Sean Carroll's Mindscape: Science, Society, Philosophy, Culture, Arts, and Ideas - 112 | Fyodor Urnov on Gene Editing, CRISPR, and Human Engineering

Episode Date: August 31, 2020

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. Support Mindscape on Patreon. 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. Web page Google Scholar publications Innovative Genomics Institute Talk on "The Next Generation of Edited Humans" Twitter Todays episode is sponsored by The Great Courses Plus. Mindscape listeners get a free trial if they sign up at http://thegreatcoursesplus.com/mindscape.

From the neon lights of the club to the harsh, buzzing lights of the office. Don't let the wear show on your face. Just swipe Mabeline instant eraser concealer to erase the night before, wherever that happens to be. Instantly covered dark circles and under-eye bags for a brighter, more awake look. This do-it-all formula also contours, corrects, and highlights, all while staying lightweight, crease-resistant, and smooth. It may be the world's greatest eraser. Find your shade of instant eraser concealer at your local retailer. Looking to see up close, make it visible with Viz.

Viz is a once daily prescription eye drop to treat blurry near vision for up to 10 hours. The most common side effects that may be experienced while using Viz include eye irritation, temporary, dimmer, dark vision, headaches, and eye redness. Talk to an eye doctor to learn if Viz is right for you. Learn more at Viz.com. Hello, everyone. Welcome to the Minescape podcast. I'm your host, Sean Carroll. And I'm sure that you've all heard the excitement, 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 Urnod, 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, you know, 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, you know, 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? And his answer was a little bit surprising. He said, absolutely, it's going to happen. And that's a little bit of a wake-up call. You know, it is kind of easy to play around with the human genome. And we're going to have to deal with that in one way or the other.

All this stuff came about over just the last 10 years or even five years with a wonderful little gizmo called CRISPR CAS, which you've probably heard about, CRISPR CAS 9. Jennifer Dudna, Emmanuel Chompontier, and other researchers figured out how to basically borrow a mechanism that had already been invented by biology, right? is something that exists in bacteria in order to fight off viruses. So the CRISPR-Cast-9 system can recognize a bad virus and then go in and attack and neutralize it. And the way that it neutralizes it is by sniping 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.

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 Cast 9 Revolution and is still there working at the front lines on both what gene editing is, how it works, and what it's going to mean for us in the years to come. So this is a great conversation with Fyodor Ornov. 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 hard back version rather of uh it's still a hard copy if you get the paperback version the hard back version of something deeply hidden and you want to 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 bookstore and pick up a copy of something deeply hidden. I will appreciate it. The universe will appreciate it. And with that, let's go.

Peter Orinov, welcome to the Mindscape podcast. Thank you for having me. 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 slash cell. biologists onto the show. They're somehow their attention is being absorbed by something else, by this weird virus that is sweeping the world. So are you one of these people whose attention has been diverted from your regular work, or have you sort of stubbornly pressed forward with your basic research, even in the middle of the pandemic? 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 is the protein that we use 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 the 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. And productively so, do you think that the skill set that you had coming in has been well calibrated for the challenges of this? 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 going to 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. We're ecumenical here at the Minescape podcast. Don't worry. 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. 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? 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 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 student, 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. Yeah. And it seems literally, it's literally in the last century. And yet, the fundamental mechanics of how one diagnosis and individual to have the virus rely on, I guess, decades old techniques, which are tried and true. Oh, that's actually good to know. I mean, 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 the biologists. 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 it. It did happen in the Manhattan Project, but it's different now. Yeah. 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. Yeah. I think most people don't know that the GPS on their phones works on Einstein's theory of relativity, right?

Absolutely, yeah. Absolutely. And just, but I mean, no, I swear you that the majority of people who use that just don't, don't, 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. Right. It's just not something that's in the headlines daily. And yet here we are basic biologists used to sitting with our test tubes and our cells in isolation of a laboratory. finding ourselves in the in the in the in the minds of the public like I 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 preliminary chain reaction by the way would be ever would ever emerge in a lay person conversation yet here we are well this is a good segue because what I what I actually want to 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 does it go around crisping and what are we going to use it for? Oh, my goodness. You can skip the what are we going to 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. 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, due to the human genetic code, or as it happens, to the genetic code of a cow,

or to the genetic code of a maze plant. And I use these three examples deliberately because these are living things that have been, genetically edited or crispered. 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 was our explicit goal and I guess we succeeded. But I think that maybe people take that analogy too literally. You know, 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. I mean, the messy biology of it is a bit more intricate. 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.

