JAD ABUMRAD: Hey, I'm Jad Abumrad.
ROBERT KRULWICH: I'm Robert Krulwich.
JAD: This is Radiolab. Today ...
ROBERT: Blood. One time, I was in the doctor's office and they were taking blood. And they gave me all of the vials to hold, thinking of course that I would be fine with it.
JAD: This is pre drawing blood? Or post?
ROBERT: This was as they were drawing blood.
JAD: Oh, you were holding vials of your own blood as it was coming out of you?
ROBERT: Yes. They kept handing me the vials without capping them. And I fainted, so my hand flew up and all that blood and all—it poured over my face and my shirt and my clothes. And when I came to, everyone was screaming, including half of the waiting room.
JAD: You were covered in your own blood?
ROBERT: Covered in blood.
JAD: Your whole shirt was soaked in blood?
ROBERT: Oh yeah.
JAD: That's disgusting.
ROBERT: The undershirt, everything.
JAD: That's disgusting!
ROBERT: Well, it's only disgusting because you think—because you're just—we're all unfamiliar with blood, but back in the 1600s ...
JAMES SHAPIRO: It's just part of life. For Shakespeare, blood was blood.
ROBERT: This is James Shapiro, Shakespeare expert, friend of our show. And he says people back in Shakespeare's day were familiar with the sight of blood, the feel of blood, even ...
JAMES SHAPIRO: You know the smell of blood. What do I mean? Young Shakespeare, he's a kid.
ROBERT: He grew up in Stratford, and at 21 he went to London.
JAMES SHAPIRO: He came as an actor, and probably as the youngest actor in the company. What he was sent to do is to go to the shambles ...
ROBERT: That's a slaughterhouse.
JAMES SHAPIRO: ... a block and a half away, and get a bucket of blood, so that when they do the Spanish Tragedy or any other—I mean, they're not using fake blood. They're using animal blood in all these plays.
ROBERT: Really?
JAMES SHAPIRO: Absolutely.
ROBERT: They didn't use fake blood?
JAMES SHAPIRO: No fake—why fake blood? How do you get fake blood? You gotta make fake blood. You just walk two blocks on the way from where he lived to the theater. He's gonna pass some kind of slaughtering area. I don't know how much it costs for a bucket of blood, but you need a bucket of blood for Titus Andronicus. You need a bucket of blood for Julius Caesar. In that play, Shakespeare has Mark Antony say, "I stand upon slippery ground." I mean, that stage is covered in blood, and he's slipping in this blood. And all the men had just stooped and washed in Caesar's blood up to the elbows. So there is blood in this play.
ROBERT: In all of the plays, the comedies, the romances, the histories, all of them.
JAMES SHAPIRO: I have some numbers for you that shocked me.
ROBERT: Numbers?
JAMES SHAPIRO: Numbers.
ROBERT: Numbers of what?
JAMES SHAPIRO: Numbers of references to blood.
ROBERT: Really?
JAMES SHAPIRO: So the word "blood" itself occurs 673 times in 571 speeches in 41 of Shakespeare's plays and poems, which means almost every play and poem.
ROBERT: Now should I be impressed? Because does the word "house" appear nine thousand six hundred and ...

JAMES SHAPIRO: No, this is a big word. This is a word that recurs 37 times in King John.
[ARCHIVE CLIP: March to the marketplace in Frenchmen's blood.]
[ARCHIVE CLIP: Lusty blood again, which we ...]
[ARCHIVE CLIP: Living blood doth in these temples beat.]
JAMES SHAPIRO: 28 times in Richard III.
[ARCHIVE CLIP: One raised in blood, and one in blood ...]
[ARCHIVE CLIP: In that congealed mouths and bleed ...]
[ARCHIVE CLIP: ... of that royal blood.]
JAMES SHAPIRO: 22 times in Henry IV, Part One.
[ARCHIVE CLIP: ... lips with her own children's blood.]
JAMES SHAPIRO: It means a lot of different things. It means I'm of good blood, I'm of high social station.
ROBERT: And of course, there was bad blood or cursed blood or being hot-blooded or cold-blooded.
JAMES SHAPIRO: And sometimes, as in Macbeth, it just means blood.
[ARCHIVE CLIP: Blood will have blood. I am in blood stepped in so far—blood is stopped, the very source of—the handsome places were all badged with blood. His silver skin laced with his golden blood.]
JAMES SHAPIRO: He's wading. He feels he is wading in blood. Just think of that for a moment, how horrible the experience must be. Think of stepping into the ocean and it's blood. Thick, smelly, horrible to the touch. That is what Macbeth feels when he feels guilty. For most of us, this is just a metaphor. What I'm trying to say is for this culture, blood was more than a metaphor. So I have here one of his first poems, the Rape of Lucrece.
ROBERT: Lucrece is the good wife of a very honorable man. She's raped by this son of a tyrant. He comes from the ruling family, the Tarquins, so he thinks he can get away with this.
JAMES SHAPIRO: But Lucrece takes a knife at the end of this poem and stabs herself. So this is what happens. "The murderous knife, and, as it left the place, Her blood, in poor revenge, held it in chase;" which means the blood followed the knife out as she stabbed herself. "And bubbling from her breast, it doth divide/In two slow rivers, that the crimson blood/Circles her body in on every side." That's a lot of blood. "Some of her blood still pure and red remain'd,

And some look'd black, and that false Tarquin stain'd." So we're beginning to see that two kinds of blood are flowing out of her.

ROBERT: And that false Tarquin stain ...
JAMES SHAPIRO: Yeah.
ROBERT: That's the raping? That's the ...
JAMES SHAPIRO: Tarquin is the guy who raped her, and from that rape, her blood got polluted.
ROBERT: She now has two pools of blood. His dark and dangerous, hers red and pure.
JAMES SHAPIRO: And you can see this. This is a culture that understood putrefied blood looked a little off, looked a little black. And this is ...
ROBERT: And this was meant to be thought of as literal, so that if you were raped, that's what your—your blood would change color in part, in the bad part.
JAMES SHAPIRO: How do you prove intent in rape? You know, Tarquin's saying she wanted it, how would you know?
ROBERT: Would this be almost like forensic? Would this be evidence?
JAMES SHAPIRO: Absolutely. This is evidence that proves that it was rape rather than anything consensual. You would know because she was raped, and the blood showed this to be tainted. For this culture ...
ROBERT: Blood was the thing that makes you you.
JAMES SHAPIRO: ... life, death, kinship ties, and what is within you, what circulates within you. Your character.
JAD: So blood was like essence.
ROBERT: Yeah.
JAD: All right. Well, if Shakespeare saw blood as like your essential nature, well this next story is about what happens when that idea collided with science.
EDWARD DOLNICK: Yeah. How are we doing?
JAD: And to sort through the debris of this collision ...
EDWARD DOLNICK: Talking, talking, talking.
JAD: ... we talked with science journalist ...
EDWARD DOLNICK: Okay. I'm Edward Dolnick, the author of the Clockwork Universe.
JAD: A great read that opens right where our story begins.
EDWARD DOLNICK: So it's 1660.
JAD: England.
EDWARD DOLNICK: It's Shakespeare's century. Isaac Newton is a brilliant young man, but nobody knows him yet. One of the big deals of this era is that science is just starting up.
JAD: People are just beginning to tinker and fiddle with nature. And in London, much of this tinkering went on in a rundown mansion.
EDWARD DOLNICK: Every third Wednesday, some schedule like that, you would see this strange collection of men.
JAD: Known as the Royal Society.
EDWARD DOLNICK: Coming into the Royal Society quarters.
JAD: Were they like the National Science Foundation of their day? Or just like a club?
EDWARD DOLNICK: Well, it starts out as a club, but what makes it a terrific club is that at the beginning, there are essentially no rules, so you have Christopher Wren and Robert Boyle, which is to say Richard Feynman and Stephen Hawking. But next to them, you have some amateur violinist who's got a theory that if you tuned the violin some goofy way, it would sound much better. And next to him is a man with a potato in the shape of a unicorn. They're all bringing these wonders. People were thrilled at this time with experiments in general. And it didn't have to be a lot. Lighting firecrackers and throwing ice in the fireplace to see if it cracks or makes a big noise, or pump out the air from under a jar and put a mouse in it to see what happens. Any kind of experiment that you can think of is going on because nobody knows how anything works. So almost every question you can think of was in some sense a question worth asking.
JAD: And one question which endlessly fascinated these guys—lucky for us—was a simple one: what is blood?
EDWARD DOLNICK: Because blood, in this era, is this astonishing substance. Everybody knew it was vitally important. Everybody had always known that, since the first person to stab somebody else. But nobody knew what made it important. Nobody knew what it did. And it also had this mysterious spiritual quality to it. In the same way that we have this notion of the brain and the mind, and they're different things, and one is physical and one is floating around in some more abstract way, the blood was this physical red stuff that dripped on your desk, but it also carried some soulful essence that marks you as you and me as me. But how do you get at that? This is an experimental question.
JAD: So here was the first experiment.
EDWARD DOLNICK: Question number one. What would happen ...
JAD: If you took a madman ...
EDWARD DOLNICK: This mad fellow ...
JAD: A guy who was prone ...
EDWARD DOLNICK: To fits, to carrying on.
JAD: And you took this guy and you filled him up with the blood of a sheep.
EDWARD DOLNICK: And a sheep is famously docile, of course.
JAD: What would happen? Would that docile sheep blood get inside the madman and tame him?
EDWARD DOLNICK: Soothe his raging fits?
JAD: So the Royal Society ran some ads.
EDWARD DOLNICK: Can we find somebody to do this? We'll pay you a guinea, which is ...
JAD: A few bucks today.
EDWARD DOLNICK: That is to say worth having but not a fortune. And they're delighted to find this fellow, Koga, Arthur Koga, because he's like the Mad Hatter or something.
JAD: Like what we would, these days, call schizophrenic? Or I mean, was he crazy in that way, or just eccentric?
EDWARD DOLNICK: The vocabulary is so different, it's hard to know, but he was in his day, or our day, one of those people you would edge away from who's ...
JAD: He's the guy on the subway.
EDWARD DOLNICK: Right.

ROBERT: [laughs]
JAD: In any case, on the day of the experiment, they bring Koga into the Royal Society and into the big theater there.
EDWARD DOLNICK: And it is a full room. There are wooden bleachers, and everyone's crowded together on those bleachers, jostling for position. The early comers get the best seats. In the front of the room is a little table, and the sheep is on that table.
JAD: They sit Koga right next to the sheep.
EDWARD DOLNICK: The sheep