112 | Fyodor Urnov on Gene Editing, CRISPR, and Human Engineering

Not too long ago nobody carried a mobile phone; now almost everybody does. That’s the kind of rate of rapid progress we’re seeing with our ability to directly edit genomes. With the use of CRISPR-Cas9 and other techniques, gene editing is becoming commonplace. How does that work — and perhaps more importantly, how are we going to put it to use? Fyodor Urnov has worked in this area from its beginning, having coined the term “gene editing.” We talk about how this new technology can be used to cure or prevent disease, as well as the pros and cons of designer babies.

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Fyodor Urnov received his Ph.D. in Biology from Brown University. He is currently professor of Genetic, Genomics, and Development in the Department of Molecular and Cell Biology at UC Berkeley, as well as Director for Technology and Translation at the Innovative Genomics Institute. His research focuses on using CRISPR gene-editing techniques to develop treatments for sickle cell disease, radiation injury, and other conditions, as well as guiding IGI researchers as they bring these therapies from the lab to the clinic.

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0:00:00 Sean Carroll: Hello, everyone, welcome to the Mindscape Podcast. I’m your host, Sean Carroll. And I’m sure that you’ve all heard the excitement and the worries, the news overall over the last few years about gene editing, the possibility of editing human genes at a very detailed level, not to mention plant and animal genes, of course. Today’s guest Fyodor Urnov is actually not just one of the world’s experts, he coined the term “gene editing,” and he’s been active in the field since the beginning, so he knows what he’s talking about. And I know that as well as prospects for curing diseases and stuff like that, there are worries about… It would be good to cure diseases using gene editing, but what if someone made super soldiers and they became bad like The Red Skull instead of good like Captain America? Wouldn’t that be bad? So at the end of this interview, I asked Fyodor, I said, as responsible as we might want to be, as scientists, as countries, as international regulatory agencies, isn’t it coming to the point where this is almost too easy and almost anyone will be able to do gene editing and make designer babies in their basements or their bedrooms, as it were?

0:01:09 SC: And his answer was a little bit surprising. He said, “Absolutely. It’s gonna happen.” And that’s a little bit of a wake-up call. It is kind of easy to play around with the human genome, and we’re gonna have to deal with that in one way or the other. All this stuff came about over just last 10 years, or even five years, with a wonderful little gizmo called CRISPR-Cas, which you’ve probably heard about, CRISPR-Cas9. Jennifer Doudna, Emmanuelle Charpantier, and other researchers figured out how to basically borrow a mechanism that had already been invented by biology. This is something that exists in bacteria in order to fight off viruses, so the CRISPR-Cas9 system can recognize a bad virus and then go in and attack and neutralize it, and the way that it neutralizes it is by snipping its DNA and either just tearing it apart or by inserting something to make it not so bad. So the human beings realized, oh my goodness, bacteria have already figured out how to do this, we can use their technology and adapt it to our own needs. So it’s no doubt that we are at the beginning, the very dawn of the gene editing era.

0:02:17 SC: There’s no doubt this will be very, very good for a lot of reasons, there’s no doubt this is going to be scary and new for a lot of reasons. So I thought it would be a lot of fun to talk to someone who’s been there before the CRISPR-Cas9 revolution and is still there working at the frontlines on both what gene editing is, how it works, and what it’s gonna mean for us in the years to come. So this is a great conversation with Fyodor Urnov. Let me just quickly mention also before we start that this podcast is being released the day before the paperback release of my book Something Deeply Hidden, so if any of you out there are on the one hand paperback book readers and on the other hand not yet enthusiastic enough to have purchased the hard copy, the hardback version, rather, of… It’s still a hard copy, if you have the paperback version, the hardback version of Something Deeply Hidden, and you wanna know about quantum mechanics, many-worlds, and some of the interesting ideas going on in physics with emergent space-time and stuff like that, be sure to rush out to your local or virtual book store and pick up a copy of Something Deeply Hidden. I will appreciate it, the universe will appreciate it. And with that, let’s go.

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0:03:32 SC: Fyodor Urnov, welcome to the Mindscape Podcast.

0:03:44 Fyodor Urnov: Thank you for having me.

0:03:45 SC: I’ll actually give you a special welcome because I’ve noticed that in the past few months, it’s not been easy to get biologists, especially molecular/cell biologists onto the show. Their attention is being absorbed by something else, by this weird virus that is sweeping the world. Are you one of these people whose attention has been diverted from your regular work, or have you stubbornly pressed forward with your basic research, even in the middle of the pandemic?

0:04:13 FU: I have been swept away by a tsunami known as the pandemic. And as I look around my professional life, none of the objects so familiar to me, which is my beloved CRISPR-Cas, which was the protein that we used to do genetic engineering, and the human cells that I do genetic engineering on, whether they happen to be blood stem cells or lung cells or brain cells, none of them are around me. Instead I’m surrounded by snot and spit, there is no way to say it except to say it, because those are two types of specimens, or as physicians say, clinical matrices, that we use to test individuals for virus. And in fact, for the past four and a half months, I’d say 99.73% of my life has been devoted to that.

0:05:09 SC: And productively so? Do you think that the skill set that you had coming in has been well-calibrated for the challenges of this?

0:05:18 FU: You know, if you’d asked me 35 years ago when I first walked into a freshman-year biology class, would there ever be a chance that the types of things you’re gonna learn would have a real-world impact on clinical care, I’d say probably not because, as many of my peers, I signed up to be a research scientist in biology because I love the natural world, I think living systems are the most amazing thing out there, although I suspect as a physicist, you might politely disagree.

0:05:48 SC: We’re ecumenical here at the Mindscape Podcast, don’t worry.

[laughter]

0:05:56 FU: And I thought I would spend the entirety of my life in the beautiful ivory tower of academia, studying fondly my esoteric basic science question. What happened was one divided by that. 20 years ago, I had the good fortune of joining a biotech where I then spent 15 years developing ways to genetically engineer people to treat disease, which is not exactly ivory tower. And then two years ago, when I joined the faculty here at Berkeley, I did so to continue that work on trying to use genetic engineering to treat disease, and then, of course, the pandemic hit, and it’s kind of amazing to me that the central tool that the nation and the world needs so desperately to deal with the pandemic, which is testing: Do you or do you not have the virus?

0:06:51 FU: That the mechanics under the hood of what it takes to answer that question are actually taught to every single PhD in my field, which is molecular and cell biology, in the first month of them joining the lab. And again, if you walk around here at Berkeley and ask the first year graduate students: Do you think that whatever you’re learning will be used for clinical care? Not many of them will say, “Oh, absolutely,” but it happens to be the case that the elementary skill sets of testing for the virus are the same elementary skill sets that I learned. Oh, my goodness! In late September 1990, when I was a first year graduate student at Brown, and it seems, literally, it’s literally in the last century. And yet, the fundamental mechanics of how one diagnosis an individual to have the virus rely on, I guess, decades-old techniques, which are tried and true.

0:07:53 SC: Oh, that’s actually good to know. It makes me think that if ever the world comes into a state where my skill set is called upon to help in some tangible way, we’re in really big trouble, much bigger trouble even than we are now. So glad to hear that the biologists…

0:08:09 FU: I am just visualizing this gathering of some legislative body that says, “Yes, at this point, we need a cohort of theoretical physicists to help us deal with this.”

0:08:18 SC: Oh, no, yes. It did happen in Manhattan Project, but it’s different now, yeah.

