Evolution, Accelerated (Replay)

Today we’re bringing you an episode from our archives called “Evolution, Accelerated.” The story is a fascinating one, and, like most good stories, it has continued to develop. You can find our updates at the bottom of this post.

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Jennifer DOUDNA: I remember standing in my kitchen cooking dinner for my son and I suddenly just burst out laughing. It was 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? 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.

DOUDNA: The research project that led to this technology was really a curiosity-driven project.

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

DOUDNA: 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.

Stephen J. DUBNER: When you first heard the phrase CRISPR — just describe that moment, what your understanding of it was and what you initially envisioned it facilitating.

DOUDNA: 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.

DOUDNA: She was looking at bugs that grow in old mine shafts — and 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 they are surviving.

The key to their survival was called CRISPR: “clustered regularly interspaced short palindromic repeats.”

DOUDNA: 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.

DOUDNA: We ended up spending several afternoons where Jill was showing me her D.N.A. sequencing data from bacteria and 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.

DOUDNA: And I suddenly just burst out laughing.

Today on Freakonomics Radio: the mind-blowing discovery that’s already changing medicine, and more; the implications of that boundless change; and: if you think the genetic revolution is still years away — you should think again.

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DUBNER: So, congratulations on your future Nobel Prize.

DOUDNA: [Laughs]

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 CRIPSRs were D.N.A. sequences stored in the cells of bacteria.

DOUDNA: You can think about it like a genetic vaccination card. It’s a way that cells store information in the form of D.N.A. 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.

DOUDNA: We were working together to understand the molecular basis. In other words, “What are the molecules that allow bacteria to find and destroy viral D.N.A.?” That was the question that we set out to address.

And in the course of that research …

DOUDNA: 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.

DOUDNA: The amazing thing that this Cas9 protein does is it works like a pair of scissors. It literally grabs onto the D.N.A. and cuts it at that place, at that precise place.

They thought: if nature could program this Cas9 protein to precisely edit D.N.A., why couldn’t they?

DOUDNA: It turns out that when this is transplanted into animal or plant cells — or human cells — it’s possible to introduce changes to the D.N.A. 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.

DOUDNA: “Isn’t it crazy that nature has come up with this incredible little machine?” So there was that moment, and then that morphed into a growing recognition that 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.

Linda WERTHEIMER in a clip from Weekend Edition Saturday: A new kind of genetic engineering is revolutionizing scientific research.

Melissa BLOCK in a clip from All Things Considered: Scientists think CRISPR could launch a new era in biology and medicine.  

Norah O’DONNELL in a clip from C.B.S. This Morning: CRISPR could help us rid us of diseases like cystic fibrosis, muscular dystrophy — and even H.I.V. and cancer.

Jennifer Doudna had spent her career largely cloistered in laboratories. She didn’t have a high-profile background.

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

Suddenly she was a scientific super-hero.

Gwen IFILL in a clip from P.B.S. News Hour: We explore those questions with Jennifer Doudna.

C.B.S.: Jennifer Doudna.

N.P.R.: Jennifer Doudna.

FOX: Jennifer Doudna.

Cameron DIAZ in a clip from the Breakthrough Prize: For harnessing an ancient bacterial immune system as a powerful gene-editing technology …

Dick COSTOLO in a clip from the Breakthrough Prize: … the breakthrough prize is awarded to Emmanuelle Charpentier and Jennifer Doudna.

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.

DUBNER: Why the title? It refers to what?

DOUDNA: At its core, the CRISPR gene-editing technology is now giving human beings the opportunity to change the course of evolution. And human beings have been affecting evolution for a long time, right? But now there’s a technology that allows very specific changes to be made to D.N.A. that gives us a new level of control. And so it’s opening a crack. I see it as analogous to opening a door to the future that is a change in the way that we think about our world.

DUBNER: As opposed to a crack in the dimension that we will fall through and all disappear. Not that kind of crack?

DOUDNA: We hope the former, not the latter.

DUBNER: You write in the book, “We uncovered the workings of an incredible molecular machine that could slice apart viral D.N.A. with exquisite precision.” So when you call it an “incredible molecular machine” — your breakthrough, of you and your colleagues — is it essentially an external, human-guided replica of what already exists? Or are you taking over the controls of what inherently exists?

DOUDNA: This is important. We’re really taking over the controls of what already exists. We’re doing it by using this bacterial system, the Cas9 protein, to find and make a cut in D.N.A. 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.

DUBNER: 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. 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. Can you talk about the big picture of this repair mechanism and how well or poorly it does?

DOUDNA: D.N.A. 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. So we know that cells experience double-stranded breaks to their D.N.A. routinely and that they have ways of fixing those breaks. 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.

DOUDNA: I think it’s important for people to appreciate that, first of all, that humans have been modifying plants for a long time genetically.

DUBNER: Thank goodness.

