- yesterday
Human DNA editing is finally here.
There is a microscopic technology that now gives us the power to edit our own genes while we’re alive. To cure certain diseases, possibly prevent others, or boost what our bodies can do… or maybe, one day give our kids abilities no one has ever had before… effectively putting evolution into our hands.
This is not some sci-fi future! We’re already using this technology in real medical treatments in plants to grow new crops and in animals to create new species!
Just yesterday, news broke that a baby’s life was saved using personalized gene editing that fixed one tiny error in its DNA. This is truly “huge if true.”
Deciding how we use this new superpower may be the biggest challenge we have ever faced - and the biggest opportunity to reduce human suffering.
This tool is called CRISPR. Dr. Jennifer Doudna won the Nobel Prize for discovering it.
So, in this third episode of Huge Conversations, Dr. Doudna and I use specific examples to help you see how gene editing directly affects your life right now - and help you decide for yourself: How should we use it? When is it wrong - and when is it wrong NOT to?
If you want to know what the most important people building the future are imagining it will look like, Huge Conversations is the show for you.
Chapters:
0:00 Human DNA editing is here
1:20 What’s the goal here?
2:56 What is CRISPR?
4:34 How does gene editing work?
6:18 How should humans edit our genes?
7:22 You v. your kids
9:37 The first CRISPR gene therapy
12:37 What can CRISPR cure?
13:48 Challenges with delivery
16:34 Curing Huntington’s
18:34 The first CRISPR-edited babies
22:27 When should we use CRISPR?
26:03 Can I edit my DNA to prevent disease?
29:18 Can I enhance myself?
31:11 When shouldn’t we use CRISPR?
34:14 When don’t you need DNA edits?
36:32 Superpowers??
38:17 How should we edit plants and animals?
42:57 The funniest CRISPR gene edit is really useful
45:37 Editing our own microbiome
48:28 The bigger picture
50:16 What Dr. Doudna is excited about now
Bio:
Cleo Abram is a video journalist who produces Huge If True, an optimistic show about science and technology. Huge If True is an antidote to the doom and gloom, helping a wide audience see better futures they can help build. In each episode, Cleo dives deep into one innovation that could shape the future. She has explored humanoid robots at Boston Dynamics, supersonic planes at NASA, quantum computers at IBM, the Large Hadron Collider at CERN, and more. Every episode mixes high quality animations and detailed scripts with relatable vlog-style journeys, taking the audience along for an adventure to answer the question: If this works, what could go right? Previously, Cleo was a video producer at Vox and directed for Explained on Netflix. She was the host of Vox’s first ever daily show, Answered, as well as co-host of Vox’s YouTube Originals show, Glad You Asked.
Welcome to the joke down low:
"Your DNA is backwards"
"And?"
Find a way to
There is a microscopic technology that now gives us the power to edit our own genes while we’re alive. To cure certain diseases, possibly prevent others, or boost what our bodies can do… or maybe, one day give our kids abilities no one has ever had before… effectively putting evolution into our hands.
This is not some sci-fi future! We’re already using this technology in real medical treatments in plants to grow new crops and in animals to create new species!
Just yesterday, news broke that a baby’s life was saved using personalized gene editing that fixed one tiny error in its DNA. This is truly “huge if true.”
Deciding how we use this new superpower may be the biggest challenge we have ever faced - and the biggest opportunity to reduce human suffering.
This tool is called CRISPR. Dr. Jennifer Doudna won the Nobel Prize for discovering it.
So, in this third episode of Huge Conversations, Dr. Doudna and I use specific examples to help you see how gene editing directly affects your life right now - and help you decide for yourself: How should we use it? When is it wrong - and when is it wrong NOT to?
If you want to know what the most important people building the future are imagining it will look like, Huge Conversations is the show for you.
Chapters:
0:00 Human DNA editing is here
1:20 What’s the goal here?
2:56 What is CRISPR?
4:34 How does gene editing work?
6:18 How should humans edit our genes?
7:22 You v. your kids
9:37 The first CRISPR gene therapy
12:37 What can CRISPR cure?
13:48 Challenges with delivery
16:34 Curing Huntington’s
18:34 The first CRISPR-edited babies
22:27 When should we use CRISPR?
26:03 Can I edit my DNA to prevent disease?
29:18 Can I enhance myself?
31:11 When shouldn’t we use CRISPR?
34:14 When don’t you need DNA edits?
36:32 Superpowers??
38:17 How should we edit plants and animals?
42:57 The funniest CRISPR gene edit is really useful
45:37 Editing our own microbiome
48:28 The bigger picture
50:16 What Dr. Doudna is excited about now
Bio:
Cleo Abram is a video journalist who produces Huge If True, an optimistic show about science and technology. Huge If True is an antidote to the doom and gloom, helping a wide audience see better futures they can help build. In each episode, Cleo dives deep into one innovation that could shape the future. She has explored humanoid robots at Boston Dynamics, supersonic planes at NASA, quantum computers at IBM, the Large Hadron Collider at CERN, and more. Every episode mixes high quality animations and detailed scripts with relatable vlog-style journeys, taking the audience along for an adventure to answer the question: If this works, what could go right? Previously, Cleo was a video producer at Vox and directed for Explained on Netflix. She was the host of Vox’s first ever daily show, Answered, as well as co-host of Vox’s YouTube Originals show, Glad You Asked.
Welcome to the joke down low:
"Your DNA is backwards"
"And?"
Find a way to
Category
📚
LearningTranscript
00:00There is a microscopic technology that now gives us the power to edit our own genes
00:06while we're alive, to cure certain diseases, possibly prevent others, maybe boost what our
00:13bodies can do, or even one day give our kids abilities that nobody has ever had before.
00:19Effectively putting evolution into our hands. And this is not some sci-fi future. We are already
00:26using this technology in real medicines, in plants to grow new crops, in animals to create new species.
00:33It's called CRISPR-Cas9. And Jennifer Doudna won the Nobel Prize for discovering it.
