Cori Bargmann on the Genetics of Transparent Worms, Supertasters and Cancer

Cori Bargmann is a professor of genetics and genomics, neurosciences and behavior at Rockefeller University. But to host Steven Strogatz, Bargmann’s work is really all about the line between life and nonlife, and what makes it possible for something to sense its surroundings, think and respond. In this episode, Bargmann talks about being won over by a transparent worm, doing calculations at the family dinner table, and identifying a mutated gene that later inspired a revolutionary cancer treatment. This episode was produced by Camille Petersen. Read more at QuantaMagazine.org. Production and original music by Story Mechanics.

Listen on Apple Podcasts, Spotify, Android, TuneIn, Stitcher, Google Podcasts, or your favorite podcasting app, or you can stream it from Quanta.

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Transcript

Cori Bargmann: Science is an adventure, and it has all the suspense of a mystery story and the solution has all of the satisfaction of solving a murder mystery.

Steven Strogatz [narration]: From Quanta Magazine, this is “The Joy of x.” I’m Steve Strogatz. In this episode, Cori Bargmann.

[MUSIC PLAYING]

Bargmann: And that sense of adventure and discovery, not just of learning things that other people know, is the thing that I think is most wonderful about being a scientist. The idea that one day you could wake up and know something that no one had ever known before and it might even be useful.

Strogatz: Cori Bargmann is a biologist but of a very particular type. I think she would call herself a “geneticist.” I mean, the traditional way to say what she’s doing is she’s interested in the interplay of genes, molecules, neurons and behavior. That sounds like blah, blah, blah, blah, blah. Okay, what she’s really interested in is what’s the line between life and nonlife? We’re all made of atoms, we’re all made of molecules, but some of us are tables and microphones and some of us are living things that have feelings and care and live and die. And you might think there’s a big line between them, but there really isn’t.

I mean, she is looking at a worm that is so simple, it’s only got 302 neurons in its whole nervous system. And those neurons are made of molecules and this thing is really not much more than a big heaping pile of molecules, none of which is individually alive. But collectively, it’s a worm that is trying to take care of itself.

So I see her work as addressing a really profound question about this thin line between life and nonlife, and how it is that one heap of molecules can develop something that we call a “sense of smell” to detect other molecules that are essential to it.

Strogatz: How about if we do your origin story? I mean, can we rewind and take you back to your childhood place in your — it sounds like you grew up in an academic household.

Bargmann: I did. My father was a professor of statistics and computer science at the University of Georgia. I grew up having to calculate at the dinner table how many times the glasses would clink when we drank champagne, six time five divided by two.

Strogatz: Wait a second, you did a nifty little math problem there. I want to make sure that I got that. I think I got it: You’re saying there’s six people sitting around the table and so each person clinks with each of the five others, then we’re going to divide by two.

Bargmann: Mm-hmm.

Strogatz: We don’t double count the clink.

Bargmann: Mm-hmm.

Strogatz: So six times five divided by two, it’s — okay, I’m sorry I’m just catching up to you here. [LAUGHTER] That’s great.

Bargmann: That’s what we did.

Strogatz: How much champagne? Like any occasion where you’re drinking champagne, was that a regular —

Bargmann: Well, I have to say my parents were immigrants from Europe and so champagne was drunk at the table at a very early age.

Strogatz: I see, okay.

Bargmann: But in very small quantities.

Strogatz: So six meaning that there’s four kids?

Bargmann: Four girls.

Strogatz: And your mother was a translator?

Bargmann: My parents were both translators in Europe after the war.

Strogatz: Uh-huh.

Bargmann: My father was a live translator at the Nuremberg Trials.

Strogatz: Oh my God.

Bargmann: And my mother translated written texts between German and English.

Strogatz: Okay, so a very academic household.

Bargmann: Academic household, 1960s. When I was, I guess, just about to turn eight years old, a man landed on the moon. I remember squinting up at the sky, trying to decide if I could see the — spaceship or not. Answer: no.

Strogatz: No.

Bargmann: But you know, I think it was a great era for science. And a lot of children wanted to be scientists, and science was exciting, and there’s a sense of discovery and of adventure.

Strogatz: Yep.

Bargmann: And I think if you asked — I don’t know if this is true of you, but I think if you asked a lot of scientists my age, like, “What did you want to be when you were little?” “Astronaut” would come up.

Strogatz: Sure, it was big.

Bargmann: Right.

Strogatz: We used to have science books around the house. I remember a book called How Big is Big? Oh, you must have had books like that around the house.

Bargmann: So here are the science books I remember from growing up. First of all, my mother had Konrad Lorenz’s books about animal behavior.

Strogatz: Uh-huh, yeah.

Bargmann: And since that’s what I work on now, I feel like that was a good formative direction to have.

Strogatz: What is Lorenz’s thing?

Bargmann: Well, Lorenz in particular was known for, was for studying a behavior called “imprinting” that’s carried out by young geese, where —

Strogatz: Oh, okay, okay, it’s coming back to me. The pictures, I remember. Snapshots of him. Go ahead, you tell, tell.

Bargmann: Exactly. So the first moving object that a graylag geese sees when it hatches out of its eggshell, it will attach to. It will form an attachment, what’s called an “imprint,” and it will follow that object around. And usually that object is supposed to be the mother. So you see geese swimming around in a row with the little goslings behind their mother, or then when they learn to fly, they all fly behind their mother, and they waddle behind their mother when they’re going to feed.