0:08:24 FU: By the way, of course, I’m joking. One of the truly remarkable things about what you do and what I do is the relevance and the resonance is unpredictable. I think most people don’t know that the GPS on their phones works on Einstein’s Theory of Relativity, right?

0:08:41 SC: Absolutely, yeah, absolutely.

0:08:43 FU: No, I swear to you, too, that the majority of people who use GPS just don’t think about that. Similarly, I think most people who get diagnosed, who get tested for the virus, they don’t really think about the mechanics, and the fact that the mechanics of the testing have to do with really foundational tools of my field, which is molecular biology that have been developed over the past 50 years.

0:09:09 SC: Right.

0:09:11 FU: It’s just not something that’s in the headlines daily and yet, here we are, basically, biologists used to sitting with our test tubes and our cells in isolation of a laboratory, finding ourselves in the minds of the public. I say to people, “Oh, you know, RNA extraction… ” And lay people ask me, “Oh, do you do that qPCR thing? Or do you do something else?” And I go, “Well, I never thought that the word qPCR would be used,” which stands for quantitative polymerase chain reaction, by the way, “Would ever emerge in a lay person conversation, yet here we are.”

0:09:50 SC: Well, this is a good segue because what I actually wanna do is get into CRISPR and gene editing, and then we can see if that circles us back to fighting viruses and so forth. So we take it that our audience knows what DNA is, that our genetic information is stored in DNA. And also probably, most people out there have this feeling that there’s been this revolution in the past few years in terms of editing the DNA with this CRISPR-Cas stuff. So maybe you can just tell us, you’re one of the world’s experts: What is CRISPR? What is it go around CRISPR-ing? And what are we gonna use it for?

0:10:27 FU: Oh, my goodness! Asking me about…

0:10:30 SC: You can skip the what are we gonna use it for, we’ll get there. We’ll get there later. What is it? How does it work? Let’s put it that way.

0:10:36 FU: So asking me about CRISPR is a bit like asking a koala what it thinks about eucalyptus leaves. I can go on and on and on. The reason that we coined the term gene editing as an umbrella phrase to describe ways of precise genetic engineering is by explicit analogy to word processing. Both CRISPR and the technologies that preceded it, which accomplished the same thing, do to the human genetic code, or as it happens to the genetic code of a cow, or to the genetic code of a maize plant. And I use these three examples deliberately because these are living things that have been genetically edited or CRISPR-ed. This technique does to the DNA of a corn plant, a cow, or a human precisely what your favorite word processor would do to text. You open a narrative, a document on your computer screen, you use your mouse to click on a bit of text, and then you type on your keyboard whatever desired edit you wish. And so, I’m delighted that this term, gene editing, that my colleagues and I came up with 15 years ago is universally adopted. And in fact, people talk about gene-edited organisms, or we introduce this edit into a human cell precisely in the way that people describe introducing an edit into a document, that that was our explicit goal and I guess we succeeded.

0:12:16 SC: But I think that maybe people take that analogy too literally. They have the idea that you’re just laying out the DNA on a slab, and then you go and copy and paste, something like that. The messy biology of it is a bit more intricate.

0:12:32 FU: That would be the understatement of the year. I think what was Einstein’s favorite phrase, “Everything should be made as simple as possible, but not necessarily simpler.”

0:12:41 SC: Yes.

0:12:42 FU: So in telling you how gene editing, broadly, and how CRISPR specifically works, I really need to carefully walk that line to not oversimplify. I think a good place to start is by saying the following, human DNA is very long. Your audience is doubtless familiar with the number, 6.6 times 10 to the 9th, letters of genetic code is what it takes to build a human being. Now, a good way to think about how long that is is as follows, if you read the genetic code one letter at a time, A-C-T-G… One second at a time, it’ll take you a century to read the entire human genome. So first, the human genome is very long, this is also true of the cow and this is also a true for corn. Second, with the exception of microbes, like really small things that move around and live their little independent lives, most living systems don’t like their DNA changed in any way at all, and this is because DNA is essentially the storage document for who they are. And Mother Nature protects the integrity of the genetic material. And you can see how extraordinary this repair machinery is, if you look at folks who have the misfortune of not having the machinery to repair damage.

0:14:15 FU: So for example, there are folks with the rare diseases who cannot tolerate sunlight because they don’t have the right machinery to fix damage to the DNA, and they need to wear sunscreen SPF 10,000, and in fact, they’d… They will never venture out into the daylight, they have to basically be active at night. So not only does our DNA refuse to be changed, our DNA has a large number of molecular machines that literally babysit it, and if something damages it… And what are the kinds of things that the damage DNA? So I mentioned sunlight, so UV rays create a particular kind of damage. Chemicals can damage DNA, so for example, the reason that smoking causes cancer is it has a chemical which physically damages the DNA and through the repair machinery doesn’t get to it in time, and you get genetic changes that cause cancer.

0:15:13 FU: The other type of damage that our DNA gets all the time, and this is the most interesting one for people who wanna understand how gene editing works, is actually the most drastic one, which is literally taking scissors and cutting the familiar double-stranded helix into two. So if you think about the two individual strands of DNA winding around each other in that beautiful double helix, now imagine taking scissors and literally cutting that thing, so that you have now where you had one double helix, you now have two. So this is the type of damage that occurs spontaneously, just human cells just going about their business, sometimes the DNA just breaks. Humans most often experience it in fact at the doctor’s office, so when you go get a chest X-ray, I guess, I suppose, and I say, that’s really important right now, given the pandemic or when you go to the dentist to get a dental x-ray, the rays hit your DNA and your DNA… I don’t want to make your audience squirm with fear next time they’re in the dentist chair, other than for the anticipation of whatever…

0:16:24 SC: For the obvious reasons, yeah.

0:16:26 FU: Other than… We don’t need additional reasons to not wanna go to the dentist, but the bottom line is, the X-rays that are used to take a picture of your teeth and of your mouth damage the DNA, every bit of DNA they encounter by basically cutting it. And the reason this break is so dangerous is we’ve all learned about chromosomes, we have 46 of them, 23 pairs, one from mom, one from dad, for each one, and we’ve all learned and forgotten in high school about mitosis, this beautiful process where when the cell needs to divide, it makes a copy of all the chromosomes and one copy goes to the cell on the left, one copy goes to the cell on the right. Now can you imagine if one of these chromosomes has a break? This means that during cell division, that broken piece will just be left behind, and that means losing all the genes that are on that broken off piece, and that the overwhelming majority of the time is a genetic loss that human cells cannot tolerate. You can’t just get rid of human genes left and right.

0:17:36 FU: Now, you can get rid of some but the notion that there would be a break on one of the chromosomes that that an entire chunk of it just gets lost, that’s incompatible with… Forget human beings being alive, it’s incompatible with human cells being alive. But people should still go to the dentist because the reason that x-rays, whether of the chest or of your oral cavity or that your exposure to ionizing radiation from the sun when you take a commercial flight, again, not many people are flying these days, but back when they used to, the sun will emit rays and it will hit your DNA and your DNA will be broken into pieces. So Mother Nature has evolved a machine to rapidly heal the break. And I’ll speak more to this machine in a second, except I think it’s really important to appreciate how ancient the machine is, you know, life on earth is what, 4.5 billion years old, 3.5?

0:18:37 SC: Yeah.