00:40It's incredible. It's extraordinary. So deciding how we should use this new superpower will be one
00:46of the greatest challenges we have ever faced, and one of the biggest opportunities to reduce
00:51human suffering. So in this video, we're going to use specific examples to help you see how gene
00:57editing is already affecting your life and help you decide, how should we use it? When is it wrong?
01:05And when is it wrong not to? This is Huge Conversations.
01:09Genetics. They're a secret of life. DNA. DNA.
01:12What does it mean that we have this new power? To eliminate diseases like hemophilia, sickle cell,
01:16Alzheimer's, Huntington's. It would almost be unethical not to use it.
01:27It's great to be here. Thank you so much for doing this. I'm really looking forward to it.
01:31My goal for this conversation is to work together to explain how this new power to edit DNA might
01:39really impact this audience's lives. What's possible? And how can we help
01:46this gene editing future go right? The audience that you're talking to is great. They are smart
01:52and optimistic. And also because we cover so many different things, this might be the first time
01:57they're ever hearing about CRISPR. For myself, I have now done months worth of research for this
02:02conversation, but I'm no expert. Our bigger goal for this show, Huge If True, is to explore better
02:11futures because we believe that when people are able to see them, they help build them.
02:16What's your goal in this conversation? Why do this interview?
02:19I share your goals. I think CRISPR is such an exciting technology and it's the beginning of what
02:26will be possible in the future with genome editing and how we can manipulate our environment and our
02:31bodies to maximize our health and maximize our experience in life and to really understand our role in
02:39the world. So I'd love to share that with everybody in the audience and I imagine incredible insights
02:46and science coming from all of them in the future. I love that. That's huge if true.
02:54To explain why this is a huge moment in human history, we need to explain why CRISPR-Cas9 was such
03:00a big leap. My understanding is that we've known for over a century that there are specific molecules
03:06inside our cells that carry information in a four-part code. And then our cells use groups
03:11of that code as a blueprint for how to make the proteins that govern so much about us, from how
03:17we look to how we think to how we get or fight disease. But for most of that century, we could only
03:23read this genetic code. We couldn't change it. Could you help me understand how what you pioneered with
03:29Emmanuelle Charpentier was different from the gene therapies and other gene editing systems that came
03:36before? What was the big insight and why is it so important? CRISPR is a technology that came out of
03:44fundamental science. The very first tool that was used for gene manipulation really was coming from
03:50the natural world and that was viruses. Some viruses naturally insert into the human DNA and
03:57in our cells. HIV is one example of a virus that does that. By studying how viruses manipulate DNA
04:03and how they get into DNA, there were a lot of insights about how we could potentially, as scientists,
04:10change DNA sequences. But we didn't have the tools to do it. So what happened next was that there were a
04:16series of tools developed to find a particular set of letters in the DNA of, say, a human cell,
04:23and alter them using tools that were generated for that specific purpose. For the the wonkier
04:30folks in the in the audience, these include zinc finger nucleases and talon proteins. These showed
04:38that DNA manipulation was possible and also could be very powerful. But what was challenging with those
04:44tools is that they were bespoke, meaning you had to make one of them for every single change that you
04:49might want to produce in a cell, for example. And that meant that they were expensive, they took a long time
04:56to produce and then to deploy. And this is where CRISPR comes in, because what viruses and bacteria over
05:04eons interacting in nature had figured out is that they could use proteins that were directed by molecules of
05:11RNA, which are chemical cousins of DNA. They interact with DNA. So they look at the DNA sequence on a
05:18letter-by-letter basis. But they allow easy recoding. And so scientists, once we understood how that
05:26recoding works with RNA, we could easily manipulate and change the sequences in DNA that CRISPR can recognize.
05:33And that's really the crux of the technology. It becomes a programmable tool that can be directed to
05:40essentially any DNA sequence where it can make a change in a targeted way and in a way that is
05:46easily controlled in the lab. So the big change is that within the last few decades, we've gone from
05:52observing our genes to trying to change them, but slowly and with one-off tools, to now with CRISPR,
05:58we have quick, precise editing, like a text editor for the instruction manual of life. What does it
06:05mean for us that we have this new power? What are the stakes here? Well, it's kind of profound,
06:11I think, because if you start imagining what you can do when you have that kind of capability to
06:18manipulate DNA sequences, it's everything from changing the ability of crops to resist drought or
06:26to produce more tomatoes to changing sequences in a human embryo that alter heritable traits that get
06:35passed on for future generations. And so especially the latter application has truly profound implications.
06:42It means that if you think about it now as human beings, we have in our hands the technology to change
06:50chemically, fundamentally, who and what we are. It's quite extraordinary. Huge of true.
06:56Yes, thank you. You talk in your book about, you say,
07:04the question is not whether we can change our genes anymore, it's how should we.
07:11My understanding is that within that debate, there's a big divide between whether we're editing
07:15cells that are not involved in reproduction, so the change would end with us, versus cells that are,
07:21in which case they would get passed down to our kids and our kids' kids and maybe even a whole
07:25population, depending on the gene. Why is that distinction so important?
07:29It goes back to concepts like eugenics and thinking about even the Mary Shelley's Frankenstein,
07:37you know, thinking about what we can do when we have the power to alter who we are fundamentally.
07:44And to me it's, and I think in general, it's just very, it's a very different set of concerns when
07:51you're thinking about changing DNA in an individual, which of course has safety and ethical considerations,
07:58but nothing like if we're changing DNA in a heritable way, in embryos. The embryos can't make that decision,
08:05for one thing, and once that change is made, it's permanent, and it gets passed on to all future
08:10generations. And so you can imagine starting to change the, you know, the whole genetic makeup of
08:19human populations if this were to go far enough. If I'm imagining this as, you know, two columns,
08:24one is somatic and one is germline, then there's also the type of change itself, sort of with a spectrum
08:32between treating diseases that we would all agree are diseases, to prevention of future diseases,
08:40to what some people might call enhancements, or moving someone or their descendants into a new
08:48part of what is possible for humans. And I've even, because this is a show called Huge If True, heard
08:54people talk about changes that might move people out of what is now normal for others, so super
09:00enhancements. And in fact, in order to keep us grounded, I have prepared some specific examples.
