Making Sense - Sam Harris - November 29, 2017


#106 β€” Humanity 2.0

Topics
CRISPR gene editing technology CRISPR mechanism and editing CRISPR-Cas9 technology edits DNA gene editing challenges
Hosted by
Sam Harris
Mentioned
Jennifer Doudna CRISPR Emmanuel Charpentier Samuel Sternberg
#105 β€” Richard Dawkins, Sam Harris, and Matt Dillahunty #107 β€” Is Life Actually Worth Living？

Episode Stats


Length

18 minutes

Words per minute

150.42

Word count

2,847

Sentence count

168

Harmful content

Misogyny

1

sentences flagged


Summary

Summaries generated with gmurro/bart-large-finetuned-filtered-spotify-podcast-summ .

Jennifer Doudna is a biochemist, an investigator, and a researcher at the Howard Hughes Medical Institute and the Lawrence Berkeley National Laboratory. She is the author, along with Samuel Sternberg, of the book, A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution. And she is credited as one of the inventors of the CRISPR-Cas9 gene editing technology, which is the topic of today s conversation. We get into all the details and the ethics of this technology, and Jennifer s time was short, so I could only schedule about an hour with her. But I was great to have her walk me through the details, and I trust you will leave this podcast as I did, knowing much more about where this technology is at present and where it is likely to go in the future. Sam Harris Making Sense is a podcast produced by Sam Harris and the team at The Making Sense Project. They don t run ads on the podcast, and therefore, therefore, are made possible entirely through the support of our listeners. Please consider becoming a supporter of what we're doing here, by becoming a member of the Making Sense Podcast. You'll get access to all sorts of amazing resources, including blogs, podcasts, books, and more. Thank you for listening to Making Sense: Podcasts, and much more! - Sam Harris, PhD, PhD - Making Sense, and (p. ) (ABOUT THIS PODCAST SERVER. (PRODUCING THIS EPISODE) - THE MADE MADE SENSE PRODUCER AND THE MATERIALS AND OTHER THAN THAT AND OTHER LINKS). (THAT'S AVAILABLE INCLUDE) (PRODYNAMES AND MORE) ) (CRISPR & OTHER THIRD THAN A THIRD-PRODY AND SOCIAL MEDIA) (VOCAL SUPPORTED INTROLEPRODCAST, BECAUSE I'S NOT JUST A VOCABULARY AND A VOTING IN A PEDCAST AND A PAPER AND A VIDEO AND A PLATO AND A FEDERATION AND ANOTHER THIRD PLACE AND A SOCIOLOGY AND A DEDICATE AND A CREATING A VOTE IN A VEOTHEPRONE AND A BIRD AND A PROTEIN AND A TUNNTRY AND A THOTCAST)