0:18:37 FU: Whatever the number, the machinery that heals the breaks is one of the oldest molecular machines we know so to give you, just to give you a representative example, budding yeast, the tiny yeast that give us bread and wine and beer and humans, their machinery for repairing that kind of damage is so similar that biologists who study that repair machinery in human cells use the exact same nomenclature for the bits and pieces of it as the biologists who study yeast. And one thing your audience may not know about experimental biologists is they would rather use each other’s toothbrushes than use each other’s nomenclature.

[laughter]

0:19:25 FU: So when people who study human biology use the same gene names as the people who study yeast, that is really to acknowledge the majesty of Mother Nature as having evolved something a very long time ago, hundreds and hundreds of million years ago, and then preserving it. Okay. So, so far, we’ve spent a number of minutes discussing the fact that when our DNA is broken, well, it just get fixed. And what does that have to do with genetic engineering? So at this point… And one of the themes I’d love to return to a couple of times as I share with you and your audience, the marvelous thing, that’s gene editing, is how often in the… Let’s think about this 25-year-old scientific history of gene editing and ’cause that’s when gene editing really began. It began in 1994, 1995, in the laboratory of a scientist at Memorial Sloan Kettering in New York named Maria Jasin, and she’s actually still there and leads the field, and she’s absolutely wonderful. And in the 25-year history of developing gene editing as a tool, one of the things we’ve consistently marveled is, how many of the discoveries that have given us remarkable recent advances in gene editing.

0:20:39 FU: So, for example, there was recently a person, her name is Victoria Gray, and she was comfortable disclosing publicly that she is a subject. That’s a strong word to use and that’s a technical word in the world of clinical trials to describe a human being who has consented to participate in a clinical trial of an experimental therapeutic. And so she is the subject on the clinical trial to do gene editing for sickle cell disease, which she has. She got gene edited, I think about a year ago, and she no longer has sickle cell disease, which is kind of astonishing. So CRISPR, in seven years, went from being… In eight years I guess, cause it’s already 2020, time flies, my goodness. In eight years from when Jennifer Doudna here on the Berkeley campus discovered how CRISPR works, we went in just eight years from the discovery to a cure. But Jennifer Doudna’s work was focused on fundamental biology.

0:21:31 FU: She wasn’t trying to build, and she herself widely acknowledges she was not trying to build a gene editor to treat sickle. She’s just a curious scientist fascinated by how Mother Nature works. Similarly, the beginnings of gene editing emerged out of her fundamental curiosity that people had about, how do human cells repair damage? And so what emerged… By the way, it’s going to get a little bit technical, but you have my word, it’s technical of the good kind, where I’m hopeful that at the end of it, of the 60 seconds it’s gonna take me to dive into this rabbit hole of technicality, you will go, “Oh yeah, okay, that makes sense.”

0:22:08 SC: We love it, that’s why we’re here.

0:22:10 FU: Good. So there are basically two ways to repair a broken chromosome. The first one is the most logical one. You just put the DNA back together right there. So that pathway is called rather, not creatively, that’s called end joining. Again, we could have found more stylish name, but there you have it. And one of the things that’s remarkable about it is, sometimes when Mother Nature puts the two ends back together again, she loses a letter or two. Why? Well, Mother Nature has reasoned that, “Only 5% of human DNA is actually coding for genes.” And that means that only 5% of the breaks will happen in areas of the genome that make proteins that make you and I. And thus, you know what? One in 20 is okay. Furthermore, it’s not that every time a break happens, Mother Nature makes a mistake. It’s just that she makes the mistake some of the time. And that is one; the first key tool in the gene editor’s tool box is the ability to cut a gene of interest. And the two examples I will give you are ones that actually are in the clinic right now. One is to cut a gene that makes humans susceptible to HIV, and the other one is to cut a gene that prevents… This is where it’s gonna get fun. That prevents the production of a desired form of haemoglobin.

0:24:05 FU: And in both cases, you can imagine a circle where if you cut a gene that HIV needs to replicate, or if you cut a gene that prevents the production of a healthy hemoglobin, you could immediately see why that could be potentially clinically useful. You could take a person with HIV, get rid of that gene, and maybe the virus will stop doing what it does. Or you can take a human being with sickle cell disease, somebody who cannot make normal hemoglobin, cut that other gene, and Mother Nature will start making the normal hemoglobin. And I wouldn’t be dragging you through all of these technicalities if that hadn’t been done and if that hadn’t actually worked on living people not in a… One of those science fiction novels. I once type the word CRISPR on Amazon by mistake, I was going to search the literature and I was just so… I was trying to buy a book for my kid and I typed CRISPR as a Bi-Newtonian inertia in the search box, and the first thing that came out on Amazon is a novel called CRISPR: The Apocalypse.

0:25:12 SC: Sure. Someone’s gonna write that book. Once it’s out there, it’s gonna happen.

0:25:17 FU: I recommend against it because the tagline goes, “A dramatic novel of planetary disaster driven by brilliant scientists and maniacal Russians”. I’m not making this up. And so, Jennifer Doudna… I told Jennifer Doudna when I saw this, that it goes, “Brilliant scientist as maniacal Russians”. I said that between her and I, we have the two positions covered.

0:25:39 SC: There you go. But so far we’re just cutting DNA, right? My impression is we can insert also.

0:25:48 FU: We’re getting straight to that too, but when the DNA is cut, it doesn’t just shred, it comes back together again, but you gain or lose a few letters, and it turns out because of the way genes work, because of the way the genetic code works, if you gain or lose one or two letters in a gene, that actually kills the gene. Now, your audience will remember from high school biology that the elementary word of the genetic code is a group of three. For example, the word ATG is a word in the genetic code, and it says start. The word TAA in the genetic code is a word and it says stop. And the word TTT in the genetic code is a word that say, please insert the amino acid Phenylalanine. I’m not gonna recite the genetic code because that’s a fantastic way to put people to sleep, but that means that if you lose three letters, you’re still okay because you’ve just skipped a word and the text still makes sense. For example, to be or not to be, that is question whether it is noble… We just lost the word the, but it’s still intelligible, whereas in genetic text, which is read as a continuous string, if you gain or lose just a letter or two, everything after the mistake is gibberish.

0:27:19 FU: Scientists call this a frame shift, which means an inability to correctly interpret where the genetic text starts and ends its words. So this ability to break a gene or get rid of a gene by cutting it and then letting mother nature somewhat error prone and adjoining process give you what’s called a gene Knockout is actually really useful clinically, I mentioned to you this business about HIV and sickle cell disease, it’s useful for agriculture. So, for example, the first genetically engineered gene edited crop that was marketed in the United States, not GMO, GMOs have been on the market since the ’90s unless your audience knows more than 90% of corn, cotton, and soybean grown in the United States were actually old school transgenic GMOs, no, this is a gene edited crop. And the first gene edited crop will be corn, it will be waxy corn, it will be used for the production of starch, and it will not be an insertion or a precise repair of mutation, it will be actually such a gene knockout. So that’s the story of knockout, ranging from corn that has desired properties for making of starch to human beings being gene edited to deal with their HIV or sickle cell disease.

0:28:40 FU: There’s one other tool in the armamentarium of a gene editor and that’s the ability to repair mutations and if you want to be so ambitious, to insert larger stretches of genetic text. So how does that work? Well, I’m going to have to ask you and the audience to step back yet again to the fundamental biology of how mother nature deals with these rather dangerous break. We talked about the fact that the simplest thing to do is just put the two ends back together again and march on. Mother nature is concerned, in fact about precisely the gain or loss of genetic information, so she evolved a separate way to heal the brakes, which is achieves the same effect, the break is healed, but how is magnificently different. And this is one of those things… Well, I should say that podcaster one of my favorite things because I can bring them with me wherever I am. This is one of those where I wish I could magically pop out of your audiences podcast device and start waving my hands in the air, because this is one of those picture worth a thousand of words kinds of things, but let me do my best.