Yes. So in telling you how gene editing broadly and how CRISPR specifically works, I really need to carefully walk that, line to not over simplify. 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.

It's 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 true for core. Second, with the exception of microbes, like really small things that move around and leave their little independent lives,

most living systems don't like their DNA changed in any way at all. And this is because DNA is, you know, essentially the storage document for who they are. Yeah. And Mother Nature protects the integrity of the genetic material. So, and you, 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. So for example, there are folks with 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, you know, sunscreen SPF 10,000.

Right. And in fact, they sell, they 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 damage DNA? So I mentioned sunlight, so UV rays create a particular kind of damage. Chemicals can damage DNA.

So, for example, you know, the reason smoking causes cancer is it has a chemical, which physically damages the DNA and the repair machinery doesn't get to it in time, and you get genetic changes that cause cancer. The other type of damage that our DNA gets all the time, and this is the most interesting one for people who want to 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 two double helix, one double helix you now have two. So this is a 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 get a chest x-ray, I guess I suppose an assay 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's chair, other than for anticipation of whatever. Other than there's no, we don't need additional reasons to not want to go to the dentist. But 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 a cell needs to divide, it makes a copy of all the chromosomes. And one copy goes to the cell on the left. He 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.

Now, you can get rid of some, but the notion that there would be a break on one of the chromosomes, such 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, you know. whatever the number, the machinery that heals the brakes is one of the oldest molecular machines we know. So just to give you a representative example, budding yeast, the tiny yeast yeast 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 humans. 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. 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 modern 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, you know, it just gets fixed.

And what does that have to do with genetic engineering? Yeah. 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, because 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 Marie Jason, 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. 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's 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, because it's already 2020. Time flies, my goodness. In eight years from when Jennifer Dowdna here on the Berkeley campus discovered how CRISPR works, we went in just eight years from the discovery to a cure. But generally, Jennifer Dowdena's work was focused on fundamental biology. 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 a fundamental curiosity that people had about how do human cells repair damage. Let me pause for a moment to recommend the Great Courses Plus. This is a streaming service that gives you instant, access to a wide variety of high-level courses so that you can learn about things in the privacy of your own home at your convenience. I love the fact that there's such a wide variety of topics being explored, from oceanography to history, to philosophy, to food and wine and music. For

example, there's one interesting course I came across on digital media literacy. It's simply called Fighting Misinformation. So it's a great course's level introduction to how to be be a smarter consumer of what you read about and find online. The Great Courses Plus is great because it's really convenient. You can watch it on your computer, you can listen to it, it can be on your mobile device, on your TV with your family, or what have you. Now is the perfect time to sign up for the Great Courses Plus because Mindscape listeners can get a free trial today if they go to this special URL. The Greatcoursesplus.com slash mindscape. That's T-HE, greatcourses, plus.com slash mindscape.

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 this, of the 60 seconds is going to take me to dive into this rabbit hole of technicality. You will go, oh, yeah, okay, that makes sense. We love it. That's why we're here. 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 at them. So that pathway is called rather, you know, not creatively, that's called end joining. Again, we could have found a 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, you know, Mother Nature has reasoned that, quote unquote, only five. 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? 1 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 it. of the time. And that is one, the first key tool in the gene editor's toolbox 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 going to get fun, that prevents the production of a desired form of hemoglobin. And in both cases, you can imagine a second 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 you know, Mother Nature will start making 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, you know, one of those science fiction novels. I once typed 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 by Newtonian inertia in the search box. And the first thing that came out on Amazon is a novel called CRISPR the apocalypse. Sure. Someone's going to write that book. Once it's out there, it's going to happen.

You know, 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 Dowden, I told Jennifer Dowden when I saw this, that, you know, it goes brilliant scientists as maniacal Russians. I said that between her and I, we have the two positions covered. There you go. But so far we're just cutting DNA, right?

I mean, my impression is we can insert also. Oh, we're getting straight to that. 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 readers will, your audience will remember from high school biology that the genetic, the elementary work, of the genetic code is a group of three.

For example, the word A, T, G is a word in the genetic code, and it says start. The word T-A-A in the genetic code is a word, and it says, stop. And the letter, the word T-T-T in the genetic code is a word that says, please insert the amino acid phenylalanine. I'm not going to 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 nobler.

