Freakonomics Radio - Evolution, Accelerated (Rebroadcast)

Episode Date: May 3, 2018

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?

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? 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? 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. So the research project that led to this technology was really a, you know, it was a curiosity-driven project. Jennifer Doudna is a professor of chemistry and biology at the University of California, Berkeley. 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. 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. Well, when I first heard the acronym CRISPR, this was from a conversation with Jill Banfield, I had no idea what that was. This was in 2006. Banfield, also a Berkeley scientist, had been studying bacteria that grow in toxic environments. And so she was looking at bugs that grow in old mine shafts and, you know, these pools of water that build up 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.

The key to their survival was called CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats. Say that five times fast. 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. 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. What began as a casual conversation about an obscure subject grew to consume Doudna for years.

Finally, she had a breakthrough. I suddenly just burst out laughing. Today on Freakonomics Radio, the mind-blowing discovery that's already changing medicine and more. A remarkable gene editing tool called CRISPR. That's right, I said gene editing. The implications of that boundless change. As I'm telling you this story, I feel this chill in my body.

And if you think the genetic revolution is still years away, you should think again. The technology for that is here now. From WNYC Studios, this is Freakonomics Radio, the podcast that explores the hidden side of everything. Here's your host, Stephen Dubner. 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. 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 should show up again in the cell. 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 Umeå 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. 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. And in the course of that research… And in the course of that research, we figured out that a particular protein, it has a name Cas9, is programmable by the cell. A protein that can be programmed to fight viruses? You can start to see where this is going. The amazing thing that this Cas9 protein does is it works like a pair of scissors.

It literally grabs onto the DNA and cuts it at that precise place. They thought, if nature could program this Cas9 protein to precisely edit DNA, why couldn't they? 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. 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. incredible little machine. 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. Doudna, together with Charpentier and several other colleagues, wrote up their research and,

on June 8, 2012, formally submitted it to the journal 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. A new kind of genetic engineering is revolutionizing scientific research. Scientists think CRISPR could launch a new era in biology and medicine. CRISPR could help rid us of diseases like cystic fibrosis, muscular dystrophy, and even HIV and cancer. Jennifer Doudna had spent her career largely cloistered in laboratories. She didn't have a high-profile background. I grew up in a small town in Hawaii. Suddenly, she was a scientific superhero. We

explore those questions with Jennifer Doudna. Jennifer Doudna. Jennifer Doudna. Jennifer Doudna. For harnessing an ancient bacterial immune system as a powerful gene editing technology. The Breakthrough Prize is awarded to Emmanuelle Charpentier and Jennifer Doudna. Doudna has 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? Well, at its core, the CRISPR gene editing technology is now giving human beings the opportunity to change the course of evolution. And, 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 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. As opposed to like a crack in the dimension that we will fall through and all disappear. Not that kind of crack. We hope the former, not the latter. Yeah. So when you call it an incredible molecular machine, your breakthrough, if 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? 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 cut in DNA in, let's say, human cells at a particular place where the cell's 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 deb 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 how well or poorly it does? 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 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. 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. I think it's important for people to appreciate that, you know, first of all, that humans have been modifying plants for a long time, you know, genetically. Thank goodness.

Literally thousands of years. Exactly. Thank goodness, right? I mean, you realize, wow, 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 plants that have 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 don't even control for, right? So you don't even know where they are or what they might be doing. And so I think the opportunity here with gene editing in plants is to be able to make changes precisely. So not to drag along traits that you don't want, but to be able to make changes 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, you know, give plants the ability to grow with much less water or to 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. 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, forget about humans or animals yet, of, you know, governance and autonomy and so on. What are your thoughts on that in the plant slash agricultural world? I think that, you know, it's really going to come down to people having access to information about where is our food coming from so that people in different countries can evaluate these 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 better nutritional value. And 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 to, I think we have to have this tool in our toolbox. CRISPR gene editing is also being put to use on animals. Scientists in China are engaged in controversial research genetically modifying beagles to be more muscular. 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.

Researchers believe that they can recreate a woolly mammoth by combining its DNA with that of a modern elephant. There's at least one and maybe more than one company now that are using the gene editing technology in animals, like in pigs, to create pigs that would be better organ donors for humans. I like the micro pig too. Chinese genomics institute BGI began breeding micro pigs to study diseases, but now they're going to sell them as pets for $1,600 and give in to the micro pig craze. Miley Cyrus has one. Yes, pets. Yeah, right. The idea of, you know, sort of a fanciful use in a way of gene editing, you know, making animals that we think are cute.