0:29:58 FU: The other way to repair a break is to find an unbroken identical DNA molecule and literally do a control C, control V, copy paste the missing genetic information from an unbroken intact normal template. Now, where on earth does mother nature have an unbroken intact template? Well, actually, many of your cells currently have such a template, and in fact, your skin cells, your bone marrow cells, the lining of your intestine and your mouth. Any time cells divide, they have to copy the DNA. And therefore every time mother nature copies one of your chromosomes, it makes an identical copy. And I should say in one of those ways in which geneticists have come up with nomenclature that is the bane of existence of all pre-medical students on planet earth is that identical copy of DNA is not called a twin which would be logical, it’s called a sister. I can explain why it’s one of those terms that really should be retired, but never will, we just have to live with it.

0:31:21 SC: Okay, yes.

0:31:22 FU: So in all our cells that divide, every piece of DNA is flanked by an identical copy which unfortunately is called a sister. So mother nature evolved this beautiful pathway where if one chromosome is broken, that broken end literally it’s very sweet, it’s actually kind of warm and fuzzy. There’s this little broken end and it searches, it truly performs a search, like waving its little molecular hand around can somebody help me? And what’s it searching for? It is searching for a molecule, a DNA molecule of identical sequence, and when it finds it, it automatically assumes that it is the sister molecule, that is its kin, it’s identical.

0:32:10 FU: And mother nature then evolved a way to copy-paste the information at the break from the sister chromosome into the broken one and heal the break. I know that’s a lot to take in, so I’ll just recap. One chromosome was broken. The broken end starts to search for something in its molecular neighborhood that is identical in sequence, typically it’s what’s called a sister chromatid, which is identical. It copies piece the missing information from the sister into itself, and life can continue. So what in heaven’s name does that have to do with gene editing? Much to everyone’s surprise, and as discovered by a number of people actually studying little budding yeast, and then this discovery was expanded to human cells, you can fool mother nature. Now, you can’t fool her all the time, but sometimes you do so, and with spectacular results.

0:33:16 FU: What you can do is this, take a chromosome and break it. We will speak in the second as to how you actually do that, what are those molecular systems. Normally, that break would be either repaired by putting the ends back together, which is fine, nothing we can do about that, or alternatively, it will be repaired by trying to reach out to the sister and saying, “Listen, lend me a helping hand here. I’d like some missing genetic information.” So it was discovered that you can basically stick inside a yeast cell or a human cell. A bunch of DNA that is identical in… DNA that you have made in the lab. So if this is the part where your audience hears the laughter of a maniacal scientist going, “It is alive,” [chuckle] this would be a good time to evoke the stereotype. Nobody ever said, “It is alive.” In fact, all of us who work at the branch are quite silent because we focus on what we’re doing. So we don’t rip our lab coats off and run around the streets of Berkeley saying “Eureka.”

0:34:23 FU: When you break a chromosome in a precise location and then put inside the cell a piece of DNA that is identical to the broken stretch, but you make a tiny change, you literally change one letter, mother nature will not notice and will copy-paste that change into the chromosome. It’s amazing that this works, but it does, and astonishingly well. And I’ll just give you some numbers, which are kind of amazing. Scientists have performed this process on human blood stem cells, these are the cells that make red blood cells, white blood cells, platelets. So inside your bone marrow, inside inside the bones that form your pelvis, or inside the largest bone of your… One of the largest bones in your body, which is, I think, the humerus, there’s a cavity. And inside the cavity is the famous stem cell which makes all the blood stem cells that circle around you and keep you alive. People have shown that you can take a bunch of cells like that and make a break, and then provide a decoy, a Trojan horse, a repair template, that places a new piece of genetic information into the chromosome. And literally half the cells politely acquire that new genetic change. I wanna give you this…

0:35:57 SC: Well sorry, this is important, I wanna dig in on this, ’cause this is what is confusing to me. So we’re imagining that this is a potentially grown-up, adult organism. And it’s not that you have to go in with a microscope and look at every single one of their cells and edit it, you can insert and edit, and it will spread through, at least, many of the other cells. Is that right?

0:36:25 FU: Yes. And it gets even better. To some extent, we can control how this spreads. Now, I wanna be clear what it is that is spreading. It is not the case, although that would be kind of amazing, if a genetically edited cell starts to say to its neighbors, “Guess what? I’ve been gene edited. Do you want some of my DNA?” No. That’s not what happens, although that would be kind of astonishing. By the way, I should say that there are examples in biology like that, bacteria do that all the time. But human cells normally do not share DNA with each other, instead what spreads is the gene editor itself, which is… I’m about to explain is this tiny molecular machine that we engineer in the lab, and then we stick it inside the cells. And we have two ways of doing that. If you wanna gene edit an organ such as the eye or the liver, you actually have to inject the gene editor into the body. Typically, that’s done by enveloping the editor in a virus. And this is just before people… Right now saying that we’re gonna inject people with a virus is not exactly what to say.

0:37:32 SC: Yeah. You’re gonna get big bucks asking for that.

0:37:35 FU: Right. It’s a bit like saying during a plague, “Would you like some rats?” No, we do not want more rats. So no, this is a very different virus, it’s not SARS-COVID 2, it’s innocuous. And furthermore, it’s made even more innocuous by gutting it of whatever it had and replacing its insides with a gene editor. So what you basically do for the eye is you inject the virus into the eye, and it goes and enters the cells. Or for the liver, you inject the virus directly into the bloodstream, and the virus homes to the liver and infects the liver cells and delivers the gene editor. And both of these things are being done clinically right now for congenital blindness and for haemophilia respectively. So I’m deliberately not using hypothetical examples, there are gene edited people on the planet who have been treated using this approach.

0:38:23 SC: And is this stuff that you’re editing into the genes stuff that you get from a healthy cell, or are there gene programmers actually writing the GCTAs in the correct order to get something new?

0:38:38 FU: The sky is the limit. I can tell you what’s happening now and what we’d like to do. So for now, the genetic engineering of cells organs in living humans, so whether you engineer the eye or the liver and just to give you a sense of what’s on the horizon, I think the next a genetic engineering will be for muscular dystrophy, so it will be the muscle, and then people are very excited about applying gene editing to the lung. In all those cases, what’s being done is either repair of a mutation that causes disease or the addition of a normal healthy human gene that corrects the defect in a natural gene. So there’s no “genetic augmentation” or genetic embellishment. Having said that and this is where it gets fun. In fact, one of the earliest and biggest success stories, not in gene editing, but in the bigger field of human genetic engineering was in fact precisely in such genetic augmentation.

0:39:38 FU: Now, genetic engineering of people started in 1989, so started… It’s pretty remarkable, it’s 30 years old. And it started not by precise editing, “You know, here’s a gene here, let’s fix letter number four,” it started by just in searching genes using viruses. And there are many reasons why one can do that, but the most remarkable one that’s currently not just widely practiced, but there are two approved medicines in that class is something called cancer immunotherapy. And the basic idea that emerged in the late ’90s, early 2000s, was you could cause the body’s own immune system to attack the cancer. And the way that’s done is you engineer a molecule, this is literally laboratory engineering. You engineer a molecule that will cause your immune system cell to attack the cancer cell. When you take the immune system cells out, you stick a gene that encodes or specifies the production of that new molecule. You put the cells back in and lo and behold, the cells now re-routed or re-programmed. I know those are big words.