We just lost the word thee, 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. 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's somewhat error-prone and dejoining process give you a 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 will be marketed in the United States, not GMO. GMOs have been on the market since the 90s, and as your audience knows, more than 90% of corn, cotton, and soybean grown in the United States are 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 genetic to deal with their HIV or sickle cell disease. 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 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 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 podcasts are one of my favorite. think 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 audience's podcast device and start wading my hands in the air, because this is one of those picture worth a thousand words kinds of things, but let me do my best. 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 yourselves currently have such a template. And in fact, your skin cells, your bone marrow cells, the lining of your intestine and your mouth, anytime 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 premedical 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. Okay. So yes, in all ourselves that divine, 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 it's 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. 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 is 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 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. What you can do is this. Take a chromosome and break it. And we can,

we will speak in a 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, let 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 this is, if this is the part where your audience hears the laughter of a maniacal scientist going, you know, it is alive. This would be a good time to evoke the stereotype. Nobody ever said it is alive. In fact, most of us, in fact, all of us who work at the bench are quite, quite silent because we focus on what we're doing. So we don't, you know, rip our lab coats off and run around the streets of Berkeley saying urepa. 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. So, 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, wide blood cells, platelets. So inside your bone marrow, inside the bones that form your pelvis or inside the largest bone of your, of your, one of the largest bones in your body, which is, I think, the humorous, there's a cavity. and inside the cavities is the famous stem cell, which makes all the blood stem cells that circle around you and keep you alive.

You know, 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. change. I want to give you this number. This is important. I want to sort of dig in on this because 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? Yes, and it gets even better. To some extent, we can control how this spreads. Now, I want to 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 as 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 want to 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 you're going to inject people with a virus is not exactly what to say. You're not going to get big bucks asking for that. 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-CoV-2. It's innocuous. And furthermore, it's made even more innocuous by gutting it of whatever it had and replacing its insights with the 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 hemophilia respectively. So I'm deliberately not using hypothetical examples. There are gene edited people on the planet who have been treated using this approach. And is the stuff that you're editing into the genes, stuff that you get from a healthy cell,

or are there gene programmers actually writing the G-C-T-A's in the correct order to get something new? 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 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 DNA. effect in a natural gene. So there is no, quote-unquote, genetic augmentation or genetic embellishment. Having said that, and here's, you know, 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. Now, genetic engineering of people started in 1989, so it's pretty remarkable. It's 30 years old. And it's a very, it's pretty remarkable. It's 30 years old. It started not by precise editing, you know, here's a gene here, let's fix letter number four.

It started by just inserting 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.

Then 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 rerouted or rerouted or a reprogrammed. I know those are big words. Reprogrammed. Well, I mean, there is a lot of imagery associated with it. Sure. People think gotica. People think whatever they saw on Instagram. And, you know, one has to be careful with language because, you know, words have meaning. So I'm always very mindful to not say things like, you know, this is why I think partly why we invented the words gene editing because

we wanted to contrast it with, you know, good old GMOs because I don't think. Right. I think the damage that has been done by the publicity around GMOs, I think is never going to be repaired. I think we're just stuck with that. They're actually safe, but the public will never accept that fact. So, you know, we just have to move on. 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. 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. 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, Q or 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. And is this, I mean, how optimistic can we let ourselves be about, you know, the fight up against cancer and the dramatic side or even just like allergies, hay fever on the less dramatic side? Are we going to be able to wipe these out someday? I know the predicting timescales is always hard, but is that a realistic target? So I can tell you what's going to happen in the next five to ten years.

And at that point, we completely fall off the cliff of Yogi Berri. You know, it's hard to make predictions especially about the future. And the reason I say this is if, you know, if the history of science and biology, my field, over the past three decades teaches us anything is never underestimate the remarkable things that scientists can discover that mother nature gives us. You know, if you had told me 10 years ago when we were doing gene editing with first generation tools, that there is a scientist at Berkeley who will discover a molecular machine that will comes from bacteria that will use RNA to find its way to human genes and it will cure sickle cell 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 super hard to extrapolate beyond 10 years because we don't know what technologies will show up. Here's what's going to happen in the next 5 to 10. 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 ten years will see more cure than 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 it's remarkable. There is 100,000 Americans suffering from it. It's a terrible disease. Hemophilia, you know, one in five to 10,000 boys born in the United States, for example, have hemophilia disorder of 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 in the treatment of pain.