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? I mean, if you knew that your potential mate was of high likelihood of developing early dementia, you might think twice before getting married. And what keeps Jennifer Doudna up at night? And I realized with this horror, you know, that I realized that it was Adolf Hitler. 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? Hi, Stephen. How are you?

There's also social genomics. The social genomics revolution is really just getting started, I would say. Dalton Conley teaches sociology and population studies at Princeton. And I'm the co-author of The Genome Factor. You may remember Conley from an old Freakonomics Radio episode called How Much Does Your Name Matter? He has two kids, a daughter. Okay, I'm E like the letter. And a son.

I'm Yo like the slang. But those are just their first names. Full names? E, Harper, Nora, Jeremy Janko Conley. Yo, Shing, Hano, Augustus, Eisner, Alexander, Weiser, Knuckles, Jeremy Janko Conley. So Yo, okay, where's your first name Yo comes from where? I think it comes from the Y chromosome. So Dalton Conley, the sociologist's dad,

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

Everyone thought everything was going to change suddenly. We were going to have personalized medicine. We were going to, I don't know what. It will revolutionize the diagnosis, prevention, and treatment of most, if not all, human diseases. But actually, not much happened for the first decade or so. The great scientific hope was to find single, easily identifiable genes that controlled cancer or depression or intelligence or even just height. So that turns out to be an exception rather than a rule. 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. 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. Having a map of the genome was one thing, but in the Bill Clinton era, there was a lack of good data. That has changed. And now we have this, what I call the revolution,

is this surfeit of cheap data, cheap genetic data. Just two decades ago, it cost a billion dollars to sequence a single genome. And now you and I could spit in a cup and send it to one of the popular sequencing outfits, and for $100 or for $150, we can get millions of answers to the question, what does our DNA look like? Anyone who sends their saliva into 23andMe. With just a small saliva sample, you'll learn about your ancestry through your 23 pairs of chromosomes and make you who you are.

To get their ancestry and their supposed health risks has now basically agreed to be part of their database that will be studied, and that has well over a million samples of mostly U.S. citizens. 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. And that's anything from Alzheimer's and dementia on the health side to measures of educational attainment and socioeconomic position on the social science side.

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. But, warning, it's still early days. 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. So what does this mean for a technology like CRISPR gene editing? I think that's going to be very exciting for a limited number of single gene diseases.

Diseases like cystic fibrosis and sickle cell disease and Huntington's disease. But most things we care about in today's world, heart disease, Alzheimer's, IQ, height, body mass index, diabetes risk, all of those things are highly polygenic. That means that they're the sum total of many little effects all across the chromosomes. And that probably means we're not going to be doing gene editing in a thousand different locations in the genome. 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. We have a tool that's emerged called the polygenic score. So you take all the small effect sizes that you're 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. 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.

Worrying because why? 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 want to 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. 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 for... A preference for people of certain European ancestry, and not all European ancestry,

but certain, just the favored groups, to have more children and to be given resources to the exclusion of all other people. And of course, it led pretty directly to Nazism and the exterminations of millions of people. And it also was used as the pseudoscience behind at least decades of racial injustice in the United States and many other countries. That is the nightmare that has given Jennifer Doudna actual nightmares. 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 sort of a silhouette in a chair with his back to me. And he turned around and I realized with this horror, and I can feel it right now as I'm telling you the story, I feel this chill in my body, you know, that 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

profound kind of existential fear that, you know, if someone like that were to get a hold of a powerful technology like this, 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 a broader discussion about this. It's just too important a subject. I hear, I don't mean to at all diminish 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? Well, I think we're kind of building it as we're going at some level. I've been involved in organizing a number of meetings. 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, you know. Right, talking in the silo to each other. 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. I think that movie makers are going to be important. Musicians and various kinds of visual artists are going to be important. I think all of those people are very skillful at communication, communicating ideas, and they can do it in some ways much more effectively than, you know, a lot of technical jargon would ever achieve. 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 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? I've seen an evolution in my own thinking, quite frankly, you know, and I think that I sort of have gone from feeling very uncomfortable with, 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 thinking that, you know, there may come a time, I don't think we're there now, and 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 is going to be deployed. And I think that for me, the important thing is not to reject it. It's actually to understand it and really think

through the implications. Now, let me ask you to just to take a step back and talk about actual therapeutic, I guess, treatment and the difference between germline and somatic editing. Ah, yes. So that's very important to understand the difference. So, you know, most of the applications that we've been talking about, especially 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 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 safe and effective, but it affects just that one person. Whereas if you make a change that affects somebody's, all of their children, and all of their children's children, etc., that is really profound. And it really does affect, ultimately, you know, human evolution. And presumably, let's say I cared enough about some strain of heritability enough to do it, let's say, on a fairly wide scale, then presumably it would increase my incentive to maybe

diminish the supply of non-germline treated people, right? So you could imagine... Now you're getting into Gattaca territory here. Well, I mean, it doesn't take long, even for a mind as, you know, kind of flabby as mine to get there pretty quickly, right? I mean, the potential for this reminds me a bit of the potential for geoengineering, you know, intentionally altering the planet's atmosphere to change the temperature in case global warming gets really destructive. So one of the key questions there is, you know, governance. Who gets to control the thermostat? And I know you've been very outspoken in that you really flung yourself into the ethical and practical elements of this technology.