Transcript

Transcript generated with Whisper (turbo).
Misogyny classifications generated with MilaNLProc/bert-base-uncased-ear-misogyny .
Topics generated with Qwen2.5-3B-Instruct.
Hosts, guests, and mentioned names generated with spaCy (en_core_web_sm), reconciled against Wikidata.
00:00:00.000 Welcome to the Making Sense Podcast.
00:00:08.820 This is Sam Harris.
00:00:10.880 Just a note to say that if you're hearing this, you are not currently on our subscriber
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00:00:28.360 other subscriber-only content.
00:00:30.540 We don't run ads on the podcast, and therefore it's made possible entirely through the support
00:00:34.660 of our subscribers.
00:00:35.880 So if you enjoy what we're doing here, please consider becoming one.
00:00:46.820 Today I'm speaking with Jennifer Doudna.
00:00:50.220 Jennifer is a biochemist.
00:00:52.100 She's a professor in chemistry in the molecular and cell biology departments at the University
00:00:56.220 of California at Berkeley.
00:00:58.360 She's also an investigator with the Howard Hughes Medical Institute and a researcher
00:01:03.040 in the molecular biophysics and integrated bioimaging division at the Lawrence Berkeley
00:01:07.280 National Laboratory.
00:01:09.360 She is one of the world's experts on RNA protein biochemistry and, in particular, CRISPR biology.
00:01:17.580 And she's the author, along with Samuel Sternberg, of the book A Crack in Creation, Gene Editing
00:01:23.860 and the Unthinkable Power to Control Evolution.
00:01:26.280 And Jennifer is credited as one of the inventors of the CRISPR-Cas9 gene editing technology, which
00:01:35.500 is the topic of today's conversation.
00:01:37.740 We get into all the details and the ethics.
00:01:41.660 And time was short.
00:01:43.680 Jennifer is a rock star scientist, and I could only schedule about an hour with her. 0.99
00:01:49.140 But I will take it.
00:01:51.760 It was great to have her walk me through the details of CRISPR.
00:01:56.400 And I trust you will leave this podcast as I did, knowing much more about where this technology
00:02:01.280 is at present and where it's all likely to head.
00:02:04.980 So, without further delay, I bring you Jennifer Doudna.
00:02:08.700 I am here with Jennifer Doudna.
00:02:16.620 Jennifer, thanks for coming on the podcast.
00:02:18.620 Great to be here, Sam.
00:02:19.960 So, you are a co-inventor of CRISPR-Cas9, which is a gene editing technology that we'll talk about.
00:02:27.940 Before we get into this, perhaps you can just give a kind of potted summary of your background
00:02:32.240 scientifically.
00:02:32.780 Well, I'm a biochemist, so I'm somebody who studies molecules and how they work.
00:02:39.020 And I've always been interested in evolution and the way that cells have evolved to use
00:02:45.780 their genetic information in precise ways.
00:02:48.880 And that's actually how we got into the whole area of gene editing.
00:02:52.880 And you're at UC Berkeley, right?
00:02:54.560 I'm at UC Berkeley, correct.
00:02:56.160 Now, I know there's some controversy about who should get credit for inventing CRISPR-Cas9.
00:03:02.340 And we don't really have to go into that.
00:03:04.460 I think there clearly is no controversy that you are one of the world's experts on this.
00:03:09.940 Is there anything you want to say about the controversy?
00:03:11.860 Or is it kind of a distraction as far as this conversation is concerned?
00:03:15.220 Well, I guess all I would say is that my work with Emmanuel Charpentier was, you know,
00:03:20.320 going on to really, I would call it a curiosity-driven project that was aimed at discovering how
00:03:28.540 bacteria fight viral infections.
00:03:30.220 So neither of us were aiming to create a technology.
00:03:34.640 But the work that we did uncovered the activity of a protein that can be programmed to find
00:03:41.520 and cut DNA sequences.
00:03:43.820 And with that understanding, it was pretty obvious that this was going to be a great technology.
00:03:50.500 And that was work that was published in 2012.
00:03:52.900 So I don't think anybody argues about that.
00:03:54.560 Right.
00:03:55.400 Okay, well, let's talk about CRISPR and that protein.
00:03:58.480 But before we do, it might be good to give a very quick remedial summary of some basic
00:04:05.900 molecular biology.
00:04:07.400 I think we have a fairly educated audience here.
00:04:09.980 But everyone, I think, can do with a primer on DNA to RNA to protein.
00:04:15.760 And, you know, because we're going to be talking about just the mechanics of gene editing here.
00:04:20.080 So can you give us a few minutes of basic biology here?
