Evolution, Accelerated | Freakonomics podcast (Transcript)

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One of our favorite podcast series is Freakonomics Radio with Stephen Dubner and from WNYC Studios that seeks to  "have fun discovering the hidden side of everything." We highly recommend you listen to the series. We have transcribed the episode  "Evolution, Accelerated" (June 15, 2017).

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Evolution, Accelerated with Stephen Dubner

Length: 35min | Released: June 15, 2017

A breakthrough in genetic technology has given humans more power than ever to change nature. It could help eliminate hunger and disease; it could also lead to the sort of dystopia we used to only read about in sci-fi novels. So what happens next?

Jennifer Doudna: I remember standing in my kitchen, cooking dinner for my son and I just, I suddenly just burst out laughing, you know, it was just this, suddenly this joyful thought of,  "Isn't it crazy that nature has come up with this incredible little machine!"

Stephen Dubner: The history of science is full of accidental discoveries, penicillin, perhaps most famously, but also gunpowder and nuclear fission. It makes sense doesn't it? Because you don't know what you don't know. You don't always know what you're looking for or at. Sometimes you've just got a curious mind.

JD: So, the research project that led to this technology was really a, you know, it was a curiosity driven project.

SD: Jennifer Doudna is a professor of chemistry and biology at the University of California Berkeley.

JD: And I've had a longtime interest in understanding fundamental biology, in particular aspects of genetic control and the way that evolution has come up with creative ways to regulate the expression of information in cells.

SD: When you first heard, literally heard the phrase Crispr, just describe that moment, what your understanding of it was and what you kind of initially envisioned it facilitating?

JD: Well, when I first heard the acronym Crispr, this was from a conversation with Jill Banfield, I had no idea what that was.

SD: This was in 2006. Banfield, also a Berkeley scientist, had been studying bacteria that grow in toxic environments.

JD: And so she was looking at bugs that grow in old mineshafts and, you know, these pools of water that build up, um, in old mines that are often very acidic or they have various kinds of metallic contaminants to figure out what bugs are growing there and how are they surviving.

SD: The key to their survival was called Crispr, Clustered Regularly Interspaced Short Palindromic Repeats.

JD: Say that 5 times fast.

SD: Banfield thought the bacteria had developed a sort of pattern-based immune system to protect themselves, but exactly how it worked was a puzzle. To help solve it, she recruited Doudna.

JD: And we ended up spending several afternoons where Jill was showing me her DNA sequencing data from bacteria and, you know, explaining what these sequences were.

SD: What began as a casual conversation about an obscure subject grew to consume Doudna for years. Finally, she had a breakthrough.

JD: I suddenly I just burst out laughing!

SD: Today on Freakonomics radio, the mind blowing discovery that's already changing medicine and more.

Announcer: A remarkable gene editing tool called Crispr. That's right, I said gene editing.

SD: The implications of that boundless change?

JD: As I'm telling you this story, I feel this chill, uh, in my body.

SD: And, if you think the genetic revolution is still years away, you should think again.

Announcer 1: The technology for that is here now.

SD: Congratulations on your future Nobel Prize!

Jennifer Doudna hasn't won the Nobel Prize yet, but it's hard to imagine she won't. We'll go back to when she started working with Jill Banfield. Doudna learned that Crisprs were DNA sequences stored in the cells of bacteria.

JD: You can think about it like a genetic vaccination card. It's a way that cells store information in the form of DNA from viruses to use in the future to protect cells if that virus did show up again in the cell.

SD: But how did it work? And what might it mean if scientists could figure it out? In 2011, having already studied Crispr for a few years, Doudna attended a microbiology conference in Puerto Rico. There she met Emmanuelle Charpentier, then a researcher at Umea University in Sweden. Charpentier was researching a mystery protein that she felt was the key to Crispr. She and Doudna began a long running collaboration.

JD: We were working together to understand the molecular basis. In other words, what are the molecules that allow bacteria to find and destroy viral DNA? That was the question that we set out to address.

SD: And in the course of that researchÔøΩ

JD: And in the course of that research, we figured out that a particular protein, it has a name, cas9, is programmable by the cell.

SD: A protein that can be programmed to fight viruses? You can start to see where this is going.

JD: The amazing thing that this cas9 protein does is it works like a pair of scissors. It literally grabs on to the DNA and cuts it at that place, at that precise place.

SD: They thought,  "If nature could program this cas9 protein to precisely edit DNA, why couldn't they?"

JD: It turns out that when this is transplanted into animal or plant cells or human cells it's possible to introduce changes to the DNA very precisely, and that's how the technology fundamentally works.