DOUDNA: For literally thousands of years. Exactly. Thank goodness. And you realize, “Wow, I’m glad there’s plant breeding.” But 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. 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 changes to the D.N.A. that you don’t even control for. So you don’t even know where they are or what they might be doing.

The opportunity here with gene editing in plants is to be able to make changes precisely. Not to drag along traits that you don’t want; to be able to make changes that will be beneficial to plants but to do that very precisely. Then we have the opportunity to do things like give plants the ability to grow with much less water or to defend themselves against various kinds of infections and pests that are moving in due to climate change. 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.

DUBNER: 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 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 — of governance and autonomy and so on. What are your thoughts on that in the plant/agricultural world?

DOUDNA: It’s really going to come down to people having access to information about where our food is 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. Having a precision tool that allows us to generate plants that are better adapted to particular environments or maybe have even better nutritional value — I really believe that, going forward, we can’t afford to reject this. We really have to understand it and regulate it appropriately. But we do have to have this tool in our toolbox.

CRISPR gene-editing is also being put to use on animals.

Scott PELLEY in a clip from C.B.S. Evening News: Scientists in China are engaged in controversial research, genetically modifying beagles to be more muscular.

Isobel YEUNG in a clip from VICE: 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.

Ameera DAVID in a clip from R.T. AMERICA: Researchers believe that they can recreate a woolly mammoth by combining its D.N.A. with that of a modern elephant.

DOUDNA: 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.

DUBNER: I like the micropig too.

Sean DOWLING in a clip from Buzz60: Chinese genomics institute BGI began breeding micropigs to study diseases — but now they’re going to sell them as pets for $1,600 and give into the micropig craze. Miley Cyrus has one.

DOUDNA: Yes, pets. Right, the idea of sort of a fanciful use in a way of getting you know making animals that we think are cute.

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The gene editing revolution prompted by the work of scientists like Jennifer Doudna isn’t the only gene-related revolution these days.

DUBNER: Hey, Dalton. Stephen Dubner. How’s it going?

CONLEY: Hi, Stephen. How are you?

There’s also social genomics.

Dalton CONLEY: The social genomics revolution is really just getting started, I would say.

Dalton Conley teaches sociology and population studies at Princeton…

CONLEY: …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:

E JEREMIJENKO-CONLEY: I’m E, like the letter.

And a son.

Yo JEREMIJENKO-CONLEY: I’m Yo, like the slang.

But those are just their first names. Full names?

E JEREMIJENKO-CONLEY: E Harper Nora Jeremijenko-Conley.

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

DUBNER: So Yo, your first name, Yo, comes from where?

YO: I think it comes from the Y chromosome.

So Dalton Conley, the sociologist dad — he’s always had a crafty way of thinking about genetic identity.

DUBNER: 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 the arc of the revolution and where we are in that.

CONLEY: 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…

President Bill CLINTON in a clip from the National Human Genome Research Institute: 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.  

CONLEY: …everyone thought everything was going to change suddenly. We’re going to have personalized medicine, we were going to — I don’t know what.

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

CONLEY: 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.

Jason FLETCHER: 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 Conley’s co-author on The Genome Factor.

FLETCHER: 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.

CONLEY: And now we have this: what I call the revolution is this surfeit of cheap genetic data.

FLETCHER: Just two decades ago, it cost a billion dollars to sequence a single genome. Now you and I could spit in a cup, 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 D.N.A. look like?”

CONLEY: Anyone who sends their saliva into 23andMe —

Clip from a 23andMe advertisement: With just a small saliva sample, you’ll learn about your ancestry through your 23 pairs of chromosomes that make you who you are.

CONLEY: — to get their ancestry or 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.

FLETCHER: 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 socioeconomic position on the social science side.

CONLEY: And so we finally have big data sets with lots of genetic markers across the entire set of chromosomes. We’re now actually making robust discoveries that are withstanding replication and seem pretty solid. That’s the start of the revolution.

But, warning: it’s still early days.

FLETCHER: 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?

CONLEY: 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.

CONLEY: But most things we care about in today’s world — heart disease, Alzheimer’s, I.Q., 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.

CONLEY: We have a tool that’s emerged called the polygenic score.

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

CONLEY: But those scores aren’t predicting very well right now. So before anything drastic happens socially, 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?

CONLEY: The use by external authorities and companies of this information, that’s definitely scary. 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. If you knew that your potential mate was of high likelihood of developing early dementia, you might think twice before getting married. 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 …

FLETCHER: … a preference for people of certain European ancestry — and not all European ancestry, but certain favored groups — to have more children and to be given resources to the exclusion of all other people. Of course, it led pretty directly to Nazism and the extermination of millions of people. It was also 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.

DOUDNA: That really was one of the defining moments for me in terms of thinking about getting involved in the ethical conversation. 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’d like you to explain the CRISPR technology to him.” And he led me into a room. There was a light in the room and there was someone sitting in silhouette in a chair with his back to me. 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 — I realized that it was Adolf Hitler. And he was looking at me with very intent look on his face, an eager look. He wanted to know about this technology.