09:08I'd love to use each of these examples and get your help to understand where do they fit into this
09:13debate, how real or not real are they scientifically, how could they actually impact the audience's lives or
09:20not? And what gets you most excited in these different categories? Okay, so my first example is
09:28curing sickle cell in one individual. Could you tell me the story of Victoria Gray and what's happening
09:34with CRISPR right now in sickle cell disease? Well, this is a big success of the CRISPR field. In the,
09:42I think, late fall, it was November and December of 2023, the Food and Drug Administration in the US and
09:49their counterpart in the UK approved a CRISPR based therapy for sickle cell disease patients. So these
09:56are people that have a single genetic mutation that gives them a very severe blood disease that results
10:05in frequent, you know, requirements for frequent blood transfusions. And if they don't have those,
10:11they have organ failure over time, they have very severe crises that happen frequently that are very
10:18painful for them. So you can imagine extremely disruptive to their lives. And with this CRISPR based
10:25treatment, it's a one and done therapy that doesn't exactly cure the disease at the genetic level. But
10:33what it does is suppress the effect of the disease causing mutation. And it does that by turning on the
10:39production of a protein normally only made when we're developing in the womb, which is a protein called
10:46fetal hemoglobin, that when turned back on using CRISPR, can suppress the effect of the disease causing
10:53mutation in adult hemoglobin. And as a result, people like Victoria Gray, and she was the first US
10:59patient to receive this therapeutic, have not had another sickle cell crisis since receiving this one
11:05and done therapy. So it's, it's incredible, it's extraordinary. And having talked to her and a
11:10couple of other folks that participated in that very first clinical trial, I've heard their stories
11:16about being just, you know, their lives being completely transformed by this, and their ability
11:23to then function in a way that they never imagined to be possible, given their previous disease experience.
11:30So it's amazing, I would put this in the category of, I'd call it a treatment, and I'd call it a
11:34treatment for an individual right now, we're not using it in the human germline. But it's, it's a
11:41clearly a very exciting advance for the field, with some caveats. Right now, this therapy is very
11:48expensive, meaning that most people who could benefit from it globally can't get access to it.
11:53It also requires hospitalization, because they have to go through a bone marrow transplant. And that's
11:58something we're working very hard on here in our institute to overcome, we'd love to have this therapy
12:04ultimately deliverable in an easy format that doesn't require hospitalization.
12:10How should I think about the fact that this treatment for sickle cell is based on the fact
12:14that sickle cell is related to one gene?
12:17Well, you put your finger on a really good point, Cleo. That's, that's exactly right. So this is a
12:21disease that results from one gene that's gone awry. And right now CRISPR is, is well suited to treat
12:28that type of disorder. It's a lot harder to think about how you would treat a disease like,
12:32let's say schizophrenia, which almost certainly results from maybe hundreds of mutations in the
12:38human genome. So those are going to be a lot harder to treat.
12:40And as I understand it, Caschevy requires removing blood from the patient,
12:48making those changes in a lab, and then putting blood back in.
12:53If we wanted to use CRISPR for single gene, or maybe very small number of gene,
12:58changes for treatments in individuals, but those treatments needed to be in our lungs,
13:04or our liver, or our brain, how would that work?
13:07Yeah, it's, that's a lot harder. It would work with difficulty. We don't have a good
13:13strategy in general for getting the CRISPR molecules into particular cells in the body.
13:19Although again, that's something that's changing quickly. It's an area to really keep an eye on over
13:23the next few years. Because many, many scientists appreciate that this is an important challenge,
13:29not only for CRISPR, by the way, but also for any kind of human therapy is how do you do the therapy
13:34in the right cell type or the right tissue in the body? How do you get it there in a safe and effective
13:39way? And that's clearly a challenge with CRISPR. I think that over time, what we're going to see
13:45is increasingly sophisticated technologies for doing exactly that. We're already at a point where
13:53for a disease like sickle cell, I think we're, you know, maybe within a few years of having
14:00that capability to deliver in the body and safely. And I think at a cost that would make this therapy
14:07much more widely available. And I can't tell you how excited I am about that.
14:11Me too. Just to be even more nerd out on this point a little bit more, because I know that delivery
14:18is a big interest area for a lot of people that are working on this. What are the actual challenges
14:26with the delivery? Is it that our immune system attacks it? Well, let's think about how the body
14:32is put together. We have a lot of different kinds of cells that make up our bodies. And even within one
14:39particular organ, like let's say our brain, many different kinds of cells are required to form the
14:45human brain. But when we have a disease that affects our brain, like let's say Alzheimer's disease,
14:50that disease is primarily affecting only some of the cells, we think, not all of them. And so ideally,
14:55what one would like to be able to do is you'd like to get the genome editor into just those cells where
15:02a change to the DNA sequence could have a positive effect on the patient and not bother any of the
15:08other cells in the body. But doing that, as you can imagine, is very tricky. And that's partly because
15:14the cells are all growing together. So you have to have sort of a chemical mechanism of distinguishing
15:20one cell type from another. Fortunately, cells often have little zip code molecules on the surface
15:26that mark them as different cell types. But so far, science is still trying to figure out what they are
15:31and figure out which zip codes go with which cell types. So that's something that's very much work
15:37in progress. And even once we know that, then the challenge is how do we recognize one particular
15:43set of molecules on certain cells and ignore all the others. That's something that viruses are actually
15:49very good at doing. So one of the motivators and sort of inspirations in the delivery field right now
15:56is looking at how viruses do that kind of recognition and delivery, and then taking advantage
16:01of it for delivering other molecules. Rather than delivering a virus, can we deliver our CRISPR cargo?
16:07I know you've used the analogy of, we now have the ability to cut and paste DNA like a text editor.