SD: Then came the night at home cooking dinner for her son when she burst out in joyful laughter at the sheer wonder and the massive possibilities.

JD: Isn't it crazy that nature has come up with this incredible little machine? So, so, there was that sort of moment and then, you know, I think that sort of morphed into a growing recognition that, you know, this technology was going to be very impactful in many different areas of science.

SD: Doudna, together with Charpentier and several other colleagues, wrote up their research and, on June 8th, 2012, formally submitted it to The Journal of Science. It was published 20 days later. Suddenly the world knew that the Crispr cas9 system could be harnessed as a new gene editing tool.

Announcer 2: A new kind of genetic engineering is revolutionizing scientific research.

Announcer 3: Scientists think Crispr could launch a new era in biology and medicine.

Announcer 4: Crispr could help rid us of diseases like cystic fibrosis, muscular dystrophy and even HIV and cancer.

SD: Jennifer Doudna had spent her career largely cloistered in laboratories. She didn't have a high profile background.

JD: I grew up in a small town in Hawaii.

SD: Suddenly she was a scientific superhero.

Announcer 5: We explore those questions with Jennifer Doudna.

Announcer 6: Jennifer DoudnaÔøΩ

Announcer 7: Jennifer DoudnaÔøΩ

Announcer 8: Jennifer DoudnaÔøΩ

Announcer 9: For harnessing an ancient bacterial immune system as a powerful gene editing technology.

Announcer 10: The Breakthrough Prize is awarded to Emmanuelle Charpentier and Jennifer Doudna.

SD: Doudna spent the past few years racing forward while also trying to slow things down. She wrestles with all this in a book she co-wrote with another Crispr researcher, Samuel Sternberg. It's called  "A Crack in Creation." Why the title? It refers to what?

JD: Well, at its core, the Crispr gene editing technology is, is now giving human beings the opportunity to change the course of evolution and it, you know, human beings have been affecting evolution for a long time, right, but I think now there's a technology that allows very specific changes to be made to DNA that gives us a new level of, of, control and so, you know, it's sort of opening a crack and I sort of see it as like analogous to opening a door to the future that is really, you know, a change in the way that we think about our world.

SD: As opposed to like a crack in the dimension that we will fall through and all disappear, and not that kind of crack.

JD: We hope the former not the latter, yeah.

SD: Okay, all right. So as you're write in the book,  "We uncovered the workings of an incredible molecular machine that could slice apart viral DNA with exquisite precision." So, when you call it  "an incredible molecular machine," your breakthrough of you and your colleagues is essentially an external human guided replica of what already exists or are you kind of taking over the controls of what inherently exists?

JD: This is important. We're really taking over the controls of what already exists. And we're doing it by using this bacterial system, the Cas9 protein, to find and make a, a cut in DNA, in, let's say, human cells at a particular place where the cells' natural repair machinery can then take over and do the actual editing.

SD: What's amazing to me is the natural repair machinery obviously exists and maybe it works really well a lot of the time. It's just, in the most drastic circumstances, like a cancer or a debilitating disease, it doesn't. I mean, the healing mechanism, from reading what you've written, it sounds as though it's quite stochastic, it's random, unpredictable, some things it catches, some things it doesn't, sometimes it works, sometimes it doesn't. So can you talk about the big picture of this repair mechanism and, and how well or poorly it does?

JD: Sure. So DNA repair happens all the time in cells and, as you alluded to, it has to work right most of the time or we would probably not be here or we would all have a lot more cancer than we have. And so we know that, uh, that cells experience double stranded breaks to their DNA routinely and that they have ways of fixing those breaks. And, so I would say that what this Crispr technology does is it really taps into that natural repair pathway.

SD: Since the announcement of the Crispr Cas9 technology, scientists around the world have been exploring its possibilities in many different arenas. Let's start with plants.

JD: I think it's important for people to appreciate that, you know, first of all, that humans have been, uh, modifying plants for a long time, you know, genetically and, you know forÔøΩ

SD: Thank goodness.