00:04:23.760 Sure, absolutely.
00:04:25.060 So I guess we could start by pointing out that people probably are familiar with the idea that
00:04:32.540 DNA encodes genetic information.
00:04:34.860 So it's really the chemical that stores information in cells and allows cells to grow and develop
00:04:41.880 and become tissues or whole organisms.
00:04:45.900 And the way that cells use that information is mostly in the form of proteins.
00:04:51.960 So the information in the DNA is converted into proteins by a process that creates the protein
00:05:00.620 molecules by reading the code in the DNA.
00:05:02.760 And the intermediary in that process is kind of what I like to call a throwaway copy of
00:05:09.460 the genetic information, which are molecules of RNA.
00:05:14.440 And what has emerged over the last probably two decades is that RNA molecules are not just
00:05:21.860 throwaway copies of the genome, but they are actually molecules that have a lot of interesting
00:05:28.340 functions in their own right.
00:05:29.800 And that's actually what I've always been interested in in my own laboratory, is the
00:05:34.340 role of RNA molecules that are involved in controlling the flow of genetic information
00:05:40.400 and helping cells decide when and how to use the information that's stored in the genome
00:05:46.860 in the DNA.
00:05:48.700 And the story of CRISPR, the story of this gene editing technology, is kind of interesting because
00:05:55.060 it really involves all three of those types of fundamental molecules, DNA, RNA, and protein,
00:06:02.040 because it's a protein that is involved in the, is really responsible for cutting DNA
00:06:08.800 at precise positions.
00:06:11.620 The places in the DNA that get cut are defined by molecules of RNA that the protein, which is
00:06:21.280 called Cas9, holds onto, and the places in the DNA that get cut are the sites in the genome
00:06:28.080 where editing occurs, where permanent changes are made to the genetic code.
00:06:33.320 And so you discovered this in bacteria, right?
00:06:38.740 CRISPR has been described as part of the bacterial immune system.
00:06:42.560 That's correct.
00:06:43.120 Take me there.
00:06:44.580 So what happens?
00:06:45.220 Viruses periodically infect bacteria.
00:06:48.820 And what does the CRISPR sequence do in that context?
00:06:52.040 Right.
00:06:52.240 So viruses infect bacteria actually all the time in nature.
00:06:56.400 And so bacteria have a very effective way of defending against viruses by storing pieces
00:07:03.880 of viral DNA in their own chromosome.
00:07:06.640 And then they use that, they use that stored viral DNA sequence.
00:07:12.600 There are actually multiple, multiple sequences coming, you know, one representing each virus
00:07:19.260 that has infected the cell over time.
00:07:21.760 So you can think of it sort of like a genetic vaccination card.
00:07:26.060 And then those, those stored viral DNA sequences are copied into RNA.
00:07:31.320 And then those RNA molecules assemble with the Cas9 protein to direct it to sequences that match
00:07:40.780 the, the, the RNA sequence.
00:07:42.400 In other words, sequences that are, uh, belong to viruses.
00:07:45.080 And when that match occurs, then the, the Cas9 protein works like a, like a molecular scalpel
00:07:51.100 and cuts the, the, the viral DNA and, and, and basically allows the cell to, to, to destroy it.
00:07:56.680 So again, this is semi-dense material and you don't have the benefit of visual aids here.
00:08:01.640 So I just want to make another pass on this just to make sure everyone has a picture of
00:08:05.700 what's happening here.
00:08:06.520 So you have this little machine, really.
00:08:09.780 It's a combination of protein molecule and RNA, which is really informing its behavior, right?
00:08:17.340 So you have an RNA sequence that matches a sequence in the DNA, which determines what part
00:08:24.160 of the DNA it will bind to and edit or cut.
00:08:28.660 And this is something you've discovered in bacteria, but which can be used as a kind of
00:08:34.940 molecular scalpel in eukaryotes like mammals, such as ourselves.
00:08:40.220 And this then becomes a way of targeting with a precision that we didn't have before spots
00:08:49.640 in the human genome that can be edited.
00:08:52.940 You nailed it.
00:08:53.500 That's perfect.
00:08:54.780 Okay.
00:08:55.680 So I guess I'm interested a little more in the mechanics of this.
00:08:59.460 So what are the chances that the CRISPR-Cas9 technology will cut in the wrong place in the
00:09:08.060 genome?