16:13And so I'm imagining if I play this analogy out a little bit, it's like,
16:16I, we now have the ability to cut and paste and create new letters, but we are still inventing the
16:23postal system. We're still trying to figure out how to send the letters. Exactly. Yeah, that's right.
16:28Got it. Yep. My second example is curing Huntington's or alleviating, removing Huntington's
16:33from all your future descendants. What do I need to know about this example and this general category?
16:40Well, Huntington's disease is a, is an interesting example because it often does run in families.
16:46And as some folks in the audience may know, it's a neurodegenerative disease. So it causes a
16:52severe degeneration of the brain over time. It often doesn't begin until somebody is in their
16:59midlife somewhere. So 20s, 30s, 40s, depending on the exact detail of the mutation they have.
17:07It's an interesting target for CRISPR because like sickle cell disease, it's a single gene
17:12that causes the disorder that's very well defined. And furthermore, we know of families in the world
17:18where this disease gene is inherited by, by, by kids, you know, from their parents. And so it's a,
17:25it's terrible in the sense that they can see what's coming and know that they have this genetic
17:32predisposition, but they can't do anything to prevent it. So it's, you know, it's really a sort
17:36of a horrible thing to contemplate. And with CRISPR, one could imagine at some point being able to remove
17:43that disease causing mutation from an embryo, such that not only does the individual, once they're
17:50born, not bear the Huntington trait, but they also don't pass that trait on to their kids. It would be
17:56amazing. It could change a lot of people's lives. It could change a lot of people's lives. And I
18:01certainly think that if and when that capability is in our hands, that it would almost be unethical not
18:07to use it for that purpose. But we're not there yet. And the reason is that it's very tricky to
18:14control the way that DNA repair, which is really part of the whole editing process, the way that that
18:20is conducted, especially in embryos is still very much under, you know, investigation. And so I think
18:26until we have a good handle on how it works, and then how to do it safely, it will remain a, you know,
18:33future aspiration, but not something that I think should be done today.
18:36That brings us to my third example, which is preventing something like HIV in your future
18:44descendants. There was a scientist in 2018 that edited human embryos. And those embryos were born
18:50into babies who, as far as I can tell, are still alive. And many scientists, including yourself,
18:54oppose that decision. My understanding from your book is that you opposed it because you felt the risks
18:59to those kids were greater than the rewards. Could you explain why that was the case in that
19:05example? But also more generally, what are the other options besides CRISPR for many of these diseases?
19:13And how should we think about when a use of CRISPR is actually necessary and, and therefore potentially
19:21has a much greater incentive to use it?
19:24I think with any therapy, you have to ask yourself, do the risks outweigh the benefits or not? And with
19:31CRISPR, and especially if we're using it in embryos or the germline, the risks are, are quite significant
19:39in the sense that any change that gets made is, is permanent, and it gets passed on to future generations.
19:45So you want to be very confident that those changes are going to have a positive impact and have the
19:50desired outcome. And so in the example that you cited, yeah, it was a very, you know, very kind of
19:57alarming case because it was a situation where a scientist informed parents that they were going to
20:06receive a treatment for their unborn children that would prevent HIV transmission to those kids during
20:15birth and later in their lives. And furthermore, that that trait would then be transmissible to their kids.
20:22But I don't think from what I understand that the those parents in the trial really understood the risks of the
20:29technology and that, for example, it had never even been tested in animals prior to putting it into people, which, you know, is one
20:39really big ethical concern. Furthermore, with the the example of HIV, there already are well-known treatments
20:47that can prevent transmission in kids, even if they have an HIV positive parent, as was the case in that
20:54situation. So given that there was already a, you know, very well tested and safe way to prevent
21:01transmission, arguably it's pretty unethical to then apply an untested, untried new technology to do this
21:12in people. And then the third issue kind of gets in a little bit more in the weeds of what actually
21:18happened. But when it was revealed how the genome editing was done in those embryos, it was clear that
21:26it wasn't a clean edit. In other words, it wasn't a way of making a very precise manipulation to the DNA,
21:34that instead, what probably happened was that multiple different kinds of edits happened
21:41in the cells of those embryos, so that those kids were actually born chimeras, meaning they had a mixture
21:48of different kinds of genetic makeup in their cells. Would that be harmful or not? The answer is,
21:56we don't know, because it had never been tested before. So these are all things that I think are
22:01really important to understand when people evaluate whether a new technology, especially something to
22:07be used in embryos, would be allowed to go forward. It seems like a really hard challenge, especially as
22:13someone who's a pioneer in the field. Because we talk a lot on the show about how the status quo,
22:21the world that we live in right now sucks in all kinds of ways. It is just as bad to allow the
22:31existence of a huge amount of suffering when you could change it, as it is to cause that suffering
22:37by changing it. This is a classic human problem that we deal with in so many different ways.
22:41And one of the things that I found incredibly powerful in your book, there's this quote.
22:49This is Charles Sabine, a victim of Huntington's. And he says, anyone who has had to actually face
22:55the reality of one of these diseases is not going to have a remote compunction about thinking there's
23:00any moral issue at all. And the reason why that has really stuck with me is because I think it's one
23:05thing to talk about these weights and counterweights in theory. And then you talk to someone whose life
23:11could actually be changed. And you come away feeling like, holy cow, how can we help as quickly as we
23:19can in the way that keeps them safe and keeps the rest of us safe? What's that actually like for you
23:26when you hear from people who are experiencing diseases that you feel CRISPR could be really good
23:30good candidates to help solve? It's really getting to the heart of what it means to suffer from a
23:36disease like that. And then to have the opportunity to have a cure for it, something that might have
23:43been unimaginable even a few years ago. And you're right, I hear from people pretty much now, it's
23:49probably at least once a week that write to me about diseases in their families that are of genetic
23:55origin. Often it's disease affecting kids and asking, you know, when and how will CRISPR be able
24:02to make a change? And it's a really big challenge. I feel I'm humbled by it. I'm honored that people
24:10share their personal stories with me. And I have to admit, I sometimes feel a little bit helpless because
24:16I realize the challenges still that lie ahead scientifically and technically to make it possible.