JD: Literally thousands of years. Exactly, thank goodness, right? I mean, when you realize, wow, I'm glad there's, uh, I'm glad there's plant breeding. But, you know, the way that that's been done traditionally is to use chemicals or even radiation to introduce genetic changes into seeds and then plant breeders will select for, for, plants that have , uh, traits that they want and, of course, you can imagine when you do something like that, you drag along a lot of traits that you probably don't want and, you know, changes to the DNA that you, you, don't even control for, right, so you don't know where they are what they might be doing. And so I think the opportunity here, with gene editing in plants, is to be able to make changes, uh, precisely. So not to drag along traits that you don't want, but to be able to make changes that will be beneficial to plants, but to do that very precisely. And then we have the opportunity to do things like, uh, you know, give plants the ability to grow with much less water or to , uh, defend themselves against various kinds of infections and, you know, pests that are moving in due to climate change. I think, from the perspective of the world food supply, that's going to be extremely important going forward and will, potentially, allow us to have access to plants that are going to be much better adapted for particular environments and to grow, we hope, without chemical interventions of different types.

SD: Now given how nervous some portion of the population is about the phrase  "genetically modified organisms," even though, as you've pointed out, almost every organism on earth has been genetically modified for, you know hundreds if not thousands of years, this feels like a next level step that will raise all kinds of questions even in the plant world‚Äö√Ñ√§‚Äö√Ñ√Æ‚Äö√Ñ√§forget about humans or animals yet‚Äö√Ñ√§‚Äö√Ñ√Æ‚Äö√Ñ√§of, you know, governance and autonomy and so on. What are your thoughts on that in the, in the plant/agricultural world?

JD: I think that, you know, it's really gonna come down to people having access to, to information about where is our food coming from so that people in different countries can evaluate these , uh, plants and the technologies used to create them and make their own decisions about what they want to do. And having a precision tool that allows us to generate plants that are better, let's say, adapted to particular environments or, you know, maybe have even a better nutritional value and I, I really believe that, going forward, that we can't afford to reject this. We really have to understand it and, you know, regulate it appropriately but we do have toÔøΩ I think we have to have this tool in our toolbox.

SD: Crispr gene editing is also being put to use on animals.

Announcer 11: Scientists in China are engaged in controversial research, genetically modifying beagles to be more muscular.

Announcer 12: These mosquitoes have been genetically modified to breed with and eliminate their own species in an urgent attempt to wipe out carriers of dengue fever.

Announcer 13: Researchers believe that they can recreate a wooly mammoth by combining its DNA with that of a modern elephant.

JD: There's at least one, and maybe more than one, uh, company now that are using the gene editing technology and animals, like in pigs, to create pigs that would be better organ donors for humans.

SD: I like the micro pig too.

Announcer 14: Chinese genomics institute BGI began breeding micro pigs to study diseases, but now they're gonna to sell them as pets for $1600 and give in to the micro pig craze. Miley Cyrus has one.

JD: Yes, pets, yeah. Right, the idea of, you know, sort of a fanciful use, in a way, of gene editing. You know, make, making animals that we think are cute.

SD: The animal with the largest implications, of course, is the human.

Coming up on Freakonomics radio: How long until potential employers or mates are scouring our genetic profiles to see if we're worthy.

Dalton Conley: I mean, if you knew that your potential mate was of high likelihood of developing early dementia, you might think twice before getting married.

SD: And, what keeps Jennifer Doudna up at night?

JD: And I realized with this horror, you know, that I, I, realized that it was Adolf Hitler.

SD: The gene editing revolution prompted by the work of scientists like Jennifer Doudna isn't the only gene related revolution these days. Hey, Dalton, it's Stephen Dubner. How's it going?

DC: Hi, Steven. How are you?

SD: There's also social genomics.

DC: The social genomics revolution is really just getting started I would say.

SD: Dalton Conley teaches sociology and population studies at Princeton.

DC: And I'm the co-author of  "The Genome Factor."

SD: You may remember Conley from an old Freakonomics radio episode called  "How Much Does Your Name Matter?" He has 2 kids: A daughter.

E: Okay, I'm  "E," like the letter.

SD: And a son.

Yo: I'm  "Yo," like the slang.

SD: But those are just their first names. Full names?

E: E Harper Nora Jeremijenko-Conley.

Yo: Yo Xing Heyno Augustus Eisner Alexander Weiser Knuckles Jeremijenko-Conley.

SD: So, Yo. Okay, where's, your first name, Yo, comes from where?

Yo: Um, I think it come from the Y chromosome.

SD: So Dalton Conley, the sociologist dad, he's always had a crafty way of thinking about genetic identity. So, Dalton, the subtitle of your book is  "What The Social Genomic Revolution Reveals About Ourselves, Our History, and The Future." Just begin by telling what, what do you mean by the social genomics revolution? What's revolutionary about it? And describe kind of the arc of the revolution where we are in that.

DC: Okay. Well, the social genomics revolution is really just getting started, I would say. When Bill Clinton stood up, in the year 2000, and announced that the book of life had been decoded.