Okay. So there are forms of, you know, 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 know, you get addicted to it and you die of that, which is like, 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 breakwork cancer pain, for which there's no conventional opiate would help. So there is synthetics, such as pentanyl, which you give to folks with terminal cancer so that at least they can 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, and 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. Some pain, yeah. Yeah, you know, when you've cut yourself, you're in danger or, you know, there are many reasons why pain sensation is good. But when you have criminal 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're more rare. They don't just feel pain. They're naturally high. So they're constantly in a good mood. And so one of the, 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 painkillers that Mother Nature uses to get ourselves high in just the right way. 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, which again, you know, 10 years ago, I would have 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 some recent remarkable discoveries about natural protection for heart disease. And if there's a theme emerging, I talked about people who were resistance to HIV, I spoke to you about people who don't feel pain.

I'm now going to share information about people who never get heart attacks. And, you know, 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 jawbreaking names that mean really nothing to lay people. It's called PCSK-9. 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. Okay. So, you know, what are we going to do with that? Ask Mother Nature for a different gene? No. We ask gene editors to get rid of it. And in fact, they're 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, you know, in brass tax 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 new way to approach genetic disease, because, of course, we can repair mutations, things like hemophilia or sickle cell disease. I'm 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, you know...

Yeah, I mean, let's just go all the way and try to cure aging while we're at it, right? Well, okay, so this is where I'm going to be Debbie Downer, or I suppose not Debbie Downer, but, you know, the classic saying is that pessimist is a well-informed optimist. aging is not a disease. The Food and Drug Administration and the European Medicines Agency and the Therapeutics Good Administration in the United States in Europe and in Australia and 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. So the other problem with doing clinical trials for lungiative. is these trials take a while. Like, imagine you had the, so 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. Whoa, longer health span. So now imagine a gene editing trial where, you know, 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 and our lap coats about to inject somebody with longevity juice.

And then, of course, we wait 45 years to see if they live longer. You realize I've been deliberately sarcastic because it's actually super hard. Yeah. This is super hard to do. From the writers of parenthood and life as we know it comes, it's not like that. A new family drama about starting over and second chances. Scott Foley stars as Malcolm, a recently wind. widowed pastor and dad of three. And Aaron Hayes is Lori, newly divorced with two teens. Their families

used to do everything together. Now they're navigating single parenthood and maybe something more. Watch, it's not like that. All episodes streaming May 15th on Prime Video. So in practical terms, what I think so. Go ahead, please. I mean, 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 time scale, you're like, yeah, let's not think about it. But I want to think about that. I mean, is 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? First of all, I love the fact, you know, it's such an affecting moment for me. You know, the universe is, what, 13.4 billion years old, something like that? Point eight, yep. I love the fact that you guys know that to like the fraction of a decimal. That's just hysterical. For me, you know, 13.7 billion versus 13.9. Yeah. Yeah. And here I am stuck with the fact that something takes six months versus a year. So I love the fact that the, you know, we, the non-physicists think of the, think of the world as on are in Newtonian scale, you know,

sort of meters and centimeters and you think in angstrom or subangstrom, 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 going to 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 want to be very careful because the world has enough novels on Amazon that describe maniacal science and engineering and gothic-like futures. So I do imagine a future where humans acquire a molecular machine in their liver that helps the liver tolerate the many, perform the many functions that it does. And you know, the liver is a primary organ for detoxification. Right. 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, it's not the brain, it's the kidney.

So chronic kidney disease, you know, 30 plus million Americans have it. You know, Medicare spends more money on dialysis for that condition than the National Institutes of Health spends a year on its research budget. So it's a huge public health burden, and it's a 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. So I think the same could be true for the heart. Do I see a future where we either genetic, where we sort of place inside the human heart, a molecular entity

that is wired? I don't want to say, like I don't see a future where, I don't see a future where we have a myocardial infarction and the infarctrine 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 factor. I absolutely see that. That is not, in other words, all the bits and pieces exist. You know, it's a little bit like living on Mars, right? I mean, can we live on Mars? I mean, yeah, we have to, first of all get there safely. Then we have build a habitat, and then we have to find people who actually want to do this. But like, kind of 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, you know, the concept of creating a habitat on Mars. All the pieces are there. It's just going to take us to together. 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, very. important and maybe you're a better person than me to explain what the difference is. Oh my goodness. I hope your podcast is five hours long. No, I'm judging. 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 is quite substantial can be and is being addressed by other means which are safe and ethical. ethical. Germline editing is unethical and in fact illegal and useless for that purpose.