24:23But at the same time, I feel an incredible sense of motivation and passion because you can see how,
24:32especially with the sickle cell story, how it can be so positive and so beneficial. So it's a,
24:38you know, it's a real motivator getting out of bed every day. Yeah, I bet. Speaking of good health,
24:43I want to show you something. I'm wearing the Whoop MG. It just came out and I've been testing it over the
24:48last month. So let me show you what I find most interesting. My goal is to just feel great. I want to
24:53wake up and I want to have energy and I don't want to feel tired. And I want to be able to make this
24:57show and learn and I want to feel strong. And I want to feel that way for as many days as I can for
25:03the rest of my life. So I use Whoop to set a goal to feel better and to keep track of my daily habits.
25:08It uses these sensors to measure, among other things, nine biometrics that have a long-term impact
25:14on my health outcomes. And it combines them into what Whoop calls my health span. And that helps me
25:18understand how my habits right now affect my long-term ability to have as many healthy days
25:23as possible. One thing I found helpful is the Whoop AI coach. Today, for example, I was feeling
25:28tired. So I just asked it, I'm feeling tired. Why? Then it analyzed my real data from the last month
25:35and helped me understand a couple of things that I could do, especially around hydration and workouts.
25:39And it also has sensors that measure electrical activity from my heart through my skin. So I can do an ECG.
25:46All of this just helps me feel better day to day and hopefully long-term too. So if you want to try
25:51it, go to this link right here or click the link in the description. Now back to gene editing.
25:56As someone who is lucky enough not to be currently struggling with disease, when I think about how
26:02CRISPR might most directly impact my life, I think about the genes that correlate to future disease
26:11disease and how we might prevent future disease. I think about reducing Alzheimer's risk, which I
26:18understand relates to ApoE4 or heart disease and PCSK9 or cancer and BRCA. That would completely change my
26:30life. And I'm curious, what are the most interesting relevant examples in this category that you think
26:37about? I think those are three great ones. And in fact, it's probably worth pointing out that
26:43there's already a clinical trial running for people who have the gene that makes them susceptible to
26:50high cholesterol buildup and hence to cardiovascular disease. Yes, many of us do have this. And the idea
26:58in that clinical trial is to use CRISPR as a preventative. So can you make edits in the DNA
27:04of the liver that would prevent cholesterol accumulation in people that are otherwise
27:10susceptible to this? If it works, it would be incredible because again, it's a one-time therapy
27:16that avoids the need to take drugs daily or weekly or monthly to control cholesterol levels and would give
27:25people freedom from worrying about, you know, heart attacks at a young age if that would be otherwise
27:30something they might experience. So I think that's really exciting. It also, you know, raises the bar,
27:36I think, for what we would demand in terms of safety because probably none of us would want to,
27:41you know, if we're not currently ill, we don't want to take something that might make us ill and we want
27:46to take something only if it can really improve our health. Does that study that you just mentioned
27:51relate to what we talked about with the challenge of delivery? Because if they're delivering it to the
27:55liver, that implies that they, are they editing it in a lab in the liver? Are they also trying to
28:01find a delivery mechanism that works? They are. Yeah, amazing, right? Now, here's the thing. So the
28:06liver is an organ that naturally filters toxins in our body. So a lot of molecules will end up in the
28:13liver quite naturally. So it's a bit of a unique organ in that regard. And so it means that for a lot of
28:20the interest in CRISPR, at least in the very early days before there were many strategies for delivery,
28:27it was, you know, people kind of recognize that the liver would be a great organ to target because it's
28:33it very naturally accumulates molecules, including CRISPR. So that's been the the basis for this ongoing
28:42trial. And they're actually using little greasy blobs that are known as lipid nanoparticles. These are
28:48known to any of us that have had the COVID vaccine, because that's the the basis for delivering the
28:54COVID vaccine is using these little lipid nanoparticles. And those particles will naturally
28:58traffic to the liver in the body, and they'll carry along other molecules like CRISPR. So that's been
29:04the basis for for that trial. Cool. Yeah. Okay, so now we're getting into the category that I think
29:12people would call enhancements. Here, people talk a lot about eye color and height and things like
29:19that. But there are also, and these are the ones I find most interesting, genes that might relate to
29:25enhancements for health that are not related to disease. So genes, for example, like the MSTN gene
29:34associated with building larger muscles, or, and this one I get very excited about,
29:39DEC2, which I understand is associated with needing less sleep. What examples do you think
29:46about in this category that are most genuinely interesting? And what should people know about
29:50what's realistic here? Well, I think those who you brought up are interesting. There's also a gene
29:55that was identified by a colleague of ours at UC San Francisco. In fact, he won the Nobel Prize for that
30:00work that is involved in pain perception. And so you could imagine, you know, in fact, there are natural
30:06variations of that gene in the human population, people that have a certain type, a certain format
30:13of that gene are naturally pain tolerant. And so you could imagine ways that you might use that
30:21type of genetic manipulation to remove experience of pain in, you know, say cancer patients or, you know,
30:27people that have a chronic pain causing disease. And so I think those are all extremely interesting.
30:36And yeah, do we, you know, it's a little bit, this starts to get into, to me, a bit of a gray area.
30:41Are those enhancements? Like if we're talking about pain perception, that's, you know, it's really a
30:45health related thing. But it's an important aspect of thinking about genetic manipulation, because it
30:53forces us to, you know, to really ask ourselves, where do we draw that line? And I argue that it's
30:58very hard to do that. I think it's, you know, there's a kind of a continuum. And there's certain
31:03certain modifications that some of us might call enhancements, and the rest of us might call
31:08health related. So who decides? And I think those are those are some of the real issues that we're
31:13grappling with. This is the area, if I'm honest, I started to struggle with a concern that came up a lot,
31:20and I'm sure is coming up right now for the audience as they're watching this, is that we
31:23move into a world more like the movie Gattaca. That there is a divide between what people can and
31:29can't get, maybe based on wealth, maybe based on other factors, that that harms society because
31:36there is a gene gap, as you call it. At the same time, I've, and I think everyone has witnessed over and
31:44over again, an expensive technology becoming less expensive over time as it's used by more people.