[chuckle]

0:40:47 FU: Reprogrammed. Well, there’s a lot of imagery associated with this.

0:40:51 SC: Sure, yeah.

0:40:52 FU: People think Gothika, people think whatever they saw on instagram, and one has to be careful with language, because words have meaning. So I’m always very mindful to not say things like… This is why I think a partly, why we invented the words gene editing, because we wanted to contrast it with good old GMOs, because I don’t think… I think the damage that has been done by the publicity around GMOs I think is never gonna be repaired. I think we’re just stuck with us. They’re actually safe, but the public will never accept that fact, we just have to move on.

0:41:25 SC: But the big point that you seem to be making about the use of gene editing for fighting diseases is in some way you’re giving the body the resources that it needs to fight it in a very natural biological way.

0:41:39 FU: Correct. So for example, our ability to fight HIV by getting rid of that CCR5 gene, that’s the name of the gene is based on a discovery made here in the San Francisco Bay Area during the tragedy of the AIDS pandemic, when physicians discovered here in San Francisco, actually that there are folks, whose partners had succumbed to AIDS, and these folks reported having unprotected sex with them and yet were virus-free. And when their DNA was studied, they turned out to be naturally lacking that gene. And that told physicians, first of all, that you can lose that Gene without any overt symptoms. And second, that if you get rid of that gene, you could potentially protect a person from HIV.

0:42:16 FU: So, natural genetic variation or transferring genetic variation naturally from one person to another became a therapeutic modality. Similarly for the sickle cell disease treatment strategy that was used to treat as best as we can tell cure Victoria Gray, there are people who have this natural variant of this gene. It’s basically a reduced function of that gene, that really make normal globin. And it was the transfer of that natural variation from those people to people with the disease that is currently being practiced, so yes, you’re exactly right. This is moving natural variants from one person to another.

0:42:51 SC: How optimistic can we let ourselves be about the fight up against cancer on the dramatic side, or even just like allergies, hay fever on the less dramatic side, are we gonna be able to wipe these out some day? I know that predicting timescales is always hard, but is that a realistic target?

0:43:09 FU: I can tell you what’s gonna happen in the next five to 10 years, and at that point, we completely fall off the cliff of yogi bearing, it’s hard to make predictions, especially about the future. And the reason I say this is, if the history of science and biology, my field, over the past three decades, teaches as anything is never underestimate the remarkable things that scientists can discover that mother nature gives us. If you had told me 10 years ago when we were doing gene editing with first generation tools, that there’s a scientist at Berkeley who will discover molecular machine that will… Comes from bacteria that will use RNA to find its way to human genes and will cure sickle disease. I would probably ask for you to get some help with your mental health. And I would be egregiously wrong, because that’s exactly what happened. So, it’s super hard to extrapolate beyond 10 years because we don’t know what technologies will show up. But here’s what’s gonna happen to the next 5 to 10.

0:44:03 FU: There absolutely will be dramatic advances in the treatment of certain forms of cancer using this approach. So, certain previously incurable cancers are now curable, a lot of people are working on the application of gene editing of the human immune system to eradicate more challenging cancers. There’s early stage progress, a lot of work remains, but I am completely convinced that the next five to 10 years, we’ll see more cures, and I know cure is a big word. The other one is certain forms of genetic disease. So the particular ones that I’m thinking about are sickle cell disease, which is remarkable, there is 100,000 Americans suffering from it, it’s a terrible disease. Haemophilia, 1 in 5 to 10,000 boys born in the United States, for example, have haemophilia disorder, blood clotting. I think those two, we can realistically expect for the public health burden of those diseases and on the folks who have the disease will be dramatically reduced. I think my other biggest area of excitement for this technology is actually the treatment of pain…

0:45:06 SC: Okay.

0:45:09 FU: There are forms of… The tragedy of the fact that tens and tens of thousands of our fellow Americans have died due to overdoses from Synthetic pain killers, is these things are addictive, they’re very powerful, but they’re very addictive. So you get prescribed something for pain and you get addicted to it and you die of that, which is such a tragedy. So the worst offender is this thing called fentanyl which really, really kills. Why does fentanyl exist? Well, fentanyl exists because there are certain forms of pain that don’t respond to morphine, like cancer pain if you have cancer and if you have metastasis. I’m not a physician, but I’ve worked with physicians for 25 years so I try to carefully reproduce what I learned from them. There are certain forms of cancer pain, they’re called breakthrough cancer pain for which no conventional opiate would help, and so there are synthetics such as fentanyl which you give to folks with terminal cancer so that at least they could die in dignity rather than succumb to horrific pain. So we don’t need that thing to exist. We now know, thanks to some remarkable discoveries by geneticists that there is a gene, it’s kind of astonishing, there is now we know two genes and if you get rid of it, people feel no pain. Now, that’s a bad thing, right? You need to feel pain.

0:46:27 SC: Some pain, yeah.

0:46:28 FU: Yeah. When you’ve cut yourself, you’re in danger, or… There are many reasons why pain sensation is good. But when you have terminal cancer and you have horrific pain, you don’t need pain. And so it turns out that there are people who don’t have that gene, they don’t feel pain and then there’s a different group of people, they are more rare. They don’t just feel pain, they’re naturally high, so they’re constantly in a good mood. And so one of these genetic changes is in a system that transmits pain from your fingertip, for example, or your toe you stubbed through the spine to the brain and the other genetic system is the so-called endocannabinoid system, it’s Mother Nature’s natural pain killers that Mother Nature uses to get ourselves high in just the right way.

0:47:19 FU: And so it turns out that we can use gene editing to get rid of either one of the systems or the other and there are, in fact, early stage efforts to try to make that into a therapeutic. And so in just very realistic terms, do I see this entering the clinic in the next three to five years? Absolutely. Do I see this as having a strong potential for becoming a non-opioid, non-addictive way to treat certain forms of chronic pain? I absolutely do. And then the last… Again, 10 years ago, I would’ve probably suggested you get a reality check but today, this is how fast things are moving. I think there are certain forms of common disease for which I really see a major promise for gene editing and I say this because of some recent remarkable discoveries about a natural protection for heart disease.

0:48:08 FU: And if there’s a theme emerging, I talked about people who were resistant to HIV, I spoke to you about people who don’t feel pain, I’m now gonna share information about people who never get heart attacks. I have a family history of cardiovascular disease, so I would love to have that form of that gene but unfortunately, I don’t. The gene has one of those do jaw-breaking names that mean really nothing to lay people. It’s called PCSK9, but it turns out that those rare individuals who don’t have a normal copy, they seem to be fine, except they don’t get heart attacks. Well, it’s an exaggeration, of course, but their risk for heart attack is just vanishingly low.

0:48:44 SC: Okay.

0:48:45 FU: Okay. So what are we gonna do with that? Ask Mother Nature for a different gene? No. We ask gene editors to get rid of it and in fact, there are active efforts and clinical trials could start as early as 2022, to take people with a severe risk for cardiovascular disease, in particular, for heart attacks and just get rid of this gene prospectively before they die of a heart attack. So in brass tacks terms, you ask me, “Well, what are we looking forward to?” I’m looking forward to a fundamentally new way to treat cancer, a fundamentally a new way to approach genetic disease because, of course, we can repair mutations, things like haemophilia or sickle cell disease. I am excited, hugely excited, about pain, not experiencing it but getting rid of it and I’m really excited about certain common diseases, in particular, cardiovascular disease. Beyond that…

0:49:38 SC: So, yeah. Let’s just go all the way and try to cure aging while we’re at it, right?