The only potential reason why people would want to do the germline editing is for human enhancement. And the reason that should be forever banned is we don't know how to enhance people. 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, you know,

we fertilize an embryo and a human embryo, and then we 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, mechanical way.

by mechanical, I mean just the way the physical world works. I shouldn't probably say in your presence physical. That's okay. It makes sense. Society. As I've learned through years of reading and marveling at a layperson's books about theoretical physics, your world is getting more, in the words of Alison Wonderland, curiouser and curious.

Exactly. It is. You're not wrong. Yep. 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. But what epigenetics? Epigenetics is a change in the way an organism looks without a change of their DNA. And this is basically, an epigenetic mark

is basically molecular makeup, you know, literally like lipstick or, 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. Right. So a prime example of epigenetics gone wrong are neural tube defects in newborns. I'm sure you've heard in 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 neurotube develops and how during development of that neurotube, the genes acquire these epigenetic marks. So not changes in the DNA, but in this molecular makeup. 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

bichemical piece to the epigenetic machinery. So if mom doesn't get 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 at risk for getting spina bifida,

which is why folate supplementation is a major success of public help for prevention of neural tube defects. 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 both 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 Bufida. Although, full disclosure, I want to be very,

very, what's the word I'm looking for? I want to be very respectful as all people in my field of the fact that ultimately what we do is about folks with the conditions, with the disability, and their rights, their interests, their feelings are,

I don't want to, sacred is a very strong word, but they kind of are. Yeah, put them first, primary. Right. And so I want to be very careful here. I'm sure 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 woman having a child with a neural tube effect. Why? Because of an epigenetic effect. So believe it or not, recent developments have created not just gene editing, which as 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 the genes. You just change. what the genes do. And that, as it turns out, can have real benefits in some settings. So, for example, you can tune the duration of the effect where, you know, genetic changes like diamonds are 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're humble servant together with some colleagues at the University of California, San Francisco, Carnegie Mellon at the Whitehead, wasn't working on a project funded by DARPA to create such an epigenetic change using CRISPR in America's warfighters

to protect them from radiation damage in the theater 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 treatment 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 gut of these individuals, whether the warfighter, the first responder, or the patient in a radiation oncology ward for just a month or so from the day, danger of radiation poisoning. So this is a scenario where an epigenetic edit is preferable to a genetic one. Well, I want to dig into why it's preferable. I mean, if you could do the same

thing, but make these soldiers stronger and more resistant to bullets as well as radiation, and why not make it last a long time. I mean, I'm asking leading questions because I think these are good issues and we shouldn't just zoom over them. We should sort of sit down think about what the issues are. So this is something that I myself and all our colleagues and the Department of Defense has thought hard about. You know, America's warfighters will stand up and defend her whatever the need. And so, but we 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, right?

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 judgment, 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 counterist change. Yeah. 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,

you know, have to be dropped from a helicopter into a regime-changed scenario where there is a nuclear fuel, and this is a realistic thing to contemplate, where that fuel can fall into the wrong hands. I mean, 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 with. But when they go, when they, when they're honorably discharged or to leave the military or whatever, we want them to go back to lives pre-military. So I would be, I tell you, I would be, I would not agree right now to work on a gene edit program

for enhancing, enhancements of that type. I just wouldn't. Epi edits, sure, but the idea that I would permanently genetically 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. Well, I'm very sympathetic to this idea that it's incredibly difficult to know what all the possible ramifications are

where you to go down that road, right? Like, even with the best of intentions, if you tried to make people, you know, healthier, or had better eyesight or whatever, or taller or bigger IQs, it could ruin other things that we have a difficult time anticipating. But I guess what I'm thinking of, what I'm not doing is advocating it, but what I'm doing is guessing that someone's not going to feel that way. Someone's just going to do it, right?

It's going to be done. Somewhere in the world, this technology is becoming easier and easier to use, right? Like, are there going to be people in their garages, 3D printing CRISPR programs to make different babies? Absolutely. And that's, in fact, already happening. Yeah. I think that the tragedy of Gen Quay has alleged crime is that I don't want to swear on air, but like I'm, you can imagine I'm inserting words here with your work, you know, language that I learned to use when I was drafted at the age of 18, when I was drafted.

when I was drafted into the Soviet military. That I would have to flag on YouTube. I understand. Yeah, no, let's, but Gen Quay Ha is a criminal. This is the Chinese scientist who actually did this to human babies, right? Allegedly.