Bill Clinton: We're here to celebrate the completion of the first survey of the entire human genome. Without a doubt, this is the most important, most wondrous map ever produced by humankind.

DC: Everyone thought everything was gonna change suddenly. We were gonna have personalized medicine, we were gonnaÔøΩ I don't know what.

BC: It will revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases.

DC: But actually, not much happened for the first decade or so.

SD: The great scientific hope was to find single, easily identifiable genes that controlled cancer or depression or intelligence or even just height.

Jason Fletcher: So that turns out to be an exception rather than a rule.

SD: That's Jason Fletcher. He's an economist at the University of Wisconsin in Madison, and he's Conley's co-author on  "The Genome Factor."

JF: Most of what we care about, most of life's important outcomes, are not one gene and one disease; they're more like hundreds or thousands of genes all with really tiny effects if you can even find them.

SD: Having a map of the genome is one thing but, in the Bill Clinton era, there was a lack of good data. That has changed.

DC: And now we have thisÔøΩ What I call the revolution is this surfeit of cheap data, cheap genetic data.

JF: Just two decades ago it cost a billion dollar to sequence a single genome and now you and I could spit in a cup and send it to , uh, one of the popular sequencing outfits and for $100 or for $150, we can get millions of , um, answers to the question,  "What does our DNA look like?"

DC: Anyone who sends in their saliva into 23andmeÔøΩ

Announcer 15: With just a small saliva sample, you'll learn about your ancestry through your 23 pairs of chromosomes that make you who you are.

DC: To get their ancestry and their supposed health risks has now, basically, agreed to be part of their database that will be studied and this has well over 1 million samples of mostly US citizens.

JF: And all that data is being pulled together in both genetic analysis and social science analysis to try to understand the vast array of outcomes we're all interested in. That's anything from Alzheimer's and dementia on the health side to measures of educational attainment and socio-economic position on the social science side.

DC: So we finally have big data sets with lots of genetic markers across the entire set of chromosomes and we're now actually making robust discoveries that are withstanding replication and seem pretty solid and I think that's the start of the revolution

SD: But warning: It's still early days.

JF: That's right. So humans are very complicated and the amount of data we're talking about is in the millions or tens of millions of locations on our genome.

SD: So what does this mean for a technology like Crispr gene editing?

DC: I think that's going to be very exciting for someÔøΩ A limited number of single gene diseases.

SD: Diseases like cystic fibrosis and sickle cell disease and Huntington's disease?

DC: But most things we care about in today's world, heart disease, Alzheimer's, IQ, height, body mass index, uh, diabetes risk. All of those things are highly polygenic. That means that they're the sum total of many little effects all across, uh, the, uh, chromosomes. And that probably means we're not going to be doing gene editing in, in a thousand different locations in the genome.

SD: At least not anytime soon. But with all the genomic data that are being accumulated, scientists have been devising a system to make sense of it all.

DC: We have a tool that's emerged called the polygenic score.

JF: So you take all the small effect sizes that you are finding across many, many, many genes and you add them all up and then you've created a summary scale of your predicted likelihood of doing X where X could be smoking or getting dementia or going to college.

DC: But those scores aren't predicting very well right now. So before anything drastic happens socially, I would think that those scores would need to get a lot better. Once they really start explaining a lot of the variation in society, then I would start worrying.

SD: Worrying because why?

DC: The use by external authorities and companies of this information; that's definitely scary. And I think the other dimension is going to be in the marriage market where people just take it upon themselves to wanna know genetic information about their potential mates. I mean, if you knew that your potential mate was of high likelihood of developing early dementia, you might think twice before getting married. I mean, you know, phenotypes are for hookups, but genotype is forever. So the technology for that is here now. It could be used in fertility clinics; it could be used on dating apps where people could put their genetic profile linked from 23andme to OkCupid.

SD: Selection, of course, is something we all do every day. It's how we choose our friends, our allies and enemies, our political leaders. Some traits are observable; others less so. Some are heritable; others not. If the selection potential afforded by these new technologies is frightening to you, keep in mind the thing that's new about this is the technology. Remember the eugenics movement? That was justified by a preference forÔøΩ

JF: A preference for people of certain European ancestry‚Ää‚Äî‚Ääand not all European ancestry but certain� Just the favored groups‚Ää‚Äî‚Ääto, um, have more children and to be given resources to the exclusion of all other people. Then, of course, it led, pretty directly, to Nazism and the exterminations the millions of people and it also was used as the pseudo-science behind at least decades of racial injustice in the United States and many other countries.