I felt this incredible sense of fear; both personal fear, but also a profound existential fear that if someone like that were to get a hold of a powerful technology like this, how would they deploy it? And when I woke up from that dream — and thinking about it subsequently — it was really scary to think about. I thought, “We have to proceed responsibly here.” We cannot just — or at least for myself — I can’t just carry on with my next experiment at my lab. I really have to get involved in a broader discussion about this. It’s just too important a subject.

DUBNER: I don’t mean to at all diminish your argument, but I hear a lot of scientists make a similar argument, which is, “Look, we’re doing our best on our end, and we really want to have this conversation in public, especially with people who have the leverage,” mostly politicians, “to make smart choices.” Does a good mechanism or forum for that conversation really exist?

DOUDNA: Well, we’re 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: how do you do that? How do you bring people from these different walks of life together so they can have a meaningful discussion? 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.

DUBNER: Talking in the silo to each other.

DOUDNA: Right, exactly. It cannot be that. It has to be using various ways. The media are going to be very important. People that write science fiction are going to be important. Movie makers are going to be important. Musicians and various kinds of visual artists are going to be important. All of those people are very skillful at communication, communicating ideas, and they can do it in some ways much more effectively than a lot of technical jargon would ever achieve.

DUBNER: 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, a generation of a family, or maybe an entire population. Obviously, it’s a gigantic area and something that probably brings a lot of strong priors to the table with already. But can you just talk about this issue, your thinking about the issue and where you’ve landed?

DOUDNA: I’ve seen an evolution in my own thinking, quite frankly. I have gone from feeling very uncomfortable with the idea of making changes to human embryos, especially for anything that would be considered not medically essential, to thinking that 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 application is embraced and it’s going to be deployed. For me, the important thing is not to reject it. It’s actually to understand it and really think through the implications.

DUBNER: Let me ask you to just take a step back and talk about actual therapeutic treatment and the difference between germline and somatic editing.

DOUDNA: Ah, yes. That’s very important, to understand the difference. Most of the applications that we’ve been talking about, especially in medicine right now, involve what we call somatic-cell editing. That means making changes to the D.N.A. 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. That means making changes to the D.N.A. of embryos or eggs or sperm, changes that are inherited by future generations and become effectively permanent in the human genome.

There’s a profound difference between those two uses. If you’re doing something that affects one person, 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 children and all of their children’s children, etc. — that is really profound and it really does affect, ultimately, human evolution.

DUBNER: Let’s say I cared about some strain of heritability enough to do it 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 —

DOUDNA: Now you’re getting into Gattaca territory here.

DUBNER: Well, it doesn’t take long, even for a mind as flabby as mine, to get there pretty quickly, right? The potential for this reminds me a bit of the potential for geoengineering, intentionally altering the planet’s atmosphere to change the temperature in case global warming gets really destructive. One of the key questions there is governance. Who gets to control the thermostat? And I know that you’ve been outspoken and you’ve really flung yourself into the ethical and practical elements of this technology, but I’m curious where you stand on the 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 your thinking on that.  

DOUDNA: You alluded to this, but I think it’s very important to emphasize that this technology is going to, overall, have a very positive benefit to human beings in many ways. I’d really like to make sure that people get that message. Because I think it’s easy to try to make things sound exciting by making them sound really scary.

DUBNER: Sure.

DOUDNA: This is a technology where we’re already seeing incredibly exciting advances: opportunities to cure genetic diseases that have had no treatments in the past, to advance the pace of clinical and other types of research, to make it possible to understand the genetic basis for disease and then be able to do something about it when you have that information. 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.

DUBNER: Let’s pretend that this technology within a couple of 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 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, the scarcity being a short lifespan? It seems that humans are relatively slow to adapt to the diminishment of scarcity over time. It seems we still eat, for instance, in the 21st century, as though the next meal may or may not appear on the horizon. 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 Jennifer Doudna and her colleagues helped facilitate?” Do you think about those things?

DOUDNA: There’s lots of interest in that topic right now as you know, especially here in Silicon Valley. For me, it really would come down to, are those extra years high-quality years? Are they years where people could be contributing importantly to society? And if the answer is yes then that is very interesting to think about. If the answer is no, then I certainly don’t think that sounds very appealing at all. I’d rather take short and healthy than the long and miserable. But 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.

As much uncertainty as there is around 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 M.I.T. 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 Zhang’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 U.S.D.A. 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.

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Freakonomics Radio is produced by WNYC Studios and Dubner Productions. This episode was produced by Greg Rosalsky. Our staff also includes Alison Hockenberry, Merritt Jacob, Stephanie Tam, Max Miller, Harry Huggins, and Andy Meisenheimer. You can subscribe to Freakonomics Radio on Apple Podcasts, Stitcher, or wherever you get your podcasts.