0:49:44 FU: Well, okay. So this is where I’m gonna be Debbie Downer or I suppose, not Debbie Downer, but the classic saying is, “the pessimist is a well-informed optimist.”

[chuckle]

0:49:53 FU: Aging is not a disease. The Food and Drug Administration and the European Medicines Agency and the Therapeutics Goods Administration in the United States, in Europe, and in Australia and the Health Canada in Canada, do not recognize aging as a disease and this is for a good reason and you cannot, by definition, begin a clinical trial for a disease that doesn’t exist.

[chuckle]

0:50:17 SC: Okay.

0:50:18 FU: So the other problem with doing clinical trials for longevity is these trials take a while. There is a well-studied variant of a gene called IGF, it doesn’t matter what that stands for, and folks with certain variants of it consistently live longer. They don’t just live longer, they have a longer health span, which is kind of amazing. Oh, longer health span. So now imagine the gene editing trial where the scientists at the Innovative Genomics Institute at the University of California, Berkeley have found a way to crank up the longevity gene and there we are, with our frantic look in our eyes, in our lab coats, about to inject somebody with longevity juice and then of course, we wait 45 years to see if they live longer. You realize that I’m being deliberately sarcastic because it’s actually super hard.

0:51:07 SC: Yeah.

0:51:08 FU: This is super hard to do. So in practical terms what I… Go ahead, please.

0:51:11 SC: This is the difference, right? Because I’m a physicist who thinks about the cosmological lifespan of the universe and you’re someone who actually has the capability of affecting things in real ways over five-year timescales. So if something takes a century timescale, you’re like, “Yeah, let’s not think about it.” But I wanna think about that. In a few generations, could we have little molecular machines running around inside of us, curing or patching us up as we get tiny little dings on our DNA and therefore, not maybe making us immortal but extending our lifespan by quite a bit?

0:51:50 FU: First of all, I love the fact… It’s such an affecting moment for me. The universe is what, 13.4 billion years old, something like that?

0:51:58 SC: 0.8, yup. [chuckle]

0:52:00 FU: Yeah. I love the fact that you guys know that to like a fraction of a decimal. That’s just hysterical. For me, 13.7 billion versus 13.9… Yeah.

[chuckle]

0:52:08 SC: Yeah.

0:52:10 FU: And here I am stuck with the fact that something takes six months versus a year. So I love the fact that the non-physicists think of the world as on our Newtonian scale of sort of meters and centimeters, and you think in angstrom or sub-angstrom. And we think in years, and you think in billions of years. I love that, that’s amazing. So in practical terms, the way this is actually gonna proceed is we need molecular machines that crank up the body’s defenses against damage, and that’s imaginable. That’s, in fact, not science fiction. So yes, I do envisage a future, for example, and this is, again, I wanna be very careful because the world has enough novels on Amazon that describe maniacal science and engineering and Gothika-like futures. So I do imagine a future where humans acquire a molecular machine in their liver that helps the liver perform the many functions that it does. And you know the liver is a primary organ for detoxification.

0:53:17 SC: Right.

0:53:18 FU: And I absolutely see that. The other organ that I think is of huge, huge interest, and you will say the brain. No, in fact, that’s not the brain; it’s the kidney. So chronic kidney disease, 30 plus million Americans have it. The Medicare spends more money on dialysis for that condition than the National Institutes of Health spends a year on its research budgets, so it’s a huge public health burden and it’s tragedy for folks who have it. Do I see a future where we engineer ways to make human kidneys carry some form of a machine that protects it against chronic kidney disease? Yes, I do.

0:53:57 FU: So I think the same could be true for the heart. Do I see a future where we either genetic… Where we sort of we place inside the human heart a molecular entity that is wired? I don’t wanna say… I don’t see a future where we have a myocardial infarction and the infarct is repaired immediately, but I absolutely see a future where the heart carries now a molecular machine where when there is a heart attack, if the person who had it survives it, that the heart heals faster. I absolutely… That is not… In other words, all the bits and pieces exists. It’s a little bit like living on Mars. Can we live on Mars? Yeah, we have to first of all get there safely. Then we have to build the habitat. And then we have to find people who actually wanna do this. But all the bits and pieces are in principle there; you just have to put them together. So when I’m describing all of these things, it’s a little bit like the concept of creating a habitat on Mars. All the pieces are there; it’s just gonna take us to meet together.

0:55:04 SC: Right. How much of what we’ve been talking about is… There’s this divide between epigenetic editing and germline editing, which I suspect is very, very important, and maybe you’re a better person than me to explain what the difference is.

0:55:22 FU: Oh, my goodness! I hope your podcast is five hours long. No, I’m just kidding. So let’s do germline first. Very simple, it’s one of those things where things are as binary as it gets. Germline editing of human beings should never be allowed under any circumstances. Period, end of paragraph. Scientists don’t like to use the word never, but this is one of those. What is germline editing? It’s gene editing or other genetic engineering that can be passed on to future generations. There is no unmet medical need for it. The public health burden of genetic disease that exists, and it’s quite substantial, can be and is being addressed by other means, which are safe and ethical. Germline editing is unethical and in fact, illegal and useless for that purpose. The only potential reason why people would wanna do the germline editing is for human enhancement. And the reason that is should be forever banned is we don’t know how to enhance people.

0:56:33 FU: And imagine a setting, the classic example is we know of a gene, getting rid of which will somewhat protect you from Alzheimer’s. It’s called APOE4. If you happen to have APOE4 and if you get rid of it, your risk of Alzheimer’s will be dramatically reduced. So now, imagine we fertilize an embryo, and a human embryo, and then we now get rid of that gene, and then we wait 18 years to see whether that child became an adult, and then became an elderly human and is, in fact, protected against Alzheimer’s. There is no way to do this. There’s just no mechanical way. By mechanical, I mean just the way the physical world works. I shouldn’t probably say in your presence physical.

0:57:18 SC: That’s okay, it makes sense. [chuckle]

0:57:20 FU: Society. As I’ve learned through years of reading and marvelling at lay persons’ books about theoretical physics, your world is getting more, in the words of Alice in Wonderland, “Curiouser and curiouser,” with every minute, with every…

0:57:34 SC: Exactly, it is. You’re not wrong.

0:57:37 FU: Yup. So I think that germline editing is just a non-starter, is fortunately illegal… Well, it’s not illegal; it’s just not allowed in the United States. It should be banned forever. So now, epigenetic editing, oh, goodness! I think you should start a timer because I might just rant on and on. So what is epigenetics? Epigenetics is a change in the way an organism looks without a change in their DNA. And this is basic… An epigenetic mark is basically molecular makeup. Literally, like lipstick or mascara that human DNA wears to try to instruct it what to do. So the genetic code specifies what the genes say; epigenetics specify whether they say it and how they say it and when.

0:58:31 SC: Right.