SD: That is the nightmare that has given Jennifer Doudna actual nightmares.

JD: That really was one of the defining moments for me in terms of thinking about getting involved in the ethical conversation. So I had a dream in which I was working away, I think I was in my office actually, and a colleague of mine came in and said,  "I'd like to introduce you to someone and I would like you to explain the Crispr technology to him," and he led me into a room and there was a light in the room and there was someone sitting in, in sort of, uh, silhouette in a chair with his back to me. And he turned around and I realized with this horror‚Äö√Ñ√§‚Äö√Ñ√Æ‚Äö√Ñ√§and I can feel it right now as I'm telling the story, I feel this chill, uh, in my body, you know‚Äö√Ñ√§‚Äö√Ñ√Æ‚Äö√Ñ√§that, that I, I realized that it was Adolf Hitler and he was looking at me with very, very intent look on his face and an eager kind of look, you know, and he wanted to know about this technology. And I felt this incredible sense of fear, both sort of personal fear but also a profound, kind of existential fear that, you know, if someone like that were to get ahold of a powerful technology like this , um, how would they deploy it? And, of course, it, you know, when I woke up from that dream and I, you know, thinking about it subsequently and it was really scary to think about and I thought, you know, this, we have to proceed responsibly here. We cannot just, you know, I, or at least for me, myself, I can't just carry on with my next experiment in my lab; I really have to get involved in, in a broader discussion about this. It's just too important a subject.

SD: I hearÔøΩ I don't mean to at all diminish your, your argument, but I hear a lot of scientists make a similar argument, which is, you know,  "Look, we're doing our best on our end and we really want to have this conversation kind of in public, especially with people who have the leverage, mostly politicians, let's say, to make smart choices." My question is does a good mechanism or forum for that kind of conversation really exist?

JD: Well, I think we're kind of building it as we're going at some level. I've been, uh, involved in organizing a number of meetings. They're, they're right now they're fairly small in focus, but the idea is to really answer, we hope, that question that you just posed, is how do you do that? How do you bring people from these different walks of life together so they can have a meaningful discussion? And I don't have the answer yet, but I do think that it has to involve formats that are accessible to people. It can't just be a bunch of academics, uh, you knowÔøΩ

SD: Right, talking in the silo to each other.

JD: Right, exactly. It cannot be that. It has to be using various ways. I think the media are going to be very important, I think people that write science fiction are going to be important, I think that movie makers are going to be important, musicians and various kinds of visual artists are going to be important because I think all of those people are very skillful at communication, communicating ideas, and they can do it, uh, in, in some ways much more effectively than, you know, a lot of technical jargon would ever achieve.

SD: So probably the most enticing, and certainly the most controversial, aspect of Crispr is the power to reshape human beings whether an individual with an illness or a generation of a family or maybe an entire, you know, population. So, obviously, it's a gigantic area and something that probably nobody doesn't bring a lot of strong priors to the table with already. But can you just talk about this issue and your thinking about the issue and kind of where you've landed?

JD: I've seen evolution in my own thinking, quite frankly. You know, and I think that I sort of have gone from feeling very uncomfortable with , uh, you know, sort of the idea of making changes to human embryos, especially for anything that would be considered, you know, not medically essential to, to thinking that you know there may come a time, I don't think we're there now and it's, I don't think it's right around the corner, but I think there may come a time when that sort of application is embraced and, and is going to be deployed and, and I think that, for me, the important thing is not to reject it, it's actually to , uh, understand it and, and really think through the implications.

SD: Now let me ask you to just take a step back and talk about actual, um, therapeutic, I guess, treatment and the difference between germline and somatic editing.

JD: Ah, yes. That's, that's very important to understand the difference. So, um, you know, most of the applications that we've been talking about, especially in, in medicine right now, involve what we call somatic cell editing, and that means making changes to the DNA in cells of a particular tissue, uh, in a person that's already fully developed but those changes do not become heritable; they can't be passed on to the next generation. But, the contrast to that is changes to the germline, and that means making changes to the DNA of embryos or eggs or sperm, changes that are inherited by future generations and become, effectively, permanent in the human genome. And so I think there's a profound difference between those two uses because, if you're doing something that affects one person, you know, it has to be regulated, of course, and you have to make sure that it's a safe and effective, but it affects just that one person. Whereas, if you make a change that affects somebody'sÔøΩ All of their children and all of their children's children etc., that is really profound and, and it really does affect, ultimately, you know, human evolution.

SD: And presumably, let's say I cared enough about some strain of heritability enough

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