31:50A sort of sub subsidy, maybe, of that technology early on that then ends up benefiting the rest of
31:58us because it gets time to develop and exist and and just sort of comes into the world. And I have
32:05a hard time with the argument that we shouldn't use something because only a few people could use it
32:11in the short term when the hope, right, is that everyone can use it. And I wonder, you know,
32:19why do we care about this when it is a huge opportunity to reduce human suffering,
32:26but not when it's our iPhones? How do you think about something like that?
32:31I think I'm with you, Cleo. I really, it doesn't sit right with me to argue that
32:37we shouldn't develop a technology because today it's only available to a few. And as you said,
32:43that's, that's often true when new technologies come along. They're not easily distributed early on,
32:49typically, and they often are expensive in the early days. I mean, think of even personal
32:53computers kind of went through that transition. And so I think that we have to be very forward
33:00thinking and we have to be imagining what could be possible in the future. I'm highly motivated,
33:06for example, by the idea that CRISPR, although today as a therapy, it's only available to a few,
33:13that's not going to be true forever. It's clearly not. And also, I'm a big believer in you have to,
33:19you have to imagine the future to create it. You have to think about where you want to go
33:24and then work to get there. Me too. My understanding is that one of the ways that people can
33:31get some of these, all the above prevention, enhancements, treatments,
33:38is through selection of the embryos that they actually end up using in the first place, PGD.
33:45Could you explain how that works and how the existence of that option influences how we might
33:51or might not find it appropriate to use CRISPR? So one thing that's important to point out with
33:55CRISPR when we think about using it in embryos is that it would be done in the context of in vitro
33:59fertilization. Maybe that's obvious, but in vitro fertilization or IVF technology has come a long
34:05way from where it started. And today it's possible for people that are having a child using in vitro
34:13fertilization to actually conduct embryo selection if they want to. They can identify embryos that have
34:19certain traits or avoid certain traits that they otherwise might inherit. And so that's been a great way
34:24for families to screen out disease-causing mutations, for example. I think that with CRISPR you could
34:32imagine using it similarly where you could use it to remove a trait and then screen embryos for the
34:38ones that have, you know, where you've successfully done that. Yeah. And also the key difference would
34:44be that CRISPR can actually make changes that might be present in all embryos for that specific couple.
34:50CRISPR could edit whereas PGD merely selects. Correct. Yeah. I also think an important thing to
34:58talk about with respect to PGD is none of this is easy. I did the egg freezing process and I can tell
35:04you that getting that number of eggs out is hard. That's the first step in IVF. It's difficult and
35:11time-consuming and expensive no matter what. And so, you know, we're dealing with a lot of different
35:16weights and counterweights about what might be easy or difficult for people in different ways.
35:21Yeah, absolutely. You know, I think there are going to be some interesting changes over time. Again,
35:26I don't think they're happening, you know, immediately, but I do think that there's a lot
35:29of work being done on human reproduction, about gametes, you know, eggs and sperm that are, you know,
35:37going to probably change the landscape of what's possible in the future. And I'm talking about over the
35:43coming decades, right? So, you know, for folks that are, you know, very young kids right now, you know,
35:49this might be something that would be become possible in their lifetime or something they would
35:53want to consider doing. So that's an area definitely to keep an eye on because I do think there's a lot
35:58of activity before we move into plants and animals, which I really want to get to, because I think
36:02it's one of the biggest ways CRISPR might impact people's lives. There is one additional category
36:09here within humans. The final category, and this is a show called Huge If True, is as we understand
36:19more about our genes, there could potentially be ways to move people beyond what is possible for
36:25anyone right now. Helping you heal faster, extending your life beyond what's normal,
36:30giving your kids abilities that seem like superpowers. I don't know what's possible.
36:35How do you think about this? I had a call years ago now from a reporter at Sports Illustrated.
36:40They wanted to do a story on enhancements, or maybe even you could call them super enhancements,
36:45that would create super athletes. You know, imagine basketball players that were eight feet tall,
36:51or, you know, could jump unreasonably high, or people that had, and I guess this is already one
36:58thing that is theoretically possible, having, you know, very, very well-developed muscles and muscle
37:03structure. I think these are fascinating. I think for the most part they're not really realistic at the
37:10moment, mostly because we don't understand the genetics well enough to understand how manipulating
37:16those genes would affect our health in other ways. And we know for sure that, you know, our genes are
37:22interconnected. So when you tweak one thing, you're probably not just changing one effect, you're
37:28changing lots of other things. So I think that for any of those kinds of manipulations, clearly a lot
37:33of research would need to be done. But I'll just mention that since I know we're going to get to plants
37:38and animals in the plant world, we're already seeing just incredible advances using CRISPR to create
37:46the type of plants that, you know, certainly breeders have never had success in creating,
37:52and that if you tried to do it with traditional breeding would take inordinate amounts of time,
37:57probably decades, that increase the yields of crops, that increase the nutritional value
38:03of crops in ways that could be incredibly valuable and exciting for probably all of us and probably
38:09not in the distant future. So I think that's an example of the kinds of super enhancements in
38:14organisms that we're going to see with CRISPR. So play that out for me. What happens next in the
38:21world of plants and animals using CRISPR? I've thought for a long time that the extraordinary global
38:28impact of CRISPR will probably happen first with plant and animal manipulations. And the reason is
38:35when we're talking about making changes in human beings, that obviously requires a lot of testing
38:40to make sure that it's safe. We have to do a lot of research so we understand how a genetic
38:45manipulation will affect our health. Whereas if we're making changes in, let's say, a plant, you know,
38:51we can conduct that as an experiment, and many of those can be performed at the same time.