But I'm curious where you stand on the kind of biggest, I don't want to say scariest, because I hate when we're knee-jerk scared of new technologies that are prima facie wonderful. But I do wonder's very important to emphasize that, you know, this technology, I think, is going to overall, it's going to have a very positive benefit to human beings in many ways. And I'd really like to make sure that people get that message because, you know, I think it's easy to, you know, try to make things sound exciting by making them sound really scary. And I think this is a technology that really we're already seeing incredibly exciting advances, you know, opportunities to cure genetic diseases that have had no treatments in the past, to advance the pace of clinical and other types of research, make it possible to understand the genetic basis for disease and then be able to do something about it when you have that information. So I think what needs to happen is that scientists need to really engage with government regulators and frankly also with religious leaders and other kinds of thought leaders to make sure first and foremost that there's a very clear understanding of the science behind this as much as possible. Let's pretend that this technology within a couple generations works so beautifully that

it extends lifespan by 20 percent or 50 percent or 200 percent. Do you think about what happens in terms of obvious things like, you know, global resources if people are living twice as long, but also how we as animals would respond to that scenario in which scarcity diminishes so much, you know, the scarcity being a short lifespan. It seems that humans are relatively slow to adapt to the diminishment of scarcity over time. Like, it seems we still eat, for instance, in the 21st century as though the next meal may or may not appear on the horizon. So I'm curious if all of a sudden there are all these extra years in terms of everything, labor markets and retirement and existential issues, like what do I do now for those next

80 or 100 years that, you know, Jennifer Doudna and her colleagues helped facilitate? Do you think about those things? Well, there's lots of interest in that topic right now, as you know, especially here in Silicon Valley. I think for me it really would come down to are those extra years high-quality years? And are they years where people could be contributing importantly to society? And if the answer is yes, then I think that is something that is very interesting to think about. If the answer is no, then I don't think, I certainly don't think that sounds very appealing at all. I'd rather take short and healthy than long and miserable. But I think

that the prospect of enhancing human health, if that goes hand in hand with longevity, I certainly would like to see it be something that was available to communities around the world, not just to a few people. the future of CRISPR-Cas9 and the genetic revolution generally, you probably won't be surprised to learn there's also uncertainty about where the proceeds from these discoveries will flow. As you can imagine, they are potentially huge. Jennifer Doudna's team filed patent rights early on to use the CRISPR system on virtually any living thing. But not long after, a researcher named Feng Zhang from the Broad Institute of MIT and Harvard filed CRISPR patents on an important subset of living things. The conflict went to the Federal Patent Trial and Appeal Board, which ruled in Zheng's favor. But the final outcome is far from settled. A few updates since we first released this episode last year.

The research journal Nature Methods published a paper suggesting that CRISPR wasn't as precise as people like Doudna say it is. The authors claimed it caused 2,000 unexpected mutations. But that paper was recently retracted. In other news, the USDA recently approved a broad range of gene-edited foods. CRISPR even featured as a major plot point in the Dwayne the Rock Johnson movie Rampage. And on the intellectual property front, Doudna's team at UC Berkeley is appealing the patent office's decision. The European Patent Office, meanwhile, revoked the Broad Institute's CRISPR patent there. Coming up next time on Freakonomics Radio, we all love to read about the latest breakthrough in psychology research, don't we?

But the danger, I think, is quite right, which is that we can very easily push our wonder buttons and push our interest buttons using pseudoscience rather than science. What if I told you that a lot of the terms that psychologists use are all different kinds of wrong? Yes, inaccurate or misleading, frequently misused, ambiguous terms, oxymorons, and pleonasms.

For instance? So one that comes to mind is bystander apathy. The biggest error is to assume that these personality traits are unitary. They only have one cause and that they're inherited. One of the most important discoveries in neuroscience of the last few years has been that all that hardwired stuff is completely wrong. So what are psychologists good for anyway? That's not a bad question, actually. Misused and abused concepts from psychology and psychiatry. That's next time on Freakonomics Radio.

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