of treating a disease at its source. And I think that's really what CRISPR offers, is that kind of a cure, really, for genetic disease. And I think it just paves the way for future applications of this technology as well because, of course, when you start to see success and, you know, begin to see how patients' lives are being impacted beneficially by this technology, it's highly motivating to - you know, to carry it forward and see it used in other diseases.

But I think one has to think about the fact that, you know, what we're talking about here is effectively changing evolution. You know, it's changing us at our core and going back to the instruction manual that makes us who we are and making changes there. When we talk about it in the context of a disease like sickle cell disease that is so debilitating, it certainly seems like this might be something that some families might want to consider eventually, especially if the technology is vetted carefully and shown to be safe. And by the way, we're not there yet. But I think the broader issue really is equity, access to technologies. Who decides about something like that, something as profound as that? Who pays for it? Who has access to it? I think it gets complicated quickly.

ZOMORODI: Yeah. I mean, it goes from stopping a fatal disease to maybe optimizing for IQ or even, you know, being thin and tall and having a particular eye color, I suppose.

DOUDNA: I mean, in a most extreme case, you could imagine that someday, couples, you know, go to an in vitro fertilization clinic, and they receive a menu, right? And they can decide what types of traits they want for their children.

ZOMORODI: Yeah, you actually brought that up back in 2015 in your TED Talk.

(SOUNDBITE OF TED TALK)

DOUDNA: Imagine that we could try to engineer humans that have enhanced properties, such as stronger bones or less susceptibility to cardiovascular disease, or even to have properties that we would consider maybe to be desirable - designer humans, if you will. Right now, the genetic information to understand what types of genes would give rise to these traits are mostly not known, but it's important to know that the CRISPR technology gives us a tool to make such changes once that knowledge becomes available. This raises a number of ethical questions that we have to carefully consider. And this is why I and my colleagues have called for a global pause in any clinical application of the CRISPR technology in human embryos, to give us time to really consider all of the various implications of doing so.

ZOMORODI: That was more than six years ago, but not everyone stuck to a moratorium.

(SOUNDBITE OF MONTAGE)

UNIDENTIFIED PERSON #1: Overnight, an astonishing claim - a scientist in China saying he created the world's first genetically engineered babies.

UNIDENTIFIED PERSON #2: A line has been crossed that should not have been crossed.

UNIDENTIFIED PERSON #3: It's very disturbing. It's inappropriate.

UNIDENTIFIED PERSON #4: Oh, this is huge.

ZOMORODI: In a moment, more from Jennifer Doudna about the ethical implications of CRISPR. On the show today, reshaping evolution. I'm Manoush Zomorodi, and you're listening to the TED Radio Hour from NPR. We'll be right back.

It's the TED Radio Hour from NPR. I'm Manoush Zomorodi. On the show today, reshaping evolution. We were just talking to Nobel Prize-winning biochemist Jennifer Doudna, whose work on CRISPR marked a new chapter in our ability to alter our DNA. In 2015, Jennifer called for an international moratorium on applying CRISPR to human embryos, at least until the scientific community considered all the ethical implications of gene editing.

DOUDNA: That was definitely a motivation at that time, was to call to the attention of everyone, to just be aware that this technology does have the potential to create these very profound, you know, kinds of changes in human beings. What happened next was that there was an announcement in 2018, which was actually - actually happened at the second international summit on the topic of human genome editing, of a project in China in which two embryos had been edited using CRISPR and then were implanted to create a pregnancy that resulted in the birth of twin girls with edits to their DNA.

ZOMORODI: And do you remember what your reaction was after he presented his research?

DOUDNA: Well, it was pretty horrifying. You know, it was just kind of shocking to see the way that the work had been performed. It - just really an example of unethical behavior on the part of a scientist, you know, just rushing forward with something before it had been tested to be safe and also without properly understanding how to explain and consent with patients, you know, to explain to them what was actually happening to the embryos that they were using in the study. And so I think it really did galvanize the international community to realize that this type of work really shouldn't be happening right now. And there has been a concerted effort on the part of not only scientific organizations but also by the World Health Organization and the United Nations to get involved in this conversation.

ZOMORODI: OK, so you've got governments and NGOs talking. But of course, there's the other party that we're not talking about yet, which is private enterprise. There are a lot of companies who are hoping to make money off of this technology. You've started several companies that are developing CRISPR-Cas9 treatments. But should we be worried - because companies are not always known for taking the moral high ground, right?

DOUDNA: You're right - that I think this is always something that needs vigilance. One has to - you know, you can't relax. You have to remember, you know, there's always the risks that go along with a technology like this. But companies play an incredibly important role in all of this because, generally, this is not something that academic labs have the funding or the resources to do, and that's where companies come in.

ZOMORODI: So how do you balance your business interests with your ethics?

DOUDNA: I think it begins at the beginning. You have to start with creating a culture in your team that focuses on ethical use of the technology and on the, you know, benefit that can be created by developing it in the context of the company. And we've - you know, certainly, I've been proud of the teams that I've been involved with as a founder that I think, in each case, these are people who I like, I trust. I think we have aligned values, core values, in terms of both doing excellent science and doing it with an eye towards ethics and appropriate use of a powerful tool.

ZOMORODI: Your biographer, Walter Isaacson, has said that your invention of CRISPR heralds the beginning of a next great innovation revolution. What do you think he means by that?

DOUDNA: There's a lot of evidence that we're entering an era in biology in which we have increasingly, at our fingertips, a collection of tools that allow manipulation of biological systems in controllable ways. Those capabilities will advance, you know, the kinds of things that have only been dreamt of in biological systems to a point where we can actually achieve them. Imagine that someone gets a diagnosis for something. Maybe it's even pre-diagnosis. It's - they've gone to a company like 23andMe or Color Genomics, and they have their DNA sequenced. And the result comes back that they have susceptibility to Alzheimer's disease in the future. Today, that's kind of, you know, information that's not directly actionable. Whereas imagine in the future, it's possible to use a technology like CRISPR to change those genetics so that that person is - no longer has that susceptibility. That would be extraordinary if we get to that point. Will we get there in 30 years? I don't know, but I think it's entirely possible that we will.

ZOMORODI: That's biochemist Jennifer Doudna. You can see her full talk at ted.com.

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