0:58:33 FU: So a prime example of epigenetics gone wrong are neural tube defects in newborns. I’m sure you’ve heard and your audience has heard of spina bifida. So that’s not a genetic error, it’s an epigenetic error, and it has to do with how the neural tube develops and how during development of that neural tube, the genes acquire these epigenetic marks, so not changes in the DNA, but in this molecular make-up. And if the changes are placed incorrectly, perhaps because mom’s diet was deficient in folate and folate is a vitamin that provides an essential by-chemical piece to the epigenetic machinery. So if mom doesn’t give him enough folate in her diet, then the epigenome, here’s a pretty word, not genome, the epigenome, which is the collection of epigenetic marks that her baby’s DNA is acquiring. That her baby’s epigenome will be wrong and that babies are at risk for getting spina bifida, which is why folate supplementation is a major success of public health for prevention of neural tube defects.

0:59:47 FU: So scientists and physicians have learned that if you supplement the diet of a woman who would like to become pregnant and of a woman who is pregnant, then she can choose to supplement her diet with folate before becoming pregnant and while carrying the baby, and that will substantially reduce although not completely eliminate unfortunately the risk of her delivering a child with spina bifida. Although full disclosure, I wanna be very, very… What’s the word I’m looking for? I wanna be very respectful, as all people in my field of the fact that they’re… Ultimately what we do is about folks with the conditions, with the disability and their rights, their interest, their feelings are… I don’t wanna… Sacred is a very strong word, but they kind of are.

1:00:33 SC: Yeah put them first, primary.

1:00:36 FU: Right, and so I want to be very careful here. I’m sure there are… We are trying to reduce the prevalence of this medical condition while being enormously respectful and supportive and caring for the folks who have these conditions, right? I mean you know, so that is what drives all that we do. Having said that folate supplementation if a woman chooses to take it, will reduce the risk of that women having a child with a neural tube defect. Why? Because of an epigenetic effect. So believe it or not, recent developments have created not just gene editing, which is, you know, you change the sequence of DNA by either repairing a mutation or getting rid of a gene or adding a gene. You can also do epigenome editing, what does that mean? You don’t change the genes, you just change what the genes do and that as it turns out, can have real benefits in some settings.

1:01:38 FU: So for example, you can tune the duration of the effect, where, you know, a genetic change is like diamonds, it’s forever. An epigenetic change does not have to be forever, you can dial it in to last for a couple of months for some reason, and if not, it goes away. And I wouldn’t be saying this to you, if you were a humble servant together with some colleagues at the University of California, San Francisco, Carnegie Mellon and at the Whitehead, wasn’t working on a project funded by DARPA to create such an epigenetic change using CRISPR, in America’s war fighters, to protect them from radiation damage in the theatre of war, in America’s first responders to protect them for when they have to rush to the scene of either potentially a nuclear accident or a dirty bomb scenario, and also to protect folks in the United States who are about to undergo radiation treatments for their abdominal or pelvic cancers. In all these cases, we are engineering a CRISPR, which we hope will create for a few weeks an epigenetic edit to protect the bone marrow and the guts of these individuals, whether the war fighter, the first responder or the patient in a radiation oncology work for just a month or so, from the danger of radiation poisoning. So this is a scenario where an epigenetic edit is preferable to a genetic one.

1:03:05 SC: Well, I wanna dig into why it’s preferable if you could do the same thing that make these soldiers stronger and more resistant to bullets as well as radiation and why not make it last a long time? I’m asking leading questions because I think that these are good issues and we shouldn’t just zoom over them, we should sort of sit down and think about what the issues are.

1:03:31 FU: So this is something that I, myself and all our colleagues and the Department of Defense has thought hard about. America’s war fighters will stand up and defend her whatever the need, but you have to be respectful of the fact that these women and men have committed their lives to that, and we have to be respectful of that, we cannot be and I’m not suggesting you’re saying that I’m just saying we have to be respectful of their commitment to our country. And here I think the Department of Defense wisely and I concur with their judgement, has argued against making a permanent change. Because you know what? That system for protecting us against damage has its benefits, you know if a cell is too damaged, then you know, it might die a normal death rather than survive and potentially acquire a cancerous change.

1:04:23 SC: Yeah.

1:04:24 FU: In an extreme setting where a war fighter who is in the Special Forces, the tip of the spear, as the Department of Defense describes them, have to be dropped from a helicopter into a regime change scenario where there’s a nuclear fuel and this is a realistic thing to contemplate where that fuel can fall into the wrong hands. They’re putting their lives on the line to save the world from disaster, that’s one scenario, when we protect them for a month, against a harm that they can come in contact will. But when they’re honorarily discharged to leave the military or whatever, we want them to go back to life’s pre-military. So I tell you, I would not agree right now to work on a gene edit program for an enhancement of that type, I just wouldn’t. Epi edits, sure, but the idea that I would permanently genetically engineer a human being and thus commit them to having that DNA for the rest of their lives, and this was an enhancement type edit, I don’t know man. That would be a hard pill for me to swallow.

1:05:36 SC: Well, I’m very sympathetic to this idea that it’s incredibly difficult to know what all of the possible ramifications are, were you to go down that road. Even with the best of intentions, if you try to make people healthier or had better eyesight or whatever, or taller or bigger IQ’s, it could ruin other things that we have a difficult time anticipating. But I guess what I’m thinking… What I’m not doing is advocating it, but what I’m doing is guessing that someone’s not gonna feel that way, someone’s just gonna do it, it’s gonna be done somewhere in the world, this technology is becoming easier and easier to use. Are there gonna be people in their garages, 3D printing CRISPR programs to make different babies?

1:06:23 FU: Absolutely, and that’s in fact already happening.

1:06:26 SC: Yeah.

1:06:27 FU: I think that the tragedy of Jiankui He’s alleged crime is that… I don’t wanna swear on air, but you can imagine, I’m inserting words here what you’re work… Language that I learned to use when I was drafted at the age of 18, when I was drafted into the Soviet military.

1:06:47 SC: That I would have to flag on YouTube, I understand.

1:06:50 FU: Yeah. But Jiankui He is a criminal.

1:06:54 SC: This is the Chinese scientist who actually did this to human babies for…

1:07:00 FU: Allegedly.

1:07:01 SC: Allegedly, yeah. Okay.

1:07:02 FU: So he performed two crimes, the first crime is he irreversibly stained my field of genetic engineering to treat disease with a imprint of designer baby. You tell people, “I do CRISPR.” People say, “Oh, do you make babies? Do you make smarter babies?” No, we don’t. We try to cure cancer and sickle cell disease, but the other thing that’s even a deeper crime is he showed to the rogues of the world that this can be done. I am absolutely convinced that there are laboratories right now, they’re underground, I don’t mean physically, I mean metaphorically who are enhancing “embryos for people with too much money and not enough understanding of the science and not enough ethics.” That’s happening, and I don’t think there’s any way to prevent that from happening. Because again, this is why Jennifer Doudna’s discovery of how CRISPR works is… Revolution is not enough of a word, it put us in a different world.

1:08:10 SC: Right.

1:08:12 FU: As a scientist, I would say it’s phased transition, but that’s a good way to put people to sleep.

[laughter]

1:08:18 SC: Believe me, I know.

1:08:20 FU: Imagine metamorphosis where you have a crawling caterpillar and suddenly you have a flying butterfly, so Jennifer’s discovery converted my world from a crawling caterpillar to a flying butterfly, just like… We’re moving in a fundamentally different way, we have flight, thank you very much. So it’s actually high school biology, easy. So our will there be and are there people who don’t understand the literature and who are delusional doing that right now to themselves and potentially human embryos? There are. Here’s what to do about this. First, embryo and baby editing has to be a crime everywhere to ensure that 100% of the time that somebody is outed, somebody running 1800designyourbabysgenes.com. Every time these people are outed, they go to jail, period, end of paragraph. Separately, and that cannot eradicate that because CRISPR is too technologically straightforward, like I don’t know anything about nuclear reactors, but I suspect the building one requires a certain amount of know-how.