00:09:08.560 I mean, does there have to be a complete complementarity between the RNA and the DNA, or is there
00:09:13.520 some potential for error here?
00:09:15.460 Sure.
00:09:15.660 There's always potential for error.
00:09:16.960 I think the amazing thing about the CRISPR-Cas9 technology is that it's really pretty accurate,
00:09:24.380 and it's not perfect, but it's close to.
00:09:28.680 So I think what's emerged over the last few years that people have been using this, and
00:09:34.800 it's probably worth mentioning that this technology took off incredibly quickly.
00:09:39.780 It was adopted very, very rapidly after our 2012 publication, and there are now probably
00:09:48.700 thousands of people around the world using this as a tool in all sorts of systems.
00:09:53.800 And the good thing about that, or one of them, is that it's meant that there's been very
00:09:58.720 rapid development of the technology as well as understanding of how it works.
00:10:04.520 And one of the things that's emerged is that this tool is, you know, it's accurate enough
00:10:11.020 to make precise changes in even very large genomes, like the human genome or plant genomes.
00:10:20.120 And when people have sort of as, I think as people have become more sophisticated about
00:10:25.940 using it, ensuring that the Cas9 protein is used in limiting amounts in cells, not present
00:10:35.520 in huge quantities and not hanging around for too long, that it's actually remarkably accurate
00:10:41.800 at generating those kinds of edits.
00:10:44.900 It's possible to find off-targets, but you have to look pretty hard.
00:10:49.380 And can you edit a single base pair, or do you have to deal with longer sequences than that?
00:10:55.140 You can edit a single base pair.
00:10:57.360 Yeah.
00:10:58.120 Wow.
00:10:59.240 So you've described this as a scalpel.
00:11:02.520 Now, what happens after the DNA is cut?
00:11:04.980 Is it always a matter of inserting more DNA, a variant sequence, or can you simply cut and
00:11:13.580 remove parts of the DNA?
00:11:15.240 Yes, you can cut and remove, or you can cut and replace.
00:11:19.300 The removal part turns out to be easier technically to do than the replacing part, but both are
00:11:26.920 possible.
00:11:28.120 So, again, this is so counterintuitive in ways when you actually picture what's happening
00:11:32.680 here, because anyone who's taken biology in recent memory will know that the genetic
00:11:37.800 material inside our cells is in the nucleus, and it's bound very tight.
00:11:42.980 It's just crammed in there.
00:11:44.240 The chromosomes aren't laid out in the pretty way that they are when we picture them in
00:11:48.660 textbooks.
00:11:49.660 And now you've sent CRISPR, this little machine, into the cell.
00:11:56.620 We'll talk about how you can target tissues later on.
00:11:59.620 But this goes into the cell and moves all over the genome and is searching for the sequence
00:12:09.020 to which it is the mate, and so that it can find the place to cut.
00:12:12.920 How does it search the whole genome?
00:12:15.700 How do you get full coverage of a genome, and how quickly does this happen?
00:12:21.260 If we could take a video camera inside a cell, what would we be seeing there?
00:12:25.200 Well, we've sort of done that.
00:12:27.220 Not quite a video camera, but it's been possible to make fluorescently labeled versions of the
00:12:33.720 Cas9 protein that can be visualized in live cells.
00:12:37.880 So, you can basically watch these little dots of light moving around in the nucleus.
00:12:44.440 And when you do that kind of experiment, what emerges is that this is a protein that has
00:12:51.020 very fast kinetics, so it's moving around the nucleus incredibly quickly, much more quickly
00:12:58.220 than what you see for other kinds of proteins that are, you know, existing in the nucleus.
00:13:04.300 And what's thought to happen is that this protein is rapidly sampling different sections along
00:13:14.280 the sequence of DNA, and it is quite remarkable to think about it because, you know, we're
00:13:18.600 talking about billions of base pairs of DNA in the cell, but somehow this protein very
00:13:27.220 quickly samples along the DNA sequence looking for a match to the guide RNA sequence.
00:13:34.920 And one thing that's important to keep in mind is that it's not a single protein that would
00:13:40.000 be in the nucleus, but instead many, many copies of this.
00:13:43.760 There might be, you know, thousands or tens of thousands of copies that are all searching.
00:13:48.720 And when one finds its target site, then it makes a cut and the edit occurs.
00:13:54.920 Now, are the sequences of DNA unique enough so that we're not getting redundant cuts?