Allegedly, yeah, okay. So he performed two crimes. The first crime is he irreversibly stained my field of genetic engineering to treat disease with a, with an imprint, of designer baby. You know, you tell people I do CRISPR, people say,

oh, do you make babies? Do you make smarter babies? Yeah. 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 mean physically, I mean metaphorically. Yeah. Who are enhancing, quote, unquote, embryos for people with too much money, too much money and not enough understanding of the science and not enough ethics. That's happening. And I think that, I don't think there is any way to prevent that from happening.

Because, again, this is why Jennifer Dowden's discovery of how CRISPR works is, I mean, revolution is not, is not enough of a word. It puts us in a different world. Right. You know, as a scientist, I would say, phase transition, but that's a good way to put people to sleep. I mean, I think maybe, you know, 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, crawling caterpillar to a flying butterfly. It's 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 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, you know, 1-800, design your baby's genes dot

call. Every time these people are out, they go to jail. Period. End of paragraph. Separately. And that cannot eradicate that because CRISPR is too technologically straightforward. Like, you know, I don't know anything about nuclear reactors, but I suspect that building one requires a certain amount of know-how.

Yes. 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 sot-de-voche. You don't have to tell the world. Oh, my God, I'm doing CRISPR and my baby. So that has to be driven into as low a prevalence as possible by making it completely illegal.

Human somatic 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 CRISPR ox? I hope it's not called that. That people inject into themselves to get rid 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.

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 by the rest of their lives, but at the end of they, it would 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. So we should maybe shift our focus from designer babies to designer grown-ups. 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, you know, the classic example I'll give you is statins.

Statins were, you know, 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, you know, they're now over-the-counter statins where I think they're about to be. So the same thing will happen with gene editing. know that it's safe and effective to treat disease, somebody will show up and say, ooh, you know, 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 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? Yes. The company that builds that, I'm sad to say, will be more, will be more expensive than Apple and Google. Yeah.

Because, you know, 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 want to emphasize. I haven't had any stimulants 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 in the stem cell at the bottom, at the root of each hair follicle and thus prevent a male pattern of allness. Absolutely. This will happen. This will happen. Well, I always like to say that I like to end the podcast on an 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? I do. I think that real world solutions require many different subunits 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's contractor. It was made by platex. Seastresses at platex sewed the spacesuit. So in 1969, I think is when the moonshot was.

This marvel of technology, the rocket, the telemetry, the fuel, the engine, blah, blah, blah, and the spacesuit was sewn by seamstresses of latex. 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 is 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 unimaginable before. And critically, these discoveries are translated into therapeutics or ways to prevent disease much faster than anyone thought possible. If you have to take 15 years, these days it takes two. Two years ago, Regeneron discovered a gene that protects from a non-alcoholic

the auto-hypotitis, which is a severe disease of the liver. Two years later, they're in the clinic with a medicine, RNAI that targets that gene, it's unimaginable that two years, only two years pass. 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. Now, frankly, where I'd like to go first with this is into the developing world, into parts of Africa and Asia, where there's not enough access to HIV medication, to use gene editing to genetically vaccinate folks at risk for HIV against it preemptively.

I think that that would be, I mean, obviously this would have to pass regulatory review and would have to pass the highest rigor of ethics in terms of informed consent, etc. But I think do I see a future where we engineer preemptively gene edits or epigenedits as this year's vaccine for SARS-CoV-7 to prevent us, protect us from COVID-2026, which there will be COVID-2020, whereas we all know, it's not just COVID-19? Yeah, absolutely. I mean, 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 going to grow in scope. It really does make me feel like the state of, you know, 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? Like 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. I could not agree with you more. And, you know, Sidney 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, 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 live in a, we are in a technology-driven space. I completely agree with you. I'm not a computer person, but, you know, clearly miniaturization, right, the transition from I'm old enough to remember floppy disks. It's impossible to explain to my 20, year old daughter, what a floppy disc is. Yeah. Yeah. 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, you know, IBM PCAT in 1986 or whatever? Absolutely. That is exactly what will happen. So I guess we just buckle our seat belts and either participate, either make them. this happen or or make use of what's happening.

Yeah, well, we appreciate very much you helping us to buckle our seatbelts here. I think it's going to be a wild ride. Fyodor Orono, thanks so much for being on the Mindscape podcast. Truly a pleasure. From the writers of parenthood and life as we know it comes, it's not like that. A new family drama about starting over and second chances. Scott Foley stars as Malcolm, a recently widowed pastor and dad of three.

And Aaron Hayes is Lori, newly divorced with two teens. Their families used to do everything together. Now they're navigating single-parenthood, and maybe something more. Watch It's Not Like That. All episodes streaming May 15th on Prime Video.