1:09:31 SC: Yes.

1:09:33 FU: And you have to have the infrastructure and you have to buy the stuff. So that’s not true for CRISPR. The know-how is relatively modest and you can buy the stuff. And you can buy the stuff sort of sotto voce, you don’t have to tell the world, “Oh my God, I’m doing CRISPR on my baby.” So that has to be driven into as low a prevalence as possible by making it completely illegal, human semantic enhancement of consenting adults. Well, let me give you an example. Botox is legal for wrinkles, Botox, is botulinum toxin. Is one of the most dangerous substances on earth by weight. The Food and Drug Administration has approved a situation where people who don’t like wrinkles inject themselves with Botox. So do I see a future where there’s CRIPSRox, I hope it’s not called that, [chuckle] that people inject into themselves to get of wrinkles or whatever. Change their eye color, I don’t care. As long as consenting adults apply to themselves things that have passed regulatory review by the FDA, by Health Canada, by the EMA, I’m totally fine, but the key issue here is consent.

1:10:47 SC: Right.

1:10:49 FU: As long as a human being with eyes open agrees, then I see no reason, difference frankly, people get tattoos all the time, and then getting rid of them is a lot harder, people need to understand that a gene edit cannot be eliminated and that they will live with the consequences of that for the rest of their lives, but at the end of the day it will come down to free will. If it’s legal for somebody to obtain a piercing in a body part where most people would rather not put a needle, it’s perfectly fine for people to create a double-strand break in their DNA using a procedure that is safe and permanently genetically modify them.

1:11:22 SC: So we should maybe shift our focus from designer babies to designer grown-ups.

1:11:27 FU: There will be designer grown-ups, for sure. There’s no question in my mind. And the only thing that needs to happen for that is a few years need to pass for the FDA to grow comfortable with a safety and efficacy record of gene editing for treating disease. And the classic example I’ll give you is statins. Statins were, everybody takes statins if they’re at risk of cardiovascular disease but they were not initially developed for prevention, they were approved for the treatment of rare forms of heart disease. And when it was seen that they’re safe, they’re now over-the-counter statins or I think they’re about to be. So the same thing will happen with gene editing. Once we know that it’s safe and effective to treat disease somebody will show up and say, oh, I’ll give you an example, if you get rid of a gene called the androgen receptor and it’s on the X chromosome and we know where it is, I know it, I can tell you everything about it. If you get rid of that gene you will get rid of baldness. So you can put CRISPR in shampoo, can you imagine?

1:12:17 SC: Yes.

1:12:17 FU: The company that builds that, I’m sad to say will be more expensive than Apple and a Google.

1:12:24 SC: Yeah.

1:12:24 FU: Because then the amount of money that people will spend on their vanity as experience has shown is pretty insane. So yeah, I totally see a setting where there is a shampoo, I wanna emphasize, I haven’t had any stimulant other than coffee today. So do I see a future where there is a CRISPR like molecule formulated in a special chemical formula to allow penetration of the scalp and editing the androgen receptor gene and the stem cell at the bottom, at the root of each hair follicle and thus prevent a male pattern baldness. Absolutely that this will happen, this will happen.

1:13:05 SC: Well, I always like to say that I like to end the podcast on optimistic note and that’s certainly one but just in case there’s another optimistic note out there, do you have some final words about how this all relates back to the pandemic and our current urge to shield ourselves from this nasty little virus that’s running around?

1:13:24 FU: I do. I think that real world solutions require many different sub-units and they don’t emerge from the same field. So for example, my favorite example is that the space suit that Neil Armstrong walked the moon in was not made by one giant contractor, it was made by Playtex. Seamstresses at Playtex sewed the space suit. So in 1969 I think is when the moon shot was, this marvel of technology, the rocket, the telemetry, the fuel, the engine, blah, blah, blah and the space suit was sewn by seamstresses at Playtex.

1:14:06 FU: Similarly, the real world impact of any technology such as CRISPR on anything such as the pandemic, requires multiple technologies and other things to converge in real, people have to wear masks, but I think we have entered two separate ages in medicine. The first one is, we have entered the age of the genetically engineered human. That is irreversible, there are now approved medicines for cancer and for genetic disease where people get genetically engineered. This will only rise and over the next decade or two the public health burden of genetic diseases and infectious diseases and cancer will start to be lower in the developed world where there’s access to treatments of that type but we have also entered the age where we don’t just read human DNA, we understand what human DNA says and we’re doing this at a pace that was… What was unimaginable before and critically these discoveries are translated into therapeutics or ways to prevent disease much faster than anyone thought possible.

1:15:12 FU: It used to take 15 years, these days it takes two. Two years ago when Regeneron discovered a gene that protects from a non-alcoholic steatohepatitis which is a severe disease of the liver, two years later they’re in the clinic with the medicine or an AI that targets that gene. It’s unimaginable that two years, only two years past. So as far as the pandemic is concerned for these viruses or other viruses, I’m actually excited about the prospect of genetic engineering of humans to genetically vaccinate them for viral infections.

1:15:44 FU: Now frankly, where I’d like to go first with this is into the developing world, into parts of Africa and Asia where there is not enough access to HIV medication to use gene editing to genetically vaccinate folks at risk for HIV against it pre-emptively. I think that that would be… Obviously, this would have to pass regulatory review and would have to pass the highest rigor of ethics in terms of informed consent etcetera, but I think, do I see a future where we engineer pre-emptively gene edits or epigene edits as this year’s vaccine for SARS-CoV-7 to prevent us, protect us from COVID… COVID-2026 which there will be COVID-2026 as we all know it’s not just COVID-19? Yeah, absolutely. We have entered a very formidable space where the technologies have now convert, where genetic engineering or epigenetic engineering of people is a clinical reality and it’s just gonna grow in scope.

1:16:47 SC: It really does make me feel like the state of gene editing in 2020 is sort of like or making predictions about its future is like trying to predict the future of the personal computer in the early 1980s, right? There was clearly something going on and you could see that things would happen but it’s probably the unanticipatable consequences that will end up being the ones that will really change things down the road.

1:17:12 FU: I could not agree with you more. And Sydney Brenner, one of my scientific idols, a Nobel Laureate and one of the founders of modern experimental biology said, “Progress in science comes from new technologies and new discoveries and new ideas probably in that order,” which is a stunning thing to say because he was the father of so many ideas that changed the world but… We are in a technology driven space, I completely agree with you. I’m not a computer person but clearly miniaturization right, the transition from I’m old enough to remember floppy disks. It’s impossible to explain to my 21-year-old daughter what a floppy disk is.

1:17:53 SC: Yeah, yeah.

1:17:55 FU: And so do I anticipate exactly as you said that progress in human genetic and epigenetic engineering in the clinic and for disease protection and potential enhancement will be as unpredictably exciting as what’s happened from the good old IBM PC 80 in 1986 or whatever? Absolutely, that is exactly what will happen, so I guess we just buckle our seatbelts and either make this happen or make use of what’s happening.

1:18:24 FU: Yeah, well, we appreciate very much you helping us to buckle our seatbelts here, I think it’s gonna be a wild ride. Fyodor Urnov, thanks so much for being on the Mindscape Podcast.

1:18:33 SC: Truly a pleasure.

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