00:14:02.500 I mean, if you send a, you know, a 10-nucleotide sequence as your kind of search code, are we
00:14:09.220 expecting that to be the only place in the genome that would get modified, or just by dint
00:14:17.420 of numbers, you're going to be altering something you didn't expect to alter if you do that?
00:14:22.440 Well, in one of those interesting serendipities of science, this Cas9 protein actually uses a
00:14:28.680 20-nucleotide RNA sequence.
00:14:31.480 So it's 20 letters that it's looking for, 20 letters in a row.
00:14:35.180 And if you do the math, that's just about what you need to uniquely define a sequence
00:14:40.200 in the human genome, for example.
00:14:43.660 Good.
00:14:44.020 And numbers were on our side.
00:14:46.120 Right.
00:14:47.880 Let's back up.
00:14:48.780 So now we have a human being who has a variety of genes that are not as perfect as they might
00:14:55.780 be, and we'll talk about the conditions for which we have some understanding of the underlying
00:15:01.260 genetics and, you know, what could be modified here.
00:15:04.320 But let's say we know what genes we want to alter.
00:15:08.960 How would we target CRISPR to specific sites in the body?
00:15:14.520 And presumably, these insertions would sometimes need to be tissue-specific.
00:15:19.980 You wouldn't want to send this everywhere, right?
00:15:22.000 Right.
00:15:22.780 And I think you're putting your finger on what I think is one of the critical challenges
00:15:28.020 for gene editing in the clinic going forward, which is just what you said.
00:15:33.520 How do we deliver these editing molecules into the right cells at the right time?
00:15:38.880 One of the ways that this can be done today is actually by delivering into cells that are
00:15:45.240 temporarily taken out of the body.
00:15:47.200 So, for example, people are working hard on correcting mutations that cause blood disorders
00:15:54.400 because the blood cells can actually be taken out, edited, and replaced.
00:15:59.160 So I think that's one strategy that gets around the issue of trying to deliver something like
00:16:06.940 this into specific tissues in a person.
00:16:11.260 That's a much bigger challenge.
00:16:13.140 And why is it a challenge, though?
00:16:14.360 I mean, what would be the mechanism?
00:16:16.720 Would you use some viral vector to deliver it?
00:16:19.400 If you wanted to get it into every cell in the body, what would be the methodology?
00:16:23.420 Well, that would be hard, even using a virus, because viruses tend to target particular kinds
00:16:30.960 of cells.
00:16:32.040 So you might have to use a cocktail of viruses that are able to get into many different types
00:16:37.100 of cells.
00:16:37.940 But I think what is typically envisioned is that you might be able to use viruses that
00:16:45.040 would deliver into specific parts of the body, for example, into the liver or into the brain,
00:16:53.660 and create edits that would alleviate disease in cases where the gene edit is necessary just
00:17:01.900 in those kinds of cells.
00:17:03.340 And what is the time frame over which this would occur?
00:17:07.700 I mean, just so again, we'll talk about how difficult this might be in practice.
00:17:12.180 But let's say we know the gene we want to edit, and we have the way to target the relevant
00:17:19.220 tissue, and someone has a disease born of this malfunctioning gene.
00:17:23.860 How quickly would CRISPR change their genome and cancel the disease?
00:17:30.620 Well, in principle, very quickly.
00:17:33.780 I've seen some data in animal models of disease, for example, in mice, where mice get an injection,
00:17:41.700 and within a matter of, you know, a couple of days, you can start to detect edits in the
00:17:48.180 DNA of the cells that have been targeted in the treatment.
00:17:51.940 So I think the idea in principle, and I think this is something the field is working towards
00:17:57.500 doing, is that gene editing would be a fairly fast kind of treatment.
00:18:03.060 And furthermore, and this is actually very important to appreciate, is that it's a different
00:18:08.320 kind of therapy because it's really a one-and-done treatment in principle, right?
00:18:13.380 The idea is you would do this once, and then you don't have to do it again.
00:18:16.740 Yeah.
00:18:16.940 I really want to get into the ethics of all of this, because that is quite interesting,
00:18:21.660 and obviously this worries a lot of people.
00:18:24.820 But before we do, so what are the most plausible first uses of this?
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