But Lorenz took the mother away, and so he was the first thing the little goose saw. And the geese would follow him around. So the pictures you see are pictures of him swimming in a lake with the goslings swimming behind him instead.

Strogatz: Amazing.

Bargmann: Yeah, and this idea of instinctive behaviors, which is what these scientists described, was in many ways the most sophisticated analysis of behavior that was done, I would say, for decades.

[MUSIC PLAYING]

Strogatz: It became very clear in talking to Cori that she’s out there trying to do, you know, the real thing that biologists have to do: figure out mechanisms of life. And sure, you’re going to work with chemicals and nasty reagents and acids and all kinds of things, but she seems to love it.

Bargmann: The lab was the thing that sold the deal for me. I love the lab. When I was in college, one of my first summer jobs was making fly food in a fly lab. You cannot imagine anything more boring than, you know, than putting cornmeal into a pressure cooker.

Strogatz: I bet, making fly food, yeah.

Bargmann: But there were people in the lab, and they would talk about these really interesting questions. It was an evolutionary biology lab and they were smart and they were curious. I would just listen to them, and I would go and talk to them, and I was completely fascinated.

Strogatz: That’s an interesting point that, you know, these things are very cultural. That you need to hang around, just be there for the conversation, just show up.

Bargmann: Yeah, show up and it’s immediate in a way that other intellectual endeavors… You read a book, you read somebody else’s book. In science, you do something with your hands and then something happens. There’s something very engaging about that. People like to do things with their hands. They like to sew, they like to cook, they like to fix cars. And science is like that. It has a very practical and pragmatic aspect that’s very enjoyable.

Strogatz: So you’re in the lab then, and then at some point you go to grad school and start working on problems related to cancer and oncogenes and things like that.

Bargmann: I went to MIT, and it was a real hotbed of molecular genetics and molecular biology. My Ph.D. advisor, who… You know, in German there’s a word for what your Ph.D. advisor is; it’s your Doktorvater, it’s your academic father. So this was really… Bob Weinberg was just a great intellectual influence and a great advisor, and he was an incredibly creative person who developed ways of thinking about how you could identify genes that were involved in the generation of cancer.

And it was already — there was already some thinking that cancer was at some level a genetic disease. But figuring out what that meant at the level of what genes, and how they change, and what they were doing was what we were part of at that time. It was just incredibly exciting. Now, I have to say that I knew very little about cancer at the time. I’m still embarrassed when I think about how little I knew about the biology of what I was studying, but what I knew was that there were cells in a cancer that were growing when other cells had stopped.

Strogatz: I see, uh-huh.

Bargmann: And that there was some genetic change that allowed them to grow. And the particular cancer that I studied for most of my graduate career was an interesting one. It was actually quite an obscure tumor of rats, and it was not something that most people wanted to study in the cancer field at the time. Most people really, really wanted to study human tumors. But this rat tumor was interesting because it was associated with a change in a particular gene. At the time it was not known what that gene was. And that particular gene when mutated allowed tumors to grow, but the body’s own immune system would attack those tumors and cause them to regress, so the animal would be cured.

This idea of regression and association with the immune system attacking the tumor was what made this tumor interesting, even though it wasn’t a human tumor, even though it was a kind of brain tumor that didn’t even really seem to happen in humans. It was a neuroblastoma. So we wanted to find a gene, and that was my work. I identified the gene that was involved and determined how it was changed. And also, because of the kind of protein that it made, there was an explanation for how the whole system worked, which was the protein was on the surface of the cell and therefore it was visible to the immune system. So antibodies, which were outside of the cell, could tell that that protein was on the surface of the cell, they could attack it and thereby cause that cell to stop growing.

Strogatz: I see, I see, huh.

Bargmann: Whereas most of the genes that were known at the time, in fact most of the genes still known that are associated with cancers, are inside the cell and antibodies outside the cell can’t detect them directly or have a hard time detecting them.

[MUSIC PLAYING]

Strogatz: Wow. You know, in her soft-spoken way, Cori is saying something really amazing here, so let me just try to put it in my own words. That this is a really fantastic bit of detective work. She is responsible for identifying this mutated gene in a rat that was allowing tumors to grow, and understanding that helped her crack the code of the whole neuroblastoma cancer system in this rat.

Now that might not sound like much — I mean, it’s a rat. But it turns out that this mutated gene produced proteins on the outside of the cancer cells which allowed the immune system of the rat to spot those cells and then attack them, and essentially destroy them, causing the cancer to regress. So this is a case where the immune system could take care of cancer on its own automatically. And understanding this one thing about a cancer, an obscure cancer in rats, has opened the door to a revolutionary cancer treatment in humans.

[MUSIC PLAYING Ends]

Bargmann: Yeah, we called the gene neu for neuroblastoma. And around the same time we were working on it, a group working in human cells identified it and called it HER2. Then the story moves to a group in California that was working on human tumors, and they weren’t brain tumors, they were breast cancer. But it turned out that the human version of this gene was massively upregulated in a subset of breast cancers. And in fact, those breast cancers were the most aggressive subset, that was pretty much the worst kind you could get at the time.

The combination of recognizing that gene and knowing that the immune system could attack that cancer then moved the project to a biotech company, Genentech, which makes antibodies against the human protein and shows that they can attack those human cancers and cause those human cancers to regress.

Strogatz: Hmm.

Bargmann: So this basically, in about a 10-year period, led to the development of a drug called Herceptin, which is at this point used to treat about 100,000 women with breast cancer a year, I think.

Strogatz: Hmm, unbelievable.