38:56And with CRISPR, we now have a tool that allows the kind of precise manipulation that plant breeders
39:03could only dream of in the past. So maybe just to explain how traditional plant breeding works for
39:09people. Traditionally, plant breeders would introduce random changes into the DNA of plants,
39:15and they would do it by using chemicals that would change DNA sequences randomly, or even exposing seeds
39:22to radiation that would also lead to random genetic changes. Then planting the seeds and allowing them
39:29to grow up and looking for plants that had changes to their traits that were desirable, and then picking
39:34those and breeding them. And so you can start to think about that. There's a few issues there, right?
39:40First of all, it takes a long time. Secondly, the changes are really random. So if you wonder,
39:45why is it that we have roses that are thornless, which might be a desirable trait, but they've lost
39:51their nice smell? Well, it's because, you know, traits are coupled, right? And so you tweak one thing,
39:56and you get something that comes along with it that maybe you didn't want, but you now can't get rid of.
40:02And we see that over and over again. So with CRISPR, we truly now have an opportunity to make targeted,
40:08precise changes that only alter one trait and don't affect other things. So I think that's really exciting.
40:15And another aspect of CRISPR in plants that is just
40:19truly mind-blowing for me is that you can use CRISPR in multiple genes at one time. Now,
40:25you could do that in humans, too, and I'm sure that will come. But today in plants,
40:30it's already possible to change 5, 10, 15 genes at a time. And that means that we can make
40:37really quite sophisticated alterations to plant traits in one shot and do it safely and do it
40:44precisely. And the more that we learn about the genetics of plants, and that's a whole separate
40:49area of research for sure, but, you know, it just, they kind of go hand in hand. We learn which genes
40:55we can tweak, and then we have the tool to tweak them. Is that happening right now in a way that
41:01I might not notice when I'm at the grocery store? Am I eating plants that have been edited
41:05with CRISPR or not yet?
41:07Only if you're in Japan.
41:08Interesting.
41:09Well, in Japan, there's a tomato that's been approved that has a CRISPR change that makes it,
41:16they argue, more, have higher nutritional value. Will that happen in the US? Oh, yeah. I mean,
41:22it's certainly coming. And already there are changes in plants like, well, fungi, like mushrooms,
41:31where there are non browning mushrooms that were created using CRISPR. And a colleague of ours has
41:39created tomatoes here in his lab in the US that are much higher yielding than normal unedited tomato
41:47plants, but they don't have any other differences in the taste or the look or the, you know, the sort of
41:53properties of the tomato. So again, something potentially very exciting and very desirable.
42:00Right now, there's an ongoing sort of debate in different countries around the world about
42:06how those types of crops will be regulated. And here in the United States, the US Department of
42:11Agriculture has ruled that when changes are made to the DNA of plants that could be done by traditional
42:19breeding, if you took the decades to do it, but are sped up by using CRISPR, those are not considered
42:26genetically modified, and they're not regulated. Oh, which is so interesting, right? So I think
42:32absolutely, in that regard, at some point in the not distant future, we could see these types of crops
42:38in the grocery store. Fascinating. I know, I also know the two other categories that I want to talk about
42:44here are related to climate change and related to human health by virtue of editing other animals.
42:51So on climate change, the example that I have is making cows fart less methane.
42:56Did you tell me about that one? Yeah, that's a good one. That's a good one.
42:59So the yeah, this is this is a project that, you know, a lot of scientists have come to recognize that
43:06one of the most significant contributors to global carbon emissions in the form of methane,
43:13which is a powerful greenhouse gas, is the is the farming of animals, and in particular is cattle.
43:20And they produce a lot of methane, and they produce it primarily from bugs in their gut
43:26that are methane makers, and that that, you know, produce this this gas instead of using food that
43:33the cattle are eating to make more milk or more meat. So wouldn't it be great if there were a way to
43:40alter the metabolism of those organisms, those bacteria, we call it the microbiome in these
43:46cattle that are producing methane, dial that down and turn up the ability of their of the these
43:53metabolic pathways to generate nutrients that are actually valuable to the animal and valuable to
43:59the farmer and to the consumers of these products. That's exactly what we're doing now with CRISPR.
44:06Because again, CRISPR is a great tool for this. It's a tool that has the ability to go into the DNA of
44:12just one type of bacterium to one gene in that type of bacterium and make the kinds of changes that will
44:19alter their metabolism permanently. We've got some of the best cattle biologists in the in the world who
44:27are working at Davis, and they had already shown that if you change the cow microbiome by altering their diet,
44:36a very profound effect on methane production. So that's very exciting. We know this is an approach
44:40that can work. The challenge there is that altering the cow diet is not an approach that's inexpensive,
44:47and it's not easily deployed to farmers around the world. Whereas if we had a very easy, let's say it was
44:53a pill that you could give once to cows when they're born, that would edit their microbiome in a way that
44:59was sustainable over their lifetime. You could imagine that type of change being incredibly
45:04profound and also easy to deploy. And that's exactly what we're working on.
45:09And again, you're editing the microorganisms inside the cow, not the cow itself.
45:13That's right.
45:14So it's a different category of assistance for the animal.
45:16Completely different. That's right.
45:17Yeah.
45:17How can we do that in humans, and how might that help us? Without editing us, editing the microorganisms in us.
45:23This is such an interesting area of medicine. I think it's early days, but I think there's a lot
45:30of evidence pointing to our own microbiome, the human microbiome, having a profound impact on our
45:37health in ways that we're only starting to appreciate. And we have a colleague at University
45:42of California, San Francisco, who has shown that in people, especially in kids that are susceptible to
45:49asthma, they tend to have molecule produced in their own microbiome that's not present in people that
45:57don't have asthma. And she's shown a correlation between the concentration of that, you know,
46:03microbiome produced molecule and disease susceptibility. So again, we see a really exciting
46:09opportunity to use CRISPR to turn down the production of that molecule and potentially prevent
46:16asthma in kids. So that's something that we're currently testing with her laboratory in animals.
46:22And if it works, then we hope to test it in humans.
46:24Wow. What are the other examples that you think about often that I haven't asked you about?
