Reshaping Evolution

0:00Support for this podcast and the following message come from Recorded Future. In cybersecurity, the biggest risk isn't what you see, it's what you miss. Recorded Future, bringing clarity to the signals that matter most to your business. Recorded Future. Know what matters. Act first. This is the TED Radio Hour. Each week, groundbreaking TED Talks. Our job now is to dream big. Delivered at TED conferences. To bring about the future we want to see. Around the world. To understand who we are. From those talks, we bring you speakers and ideas that will surprise you. You just don't know what you're going to find.

0:39Challenge you. We truly have to ask ourselves, like, why is it noteworthy? And even change you. I literally feel like I'm a different person. Yes. Do you feel that way? Ideas worth spreading. From TED and NPR. I'm Manoush Zomorodi, and I want to go back about 10 years to Berkeley, California. specifically to a lab on the UC Berkeley campus run by a woman named 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. So Jennifer was studying RNA molecules, and that led her...

1:32To investigate a rumored bacterial immune system called CRISPR. CRISPR, or Clustered Regularly Interspaced Short Palindromic Repeats. Wow, impressive. Did I get it? Okay, thank you. Thank you. I have been working on that. I'm really glad you came up with the acronym. Well, I didn't, but the field did. Yeah. Okay, 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 Emmanuel Charpentier, and they began looking into CRISPR, this naturally occurring phenomenon in bacteria. Correct. It's an adaptive immune system that bacteria employ to protect themselves from viral infection.

2:19And 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. She and Emanuelle found that this CRISPR-Cas9 molecule destroys viruses by cutting up their DNA and altering their genome. Their discovery was huge. 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. Meaning they could use CRISPR-Cas9 to target and alter specific genes.

3:14It was basically immediately clear that this was an extraordinary breakthrough technology. Okay, 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? 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.

4:01And 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.

4:51Do 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? 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.

5:36And 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. 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?

6:25And 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 Emmanuel 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. Everything from sickle cell disease, beta thalassemia, which is another blood disorder, disorders of the eye, liver disease, heart disease, and muscular dystrophy.

7:13So 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. 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. 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 the sickle shape of the cells.

8:08And so how does CRISPR work to fix it? 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 their red blood cells with corrected cells.

9:05So 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. 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.

9:49And 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. 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.

10:34When 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. 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.

11:26I 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. Yeah, you actually brought that up back in 2015 in your TED Talk. 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.

12:14But 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. That was more than six years ago, but not everyone stuck to a moratorium. Overnight, an astonishing claim. A scientist in China saying he created the world's first genetically engineered baby.

12:55A line has been crossed that should not have been crossed. It's very disturbing. It's inappropriate. Oh, this is huge. 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.

13:29This message comes from Superhuman, the AI productivity suite that gives you superpowers everywhere you work. With Grammarly, Mail, and Coda coming together, you get proactive help across your workflow so you can outsmart the chaos. Experience AI that proactively helps you go from to-do to done faster. Unleash your superhuman potential today. Learn more at superhuman.com slash podcast. That's superhuman.com slash podcast. This message comes from Cachava. Indulge in holiday cravings with the nutrition you need from Cachava's all-in-one whole body shake. It packs 25 grams of protein, 6 grams of fiber, greens, and more.

14:14High-quality ingredients with no fillers or nonsense. Try the newest flavor, limited edition chocolate mint. Go to cachava.com and use code NPR for 15 % off. That's cachava, K-A-C-H-A-V-A dot com, code NPR. Support for this podcast and the following message come from Recorded Future. Every day, millions of cyber threats compete for attention, but only a few truly matter to your business. As a leading threat intelligence company, Recorded Future cuts through the noise with precision intelligence. That's why top banks and governments trust them. Because security leaders don't just react, they foresee spotting the signals that others miss and acting before threats become setbacks.

15:01Recorded future. Know what matters. Act first.

15:18AI and your critical thinking to surpassing discoveries about the adolescent brain. Find TED Talks Daily wherever you listen. 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. 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.

16:18What happened next was that there was an announcement in 2018, which 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. And do you remember what your reaction was after he presented his research? 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 embryo.

17:18that 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. Okay, 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.

17:59You'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? 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. So how do you balance your business interests with your ethics?

18:36I 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 benefit that can be created by developing it in the context of the company. 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. Your biographer, Walter Isaacson, has said that your invention of CRISPR heralds the beginning of a next great innovation revolution.

19:32What do you think he means by that? 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 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.

20:42That 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. That's biochemist Jennifer Doudna. You can see her full talk at TED.com. On the show today, reshaping evolution. How recent medical advances may allow us to defeat some of today's most debilitating illnesses. Imagine you're having some strange symptoms and you don't really know what they are. This is Nabiha Saklian. You're feeling a lot of tremors. Your muscles are stiff. You're having difficulty thinking and understanding. and you go to your doctor because you want to know what's going on.

21:31And they run tests, a whole host of them. They order neurological exams, look at your family history, measure your agility, muscle tone, balance, and then... And then you find out that you have Parkinson's disease, which is devastating news. And I've had family members who've had to go through that and it's a very, very tough moment to realize you have something that's going to completely change your life and you might have these symptoms forever. Today, your doctor would review your options with you, medications you can take, lifestyle changes to make, how to manage a disease which has no cure.

22:08But Nabiha is working towards a different outcome. What if I told you there is a different future ahead for us? What if your doctor, instead of saying, okay, we're going to be treating your symptoms, your doctor actually says, no, we're going to be able to cure this disease. And the way that works is you drop off a blood sample. Those blood cells are shipped off to a cell factory to generate brand new neurons that are customized just for you. You come back the next week and a surgeon transplants those neurons into your brain and you just received a cure for Parkinson's. Okay, wait, let me see if I get this right.

22:54Take some blood cells, turn them into new neurons, put them in the right places in the damaged part of the brain, and you can essentially cure Parkinson's? Exactly. Yeah. I mean, Nabiha, I gotta say, it sounds like science fiction. It does sound like science fiction, but what's amazing is most of the pieces of the puzzle have been figured out. We know how to make patient-specific cells. We know how to transplant them into the right part of the brain. We've seen these transplants happen in patients, and the results are very, very promising. And now we just have to figure out manufacturing. How do we make these cells in a fully automated way, make them super cheap?

23:37And that's what I'm working on with my team. For years, we've heard that stem cells may eventually cure diseases and treat illnesses. That by genetically engineering them, they could fix our ailing bodies. Now, though it's still early, promising new technologies are getting us closer. In labs like those at Nabea's company, Salino. We're automating the generation of personalized human cells. And these cells can be used for a range of therapeutic applications. And because they're 100 % your cells, your immune system is extremely unlikely to reject or attack those cells. Nabiya Siklian picks up this idea from the TED stage.

24:22In fact, the body has no idea that these cells were actually made in a cell factory. All of this is possible because of a breakthrough at the intersection of biology, laser physics, and machine learning. We'll start with biology. The human body is an absolute miracle. Trillions of cells are working in synchronicity to pump blood, secrete dopamine, and let me see and speak to you right now. But as we age, our cells age too. That's why our skin starts to sag, our cartilage wears away, and your five-mile run might turn into a 20-minute walk. Yes, we're all getting older. Our bodies are taking time bombs.

25:08But stem cells could offer a solution. All right. So stem cells, remind us, why are they so useful? Yes. Stem cells are these very special cell types that have the code in them to become any cell type in the body. In our natural state of existence, we don't have absolutely 100 % pure stem cells in the body anymore because they've evolved into becoming different subsets of cells in the body. But it's possible now to generate really high-quality stem cells for each and every patient, for each and every adult, that look very much like embryonic cells. Scientists can make stem cells. Absolutely. They're called induced pluripotent stem cells.

25:58And these stem cells open up the possibility to generate neurons on demand, heart cells on demand, skin on demand, hair on demand. You name it. You can make any cell type where we know the biology of how to change the stem cell to the target cell type. Now, unfortunately, stem cells are notoriously difficult to engineer. One fundamental problem relates to how they're made, which involves taking a patient's blood cells and adding chemicals to those blood cells to turn them into stem cells. Now, during this chemical process, you never end up with a perfect set of stem cells. In fact, you get a very messy plate of cells going in different directions towards the eye, brain, liver, and every random cell must be removed.

26:44Until recently, the main way to remove cells was by hand. I remember the first time I visited the Harvard Stem Cell Institute. I watched a highly skilled scientist sitting at a bench looking at stem cells, evaluating them one at a time. and removing the unwanted cells by hand. It's a slow, tedious, and artisanal process, which is why generating a personalized stem cell bank today costs about$1 million. Right now, there are phase one slash two clinical trials, one that's already launched in the U.S. for personalized IPSC-based therapies. all of these groups have made enough patient-specific stem cells and therapies and derived tissues by hand.

27:33And that's maybe 10, 15, or 20 patients. That's it. That's it, right. So when you think about a phase three trial, you may need hundreds of patients, and there literally aren't enough scientists that can make those cells by hand. And of course, it becomes very, very expensive. running a phase three clinical trial would cost$300 million, which is not feasible in most instances. Okay. And this is where presumably your work comes in, Nabiya. Yes. So when I came into the biology space, so just a quick background, I'm a physicist by training. When I started my PhD, I joined a laser physics lab because lasers are the coolest.

28:15But I also decided to dabble in biology. I started using lasers to engineer human cells. And when I talked to biologists about it, they were amazed. Here's why. Scientists are always looking for ways to make biology more precise. Sometimes cell culture can feel a lot like cooking. Take some chemicals, put it in a pot, stir it, heat it, see what happens, try it all over again. In contrast, lasers are so precise, You can target one cell, millions, at precise intervals, every second, every minute, every hour. I realized that instead of doing this tedious process of stem cell culture by hand, we could use lasers to remove the unwanted cells.

29:00And to automate the entire process, we decided to use machine learning to identify those unwanted cells and zap them. Here's how it works. Take some blood cells, put it in a cassette, add chemicals to those blood cells to turn them into stem cells like always. Now, instead of having a human look for those unwanted cells and remove them by hand, the machine identifies the unwanted cells and zaps them with a laser. As you can see, this entire process happens by machine. The computer decides when and how often to prune the cells and uses a fully automated system to run the process. After repeated pruning, you end up with a perfect culture of your stem cells, ready to be banked and used at any time.

29:53Nabiya, we talked about how hypothetically a brain with Parkinson's could be repaired using stem cells, iPSCs. But to be clear, stem cells are already being used to treat leukemia and other types of blood cancers. I've also read about them being used to restore a patient's eyesight in clinical trials. So, so far, it seems pretty promising. Yes, and just this past month, there's been an amazing result that was put out into the world by the Vertex team, where they tested one patient with a dose of new insulin-producing cells, and this patient is not having to use insulin injections anymore. So that has happened in the past month, and it's tremendous.

30:42And now it's all about figuring out what is the right format for the specific cell therapy, how many cells should be transplanted, how to get around the immune evasion problems, and how to manufacture these cells in a scalable and cost-effective way. That's what we need to figure out. But we're going to do all of that in the next 10 years. I have so much confidence we are as an industry. Perhaps you have longevity in mind. That is certainly a possibility. In the future, we might use these exact same stem cell banks to generate entire new organs, new tissues, new skin, new bone. this technology also has the potential to revolutionize personalized pharmaceuticals.