Bargmann: And it was the first successful rationally designed anti-tumor treatment.

[MUSIC PLAYING]

Strogatz : This is actually something that I know about because it’s in my family. I have a niece who has had — was HER2-positive and had that kind of breast cancer, and Herceptin has been a lifesaver for her. So it’s just incredible that, you know, studying a rat and its gene could lead to things with such important medical benefit for people.

Bargmann: It might have not seemed as compelling as studying human cancers at that time, but it wouldn’t have been as easy to make these discoveries in human cancers at that time. And just to return to an earlier theme, there’s a paper that just came out that shows that in certain dog cancers — they’re lung cancers — there are also mutations in HER2.

Strogatz: Huh.

Bargmann: And so people are starting to think about using those same drugs to treat some of the dog cancers.

Strogatz: Whoa.

Bargmann: So you just never know.

Strogatz: Geez, okay.

Bargmann: And you know, it’s kind of funny that the human cancer thing like that… So that was the premise. If you go to the war on cancer, you go back to Richard Nixon and the whole idea of “the war on cancer,” it’s like, “Let’s just understand everything we can about cancer: cancer in animals, cancer in people, cancer in different parts of the body, rare cancers, common cancers, whatever we can learn.” And then connecting the dots. You couldn’t have connected them all the way through from the beginning. It’s really fascinating to think, “Oh this first human drug came from studying a rat,” you know?

Strogatz: It’s a great story, yeah.

Bargmann: And so — but that was always, you know, at a deep level, that was the bargain. They said if we just really fanned out and understood as much as could about cancers that we would find the leads that would ultimately allow us to move forward medically. You know, now in the cancer field, one of the most exciting areas is getting the immune system to fight the cancer.

Strogatz: Yep, yep, right. So cancer immunotherapy, right? That’s what they call it?

Bargmann: Exactly. And so that’s an approach that really has legs. And that took many, many further discoveries and lots of basic understanding of the immune system, but in the past decade has had a tremendous effect on cancers that were previously a death sentence.

[MUSIC PLAYING]

Strogatz: This is the great promise of fundamental biology, that when we work on basic questions it can provide insights into things as important as cancer research and the therapy for cancer.

Now, in that same spirit, after the break we are going to meet Cori’s scientific muse, another important player in fundamental biology. It cannot speak French, it can’t play the piano and it’s the size of a small comma.

[MUSIC PLAYING]

Strogatz: You all have this tradition of studying model organisms. That is, the rat, the lab rat, you know, we talk about guinea pigs, we study mice. I shouldn’t say “we,” you study mice. And then famously, the fruit fly has taught us so much about genetics and your favorite creature, maybe this is a good time —

Bargmann: The tiny worm.

Strogatz: Yes, please introduce us to your creature.

Bargmann: Yes, yes, my creature is the tiny worm Caenorhabditis elegans. It’s a millimeter long, it’s about the size of a comma on a printed page and it’s optically transparent. When you put it under a microscope and look at it, you can see every single cell in the animal.

Strogatz: Huh.

Bargmann: It’s like that child’s game where you have the — where you can look into all of the organs of a human body, except that you’re really doing that.

Strogatz: Oh wow.

Bargmann: You’re actually looking into all of the cells of the animal’s body. You can look at a live animal while it’s swimming around and you can watch what it’s thinking. You can actually watch the brain activity, you can see [CHUCKLES] different neurons turn on and off. But you require a little extra help to do that. It’s amazing.

Strogatz: No, but that’s amazing, because that’s, like, you’re answering the question I had where I say, “I want to look at my dog with his wiggly eyebrows” and look in his head what he’s thinking. You get to look at your worm and you have tricks for lighting up some of its neurons and you can see what it’s thinking.

Bargmann: Exactly, exactly. And that’s the value of the worm. It’s to recognize that you can study the whole brain and the whole animal and all of its genes. It’s a much simpler animal than a person, but you can try to think about the whole system at once.

And you know, in every aspect of biology, you find yourself making certain compromises. You say, “What I’m really interested in is behavior.” You can say, “Well, I can study human behavior,” but then I can’t do a lot of experiments because it’s not ethical to raise humans in identical environments, you know, and subject them to random things. So, or you can say, “Well, I want to study a nerve cell at incredible resolution and I want to study the molecules that allow it to be electrically excitable, but then I’m only going to study one cell at a time.” So you sort of make different kinds of tradeoffs I want, in terms of how complex the system can be and how much of it you can study at once and how zoomed-in you can be on the different levels of resolution.

So I come to this as a geneticist. I came to it at a time that there was still a lot of discussion in the field about whether you could study genes’ underlying behavior. It was still kind of an idea that people said, “Well, I don’t know, behavior is so complicated. It won’t have a simple genetic basis. It will be much too far away, far too many steps, far too many intervening levels to be able to make that connection.” And I thought, “Well, that’s possible.” But I remember those instinct things, there has to be some kind of genetics underlying this, because that’s what innate behavior means.

Strogatz: Uh-huh.

Bargmann: If there’s a behavior that’s shared by every individual in a species, there’s something in the biology that’s setting that up.

Strogatz: That’s, right. I see, yeah.

Bargmann: Whatever that is. And so the combination — so I thought, “I want to study something simple and I want to study where I can definitely use the tools of genetics.”

Strogatz: Huh.