46:29There are areas of sort of understanding microbial human health biology, where I think there's a lot of
46:38exciting potential. And one is really understanding the connection between our microbiome and our brain.
46:44And another is thinking about the connection between our microbiome and our immune system.
46:50So imagine that, you know, when, when, when we're born, we have our immune system is developing,
46:57we're also becoming, you know, hosts to lots of different kinds of microbes. So there has to be a,
47:03an interplay there. And we know that there's a relationship between inflammation in the brain,
47:10which often involves microbial activity and an activity of our immune system, and later
47:16susceptibility to diseases like Alzheimer's. So I think as the genetics of those interactions
47:23become better understood over time, and by the way, that's something that CRISPR can help with,
47:27is really dissecting the genes that are involved in those interactions.
47:31We now have the ability to, to change those, those genes, whether it's changing them in the microbiome
47:38of, of an affected person, or as we talked about with prevention, potentially doing it
47:42before we're susceptible to disease.
47:47If someone is coming to the end of a story about CRISPR, what do you want them to know?
47:51Well, we've talked about a lot of great applications of CRISPR. I guess I want to circle
47:55back to maybe where we started in the conversation, because I find that a lot of students today will
48:00ask me the questions about, you know, how did I get interested in this area of science? Or how did I,
48:07how did I, you know, how did I start working on CRISPR in the first place? Did I know that it was going
48:13to be, you know, a really exciting technology when we got started? And the answer is no. And I think it's
48:19important to, to emphasize a couple of things here that are, are, I feel, and especially in this moment
48:27that we're in and in our country and in the world that, that I think has been perhaps missed by a lot of
48:32people. And that is that, you know, science is really a, it's a, it's a process. And it's a process that's very,
48:39very much a human endeavor. Now, maybe AI will change that at some point, I'm sure it will, will assist us. But
48:45fundamentally, my experience is that it's very much driven by human curiosity. It's a person
48:53or a few people wondering, I wonder how something works, and then digging in to figure it out. And if
48:59you look at the fundamental breakthroughs that have happened over time in the biological sciences,
49:04certainly, the vast majority of those have come about from that type of question and answer. And
49:10CRISPR is very much in that category. So I think it's great for people to appreciate that that's
49:15kind of how science works. And so I always encourage students to think about what they're curious
49:21about, what they're interested in, what do they find fascinating? What's a, what's something that
49:26they've experienced in their lives where they have no idea how it works, and they wonder,
49:30what the heck, right? And, and they want to figure it out. Because that's always how I've, I've directed my
49:36research. And there's real value to that. And that's really how fundamental breakthroughs are made. So I,
49:42I think we have to, first of all, appreciate that. And secondly, I hope, agree that we're going to
49:48continue to support that kind of curiosity-driven science for the next generation, hopefully,
49:52who are listening to this.
49:53I hope so too.
49:54What are some of the what the heck curiosities for you right now? Feel free to get as nerdy and
50:00specific and maybe don't explain, like, just what are the, some of the things that are,
50:06that feel what the heck to you?
50:07Well, I mean, I'm curious about all kinds of crazy things. Like I heard about a great project
50:12to investigate how bipedalism emerged, how did, how it evolved, you know, why are we
50:19bipedal, whereas our ancestral apes were originally not bipedal. And so there's actually a scientist that I
50:28know who's using CRISPR to try to figure this out in rodents, because there are related rodents,
50:33some of which are bipedal naturally, and some of which are not. So she's trying to figure out the
50:37genetics of that. So there's a, that's a kind of a cool one.
50:41What the heck?
50:41What the heck. In our own research, I'm, you know, very interested in, well, as we discussed this
50:48connection between microbiomes and our health. So there's a, there's a number of things that we're
50:53investigating there by tweaking the genes of microbes and then asking, how does that affect
50:58the behavior of human cells? So I think that's a, you know, that's a, an area that there continues
51:03to be lots of kind of curiosities to, to explore. And then the third thing is more applied, but a big
51:10area that we're focused on in my own laboratory and here at our Institute is this question of how we
51:17deliver molecules specifically into cells, because that, that's really going to be transformative when
51:22we have that, that capability more broadly. And so I'm curious about how this happens in nature,
51:29and of course viruses do it, but it turns out so do bacteria, you know, certain bacteria have
51:34the capability to get into particular cell types. So we continue to investigate those
51:39fundamental processes, hoping that we can, you know, learn from them and, and learn how to do it
51:43ourselves. What the heck. What the heck. Can I ask you, what does it feel like to have been such an
51:49important part of bringing this new power into the world?
51:53Humbling, I guess is the first word that comes to mind. I feel grateful too. I feel so excited to
51:58be part of it. You know, I feel, you know, when I was a kid growing up, I just could dream of doing
52:05science in the future and imagine myself as a scientist, but I had no idea really what I would
52:10work on or where I, where I would end up. I could have never in a million years and, you know, imagined
52:16all of this coming to pass, but it's been such an incredibly interesting journey. And I also feel
52:21that I'm always learning, you know, so it's a, it's, it's given me great opportunities to learn new
52:25things. My last question for you is, could you read this? You wrote it. That last paragraph.
52:36Few technologies are inherently good or bad. What matters is how we use them. And when it comes to CRISPR,
52:42the possibilities of this new technology, good and bad, are limited only by our imaginations.
52:48I firmly believe we can use it for the former and not the latter, but I'm also cognizant that
52:52this will require determination from us individually and collectively. As a species, we have never done
52:59anything like this before, but then again, we've never had the tools to do it. The power to control
53:03our species' genetic future is awesome and terrifying. Deciding how to handle it may be the biggest
53:09challenge we have ever faced. I hope, I believe that we're up to the task. Thank you so much for
53:15your time. I really appreciate it. Awesome. Yeah, this is really fun. Thank you.
53:23Boy, I'm really impressed. You did, you clearly did a lot of homework and you had great questions.
53:28Thank you. We got more deeply into this than is usually possible in this type of a conversation.
53:33Yes, that really means a lot to me. Thank you for saying that.
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