Bargmann: And so my organism is not only simple enough that I can see all of its nerve cells, but it grows incredibly fast and it was incredibly valuable for genetics. So a worm lives for three weeks. If you want to push it, a worm can go from egg to egg in three and a half days. So you can really generate lots of animals. You can identify the genes associated with lots of different processes. The sacrifice you make is, you know it’s a worm, it does wormy things. It’s not going to speak French or play the piano, it’s going to —

Strogatz: [LAUGHS] And just to make sure, I want to underscore a thing you said a minute ago, but: People should not picture the worm that’s on the sidewalk after a rainy day. This is not that worm. This is the worm that you said is as big as a comma on a printed page.

Bargmann: Yes, yeah.

Strogatz: That is a really microscopic.

Bargmann: Yeah.

Strogatz: I was trying to think about it as I walked over to the studio today. Should I say, “It’s like the size of the smallest piece of couscous, if you’re eating…”? But it’s smaller than that, it’s a comma.

Bargmann: Yeah, yeah, it’s tiny, they are really tiny. If I — and because they’re transparent, you can hardly even see them if I had — I might have a dish in the lab that would be like three inches across and if I held it up to the light and reflected the light just right you would see that tiny specks were moving. But since they’re almost transparent, you can barely see them. We really only look at them under a microscope. Yes, they’re tiny. There’s lots of kinds of worms, let me tell you. Most kinds of animals are worms.

Strogatz: [LAUGHS]

Bargmann: And so this is what’s called a roundworm, or a nematode.

Strogatz: Yeah.

Bargmann: It’s totally different from what you’re thinking of — segmented worms or, like, nightcrawlers.

Strogatz: Yeah, yeah.

Bargmann: Also totally different from flatworms. Like, entirely different set of organisms.

Strogatz: Okay, and you grab them out of the dirt? You can just get them if you’d put your hand in the soil and pull them out? Or what, where do they come from?

Bargmann: You know, it turns out that this particular worm grows mostly in association with human agriculture.

Strogatz: Oh.

Bargmann: They are one of the animals that have hitched their wagon to us.

Strogatz: Oh really.

Bargmann: So there’s sort of a justice in us using them in the laboratory for experiments. Turns out most animals that people study in the lab are animals that live in association with humans naturally.

Strogatz: Oh.

Bargmann: So, fruit flies, you know, live in our orchards and mice live in our houses.

Strogatz: Oh, I never thought about this.

Bargmann: [CHUCKLES] Yeah. They are animals that have gotten good at getting along with us. If you wanted to find worms, you would go out into the compost of a vegetable garden or a fruit garden and you would find something that used to be a tomato, but you can hardly even recognize anymore because it’s part of the process of recycling.

Strogatz: Oh.

Bargmann: Where ,you know, the agricultural materials are turned back over. The leaves, fruits and flowers are broken down by bacteria, and then something eats the bacteria and that’s the worms.

Strogatz: I see, so those bacteria that we’re trying to agitate when we roll our composters around to — these are the guys that are eating the bacteria.

Bargmann: Yes, yes.

Strogatz: Okay.

Bargmann: Yeah.

Strogatz: So now there’s this incredible thing that, at the time you were starting — some of this work just a few years before — people had mapped out the whole nervous system of this creature.

Bargmann: Yes. So not only was this an animal that was transparent, but it was the first animal to have its brain completely mapped. Again, this is possible because this is a simple animal. It’s got exactly 302 neurons, no more, no less. To give a point of comparison, humans have about 86 billion neurons, so that’s an intimidating number.

Strogatz: Yes. [LAUGHS]

Bargmann: And that helps explain a lot about why humans can generate behaviors that worms cannot. But the basic fundamental unit of the cell, the way that the cells are connected to other cells, the way that they transmit information using a combination of chemistry and electricity, that goes all the way back. So those kinds of processes, we could study in a simple worm nervous system. And exactly being interested in behavior, being interested in how the brain could give rise to the behaviors that a worm could have, I was seduced by the fact that there was this complete wiring diagram.

Strogatz: But so, let’s now focus back in on you. You’re there as a post-doc and you come up with this what I guess must have felt like a pretty audacious idea that, “Now the nervous system is mapped out. Why don’t we … ?” And you know, we know… I guess, so the genome hadn’t been figured out yet, but still you would have thought maybe just from the nervous system, “I can infer things about behavior or somehow tie behavior to neurons?”

Bargmann: I wanted to figure out how the brain generates behavior. One of the appeals of C. elegans was the idea that you know genes aren’t going to generate behavior. Genes are going to affect neurons and neurons are going to generate behavior.

Strogatz: Uh-huh.

Bargmann: So, you wanted to have that translation layer in the middle of going through the level of the nerve cells and their connections to each other. And that was what was really compelling. But at the time that I became a post-doc, Drosophila was as compelling as a genetic system, but I was intimidated by the fly brain. I remember I went and I talked to a Drosophila geneticist at MIT, Chip Quinn, and I asked Chip, “You know, when will there be a wiring diagram of the fly brain?” He looked at me and he said, “Well, one way to describe the fly brain would be spaghetti and meatballs.”

Strogatz: Okay, yeah, why?

Bargmann: And I was like, “Oh, okay, so you’re saying it will be a while.” That’s what I said.

Strogatz: What is it? I don’t get it, what’s the —

Bargmann: No, a huge tangle of nerve cell connections.

Strogatz: Oh, okay.

Bargmann: So the spaghetti are all the wires. It’s all the wiring of the fly nerve cells, all the wiring of the neurons.

Bargmann: Yeah.

Bargmann: And it’s just incredibly mixed up. Actually, the anatomy of a fly brain is even harder than the anatomy of the mouse brain or the human brain in a lot of ways.

Strogatz: Really, huh.

Bargmann: Just, you know, some technical things about how tiny the nerve cells are, and how long their processes are and how unstructured the pathways are. They’re not laid out as nicely and logically as they are in the more complex brains.

Strogatz: Okay, hmm.

Bargmann: Anyway, it’s a detail of anatomy, but it was a hard thing. I thought, “Uh-oh I think I’m going to want to know where these genes are acting and so I think I’m going to need to know more about the cells.” That was one of the reasons for picking worms over flies.

Strogatz: Mm-hmm.

Bargmann: And then the problem there was, like, okay so you’ve decided it’s a worm. Like are there any interesting behaviors?

Strogatz: Yeah, right, what does it mean for a worm to behave? Tell us some behaviors that they can show. What tricks can they do?

Bargmann: Yeah, yeah, exactly. So that was … a lot of my post-doc was determining the worm’s repertoire of tricks, and then determining which nerve cells and then later which genes were required for that repertoire of tricks. One of the things that I found as a post-doc — which was a real stroke of good fortune — is that worms don’t see very well and they don’t hear very well, but they have an incredibly strongly developed sense of smell. And that had not been known.

Strogatz: Oh wow.

Bargmann: And if you’re a tiny organism that lives in compost, I guess you have lots of chemicals around you and lots of other organisms and there’s lots of smells to keep track of. I would go down to the MIT stock room and I would just buy whatever random chemicals were there. And the worms could detect half of them, and they liked some of them and they didn’t like some of them and they could tell them apart. And it was like this kind of giant toolbox to start to walk into the worm’s brain. So what does it detect? How does it tell these things apart? Why does it like some things and dislike others? Very simple questions. Can it learn? Answer, yes. What will it learn? Well, it will learn about smells that it experienced with food and it will prefer those to smells that it experienced without food, which makes sense. It will learn about smells that it experienced when it got sick and it will avoid those smells in the future.

Strogatz: You know, one thing I wanted to ask about was the difference between taste and smell?

Bargmann: The simple difference between taste and smell is that there are a lot of organic chemicals that travel through the air to reach you.

Strogatz: Yeah, yeah, yeah.

Bargmann: And those are things that you smell.

Strogatz: Right.

Bargmann: Whereas there is a relatively smaller number of molecules that you or a worm are directly exposed to by contact at a high concentration. So, for example, when you talk about the taste of your food, the human tastes are really only considered to be sweet, salty, sour, bitter, something called umami, which is the taste of amino acids — so “deliciousness” is the Japanese word — and then there’s some discussion about carbonation, which is sort of slightly separate from sour taste. But it’s very simple. What you think of as the flavor of food is largely organic chemicals that are released when you chew the food that go back up into your nose.

Strogatz: Hmm, so it’s mostly — smell is the more fundamental.

Bargmann: It’s mostly smell.

Strogatz: Is the more perceptive or something? I don’t know what adjective to use.

Bargmann: It’s the more complex.

Strogatz: More complex, okay.

Bargmann: So, it’s the one… Smell is what… If smell is what enables you to discriminate between many different possible foods or environments or sources of danger, and those are typically molecules that move a longer distance through the air. They’re detected at much lower levels. Whereas food is giving you some pretty basic information about whether what’s in your mouth is, you know, nutritious, has sugar in it or possibly toxic, which is what bitterness is.

Strogatz: Okay, oh yeah.

Bargmann: You know, giving you some immediate information. And so the worms have been known to detect some salt, some amino acids. Now we know that a lot of the molecules that I discovered through the important MIT chemical stockroom are in fact chemicals that are released by bacteria in the worm’s natural environments.

Strogatz: Uh-huh.

Bargmann: So people started going back now and asking like, “Well, so what bacteria are in the compost with the worms?” and “If you look at what they release, what are those chemicals?” There have just been a couple of papers published in the past couple of years that show that exactly some of the chemicals that we kind of picked out of, like, “Oh, these are really good. The worms always smell them. They always really like them.” Turns out that those are exactly the chemicals that their natural bacterial foods were making.

Strogatz: Huh. I mean, how does this get tied back to the work on the nervous system?

Bargmann: So you have to have an assay in biology. You have to have something you’re studying. So now we had these animals and they can smell these things and the question is, “How?” So the main technique of genetics is that you make a mutant.

Strogatz: Okay.

Bargmann: So you have an animal that can smell something, and you look for an animal that can’t smell it anymore.

Strogatz: I see.

Bargmann: And/or you have an animal that can only smell four out of five things, or you have an animal that has an abnormal output to the smell, where before it was attracted and now it’s repelled. And each of those represents a change in one or more genes in the animal’s genome and through a set of at this point kind of well-defined manipulations you can figure out exactly what has been changed. So I did that for behavior. I found a lot of worms whose senses of smell were funny in one way or another and I asked, like, “Well, now what? What are those molecules? Where are they? Which nerve cells? When? What are they doing?”

Strogatz: Yeah.

Bargmann: And so some of the things we found were things that were required for the nerve cells to hook-up with each other. So, they had abnormalities in the development of connections between different neurons. So if the neurons aren’t hooked-up together, then they won’t give the right behavior. So that was one body of work. But the ones that were always closest to my heart were the ones where the neurons looked fine, but somehow they were not transmitting the information that they were supposed to be transmitting. And that led, for example, to the discovery of the receptors for the odors that sort of… And it turned out that I said the worms have a really well-developed sense of smell. They do that because they have many, many, many genes whose entire and only purpose as far as we can tell is to make individual receptors that recognize individual or small numbers of odors.

Strogatz: So when you say a “receptor” I should think of a protein that’s sticking out of a cell that’s going to —

Bargmann: You should think of a protein that’s sitting on the surface of a nerve cell in the nose.

Strogatz: Okay.

Bargmann: And it is poking out into the nose so that organic chemicals in your environment can bind to that protein and cause that nerve cell to fire.

Strogatz: Mm, okay, uh-huh.

Bargmann: And we found them in the worm and there’s about a thousand of them.

Strogatz: Hmm.

Bargmann: And I think our worm still holds the ground record for largest number of different genes encoding olfactory receptors in any animal. Humans only have about 300.

Strogatz: Oh, is it thought that we sort of… Like, is there such a thing as — over evolutionary times — just getting genes going — what’s the word — like, going defunct, because they’re not getting used anymore?

Bargmann: Oh, yes. So one of the things that has, that we’ve learned as a field is that sensory systems are really rapidly evolving. That different organisms specialize in detecting different parts of the world and so they get better and worse at these processes.

Strogatz: Yeah.

Bargmann: So one of the fastest evolving parts of the genome are the olfactory receptors.

Strogatz: Which genome are you talking about? Which, whose genome?

Bargmann: They are so fast evolving… Almost the fastest evolving part of any animal genome are the genes that are involved in detecting tastes and smells and pheromones.

Strogatz: Really?

Bargmann: They’re amazingly fast-evolving. So just think about a little bit. You’re a fish, you’re in the water, there’s stuff that’s relevant to you in the water. You know, a couple of tens of millions of years pass, now you’re a frog and you’re smelling the air and, like, the molecules, they are completely different.

Strogatz: Mm-hmm.

Bargmann: And let’s, let’s, you know… And then evolution goes on and pretty soon you have animals that are herbivores and animals that are carnivores and each of them is going to specialize in detecting different sets of molecules that are relevant to their own environment.

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Strogatz : It’s just amazing to listen to Cori talking about evolution because I had this brainwashing in my head or at least a misconception that evolution is so slow. You know you think about geological time scales and missing links and all that kind of stuff, but… So honestly, I really hadn’t thought about this before, that our noses and our sense of smell would need to evolve so rapidly and dramatically, and they can do it. It’s a side of evolution we’re not used to thinking about and it’s a striking contrast to our visual system, which is pretty straightforward and established and very orderly and not evolving in any rapid way. So this world of smell is just a wild west of genetic changes. Coming up supertasters, worm mind control and why Cori thinks we may need to make a special kind of map.

Strogatz: So what about this thing I hear people talking about supertasters? I realize this is not exactly central to your work, but maybe you happen to know of something about it.

Bargmann: Yeah, super — there’s tasters and nontasters and some of those things have been really well worked out particularly for certain bitter tastes.

Strogatz: Yeah.

Bargmann: So again, there are about 30 receptors that detect bitter compounds in the human tongue, and those are compounds that are associated with toxic plants usually, and you’re supposed to not eat them so that you don’t get sick. But it turns out that some people have, you know, no active and some inactive versions of one of those taste receptors. There’s a thing that people often do in the seventh grade where they’re given a little piece of paper, it’s called “taste paper.”

Strogatz: Yeah, I remember it, I remember it.

Bargmann: People chew it. Yeah, yeah. And some people experience it as intensely bitter and they spit it out and other people don’t taste anything, it tastes like paper.

Strogatz: Yeah.

Bargmann: And they just chew it for a while and it’s like, “I’m chewing paper, I get it.”

Strogatz: [LAUGHS]

Bargmann: So I’m one of the latter and it turns out that people like me who are nontasters are much more likely to like bitter foods.

Strogatz: Okay.

Bargmann: We’re much more likely to drink lots of coffee and eat spinach and like artichokes and so we’re just less sensitive to a subset of bitter things. So that’s a very well described single gene, exactly this idea of, sort of, lock-and-key, the bitter compound, the one gene that makes the one protein that detects that one bitter compound, very simple. It’s an example of a real difference in behavior that a single gene can affect.

But there are also people who have a completely different path to sensitivity that involves just seeming to have more taste buds and more taste cells in their tongues. They are what are called “supertasters,” they are very sensitive to tastes.

So, these are the kinds of things that you learn about by studying the genetics as you start to say not just, “Oh, there’s a gene for this and a gene for that,” but, “Wait, this is how we taste things. This is how we smell things.” One of my favorite experiments that my lab ever did was, “Why do we like some things and hate others? Why do we love sweet things and hate bitter things?”

Strogatz: Yeah, okay.

Bargmann: And my lab found odors that were intensely attractive and identified the receptor for those odors. It was actually a buttery smell called diacetyl. It’s the flavor of the artificial butter that they put on popcorn in movie theaters.

Strogatz: Oh, okay.

Bargmann: And worms love it. If there are any worms in movie theaters I know where they are.

Strogatz: [LAUGHS] Wait a second, so if I’m having the butter popcorn that they want to call butter flavor, is that not really butter? Is it something made in an organic chemistry lab?

Bargmann: Artificial butter is in fact made in an organic chemistry lab.

Strogatz: Yeah.

Bargmann: Yes. The artificial butter flavor on popcorn is diacetyl. It’s just added right to it, but there are natural organisms called lactobacilli that make diacetyl. For example, they are present in the microorganisms that help ferment chardonnay and the diacetyl accounts for the characteristic buttery flavor of the chardonnay.

Strogatz: Oh this is the best, you’re giving us all this stuff, this is great.

Bargmann: Yeah.

Strogatz: So when they say, “There’s a big buttery chardonnay,” that’s what they’re talking about.

Bargmann: They’re talking about some diacetyl there, and yeah, so worms love it. And so we had the molecule to detect the diacetyl and we had the worm, and then we had a worm that didn’t have that molecule because there was a mutation, and that was how we discovered it in the first place, right?

So first we have a worm that doesn’t detect diacetyl. Then we find the molecule by finding out what’s missing in that worm. So now we have that worm and it’s like a blank slate, and we can put that molecule back in. So we put the molecule back in where it’s supposed to be in the right nerve cell and the worm loves diacetyl, very good, we have the right molecule.

Strogatz: Good.

Bargmann: But now, we take that same molecule and using some of the trickery of genetics, we make that molecule turn on in a different nerve cell, the very next adjacent nerve cell. And those worms detect diacetyl again and they hate it, they flee it in horror.

Strogatz: [LAUGHS]

Bargmann: And that nerve cell is one that normally detects repulsive odors and non- attractive odors.

Strogatz: Oh, this is great.

Bargmann: And so we could make the worm feel however — we could basically determine what the worm thought about diacetyl. What that told us is that in the nose the different neurons actually are prewired into a hardwired map of attraction and repulsion.

Strogatz: Like my genes are telling my nervous system what’s delicious?

Bargmann: So you have a nervous system that gets built up and it says, “I’m going to have some neurons for deliciousness and I’m going some neurons for some bad stuff.”

Strogatz: Yeah, yukkiness.

Bargmann: Predators and danger.

Strogatz: Yeah, okay.

Bargmann: And then I’m going to have some neurons for other worms, that will help me get together with my buddies, because we also study the social behavior of worms, actually.

Strogatz: I see.

Bargmann: So we studied their responses to what’s called pheromones, the odors that worms release that attract other worms.

Strogatz: Yeah.

Bargmann: Those neurons are going to get wired up by development and they’re each going to be different from each other. Then just by evolutionary changes popping around which gene is on, which receptor gene is on which of those different neurons you can match up different smells to those behaviors.

Strogatz: Hmm. So it’s sort of tying back to your childhood fascination with innateness — that you’re now tracing how the genes can give us innate tendencies towards certain behavior.

Bargmann: Exactly, exactly.

Strogatz: Oh, must be very satisfying to you.

Bargmann: Yes, science is really satisfying, neuroscience is really satisfying. What could be more interesting than figuring out how the brain works?

Strogatz: It’s a good one.

Bargmann: I’m sorry I realize I don’t have any perspective on this question.

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Strogatz: [LAUGHS] You have a great perspective.

Strogatz: Cori is a goldmine of fantastic information about life, and full of curiosity, and an exemplar of how to think as a scientist. She asks such interesting questions about how we can tell what a worm is thinking. I mean, I can’t even — that’s a real puzzle, I can’t even understand what my dog is thinking, yet somehow it’s almost like she’s one of those FBI profilers who can get into the mind of the criminal and knows what he’s going to do next. Somehow it’s like she can get into the mind of any animal and by getting into their brains, she’s discovering all of this amazing stuff about how the brain actually works and why it works that way.

Bargmann: Our simple experiment of moving receptors around in nerve cells is related to what is now a really active area of neuroscience where people do experiments, where they use genetics and genetic tricks to either activate or inactivate neurons in a wide variety of different animals and look at the effects on behavior.

The most widely used of those is a method called optogenetics, where people express a bacterial light-sensitive protein in the brain of a worm or a fly or a mouse and by doing so they can shine light on that part of the brain and cause those nerve cells to become active.

Strogatz: Mm-hmm.

Bargmann: You can literally beam thoughts into a mouse’s brain. And if that does not blow your mind, I did not explain it well.

Strogatz: No, it does, it does.

Bargmann: It’s crazy. You can make the mice fly into a rage and attack a glove, and you can make the mice run away or run in circles or do all kinds of crazy things.

Strogatz: Oh, my.

Bargmann: So there’s obviously a humor value to that, but the real thing about optogenetics is that it enables you to start to understand the logic of how brain regions are connected to each other, how inputs and outputs work. I would say that one of the things that has been learned from optogenetics is that there are many, many cells that are active during a particular behavior or a memory or task, and that you can activate and cause that task to take place that somehow seem to sort of complete a pattern, to turn this nonsensical light that you are beaming into the brain into a logical behavior.

So, there’s something about pattern completion, that the brain can take very degraded information and turn that into something precise, that I think is one of the deep insights from optogenetics.

Just like our crude experiment of throwing a gene into the wrong cell generated a pretty well-organized long-term chemotaxis behavior in the worm.

Strogatz: Chemotaxis meaning it moved toward the thing it liked or away from the thing that it didn’t like.

Bargmann: Yeah, it was moving, yeah, exactly it would kind of make long movements down a gradient, down an area that was to a worm the equivalent of a football field.

Strogatz: Uh-huh.

Bargmann: You know, after we did some silly genetic manipulation. This idea of pattern completion, the idea that somehow… What it probably means is that behavior comes from a network of neurons that are connected that mutually activate each other and that take even kind of partial information, really incomplete information, degraded information, and fill it out and turn it into a proper pattern or memory.

Strogatz: I see.

Bargmann: Maybe what you’re doing when you’re trying to remember something is, get at least a few of those neurons, kind of, getting going and then they recruit the rest of them.

Strogatz: That’s what it feels like. Yeah.

Bargmann: Yeah.

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Strogatz : Cori isn’t just spending time in the lab with her worms, she’s also branched out into some really big science, the Obama Brain Initiative, more recently the Chan Zuckerberg Initiative. I’m talking about big science, lots of people involved, lots of funding, lots of resources. She’s sort of pooling all these resources for a big worm-inspired project.

Bargmann: If you go back a century and you say, “What could we do about diseases a hundred years ago?” The answer is very little. There were no antibiotics. We did not know that high blood pressure causes stroke. We did not know that cigarette smoking causes cancer. We did not know about cholesterol and heart disease. It’s incredible what we’ve been able to do over the past hundred years to cure, prevent or manage diseases. If we’re going to do all of that in the next hundred years, we’re going to have to work a lot faster. The best way to accomplish that is to not try one disease at a time, but to try to accelerate all of science. We’re doing what you might even think of as a worm-inspired project, which is the human cell atlas. So you said you know every cell in a worm, and I’m like, “Well, do we know every cell in a human?” I don’t think so.

Strogatz: [CHUCKLES] I don’t think so.

Bargmann: How many cells are there in a human? About 37 trillion, that’s a lot.

Strogatz: Oh boy, wow.

Bargmann: You know, but you start thinking about it, you think, “Well, there has to be different groups of them and if we knew what they all were wouldn’t that be a great way to advance studies of all diseases?” Because every disease has a cellular basis, every disease has some kind of an abnormality in cellular function where some cells are doing the wrong thing or cells are doing what they’re not supposed to be doing.

Strogatz: It feels like such a big part of what’s difficult about biology is the complex interactions among all the parts. That if we keep compiling “parts lists,” as they used to call them in the case of the human genome project, that may not bring us — I mean, you got to do that, but the big mystery is figuring out how the parts conspire to make the functioning of the whole, right? That’s this other area that’s super conceptually difficult.

Bargmann: Yeah, I agree with you. But the big questions then become the way that cells communicate with each other. But what I know because of my earlier work in cancer, and because of my work in the brain, is that cells communicate with each other by secreting different molecules and having receptors for those molecules and through physiological interactions. So, knowing the molecules that are in one cell type and the molecules that are in another cell type will help you learn how those cells communicate with each other as well.

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Strogatz: I have to say I was pretty delighted by something that Cori and I talked about near the end of our interview, because as it turns out she sees an unexpectedly big role for my subject, math, in the future of her subject in biological and medical discovery.

Bargmann: When I was a grad student, I would do an experiment and it would involve huge amounts of radioactivity and it would take a month. Then I would look at the answer for about ten minutes and I would understand it and then I would do another experiment that would involve huge amounts of radioactivity and took a month. Literally now someone in my lab can do an experiment, sit at a microscope for 10 minutes and generate a stack of data that will take him a month to analyze.

So, the time spent spend doing the experiment to the time spent analyzing and interpreting the experiment has completely flipped. And I think we are even now going through a transition that is sort of like the transition that science went through in the 1980s where everyone in biology needed to learn molecular biology.

Strogatz: Mm-hmm.

Bargmann: Because the next stage of understanding required people to use these new tools. And I think the same thing is happening now, except that the tools people need are computational and analytical.

Strogatz: Do your colleagues agree with this or is this a radical view?

Bargmann: I just think it’s true, I’m sorry.

Strogatz: Okay. [LAUGHS]

Bargmann: You’ll have to ask them.

Strogatz: Yeah, we need to know what they think.

Bargmann: I think it’s increasingly appreciated that these tools are going to be powerful and that not having these tools is holding us back.

Strogatz: It’s an interesting problem for education because, you know, there’s often been a bifurcation in the training of scientists. That the kids that gravitate towards math go one direction and often into physics and the kids that didn’t like math go the other direction into fields like biology.

Bargmann: And there’s challenges to these things, right. So if you’re trained in physics, you’re taught to just go straight to the principles and to ignore all of the pesky details.

Strogatz: [LAUGHS] Yes, we are.

Bargmann: And if you’re working on biology there are a lot of pesky details to pay attention to.

Strogatz: There are. [LAUGHS]

Bargmann: Like when you talk about all the genes and proteins, sometimes it just feels like Pokémon characters, right? Every one of them is a little different and you have to know what each of them does.

Strogatz: Yeah.

Bargmann: So something else that we’re promoting strongly at the Chan Zuckerberg Initiative, I think, is also the wave of the future, is getting people together to work on these problems.

Strogatz: Yeah.

Bargmann: Is to take a step away from systems that have overwhelmingly rewarded individual contributions and individual scientists and say, “You know, the real problems that are out there now are hard problems, and they’re going to require people working together.”

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Strogatz: Next time on “The Joy of x,” Rebecca Goldin and Brian Nosek show off their scientific guts.

“The Joy of x” is a podcast project of Quanta Magazine. We’re produced by Story Mechanics. Our producers are Dana Bialek and Camille Petersen. Our music is composed by Yuri Weber and Charles Michelet. Ellen Horne is our executive producer. From Quanta Magazine, our editorial advisors are Thomas Lin and John Rennie. Our sound engineers are Charles Michelet, and at the Cornell University Broadcast Studio, Glen Palmer and Bertrand Odom-Reed, though I know him as Bert. I’m Steve Strogatz. Thanks for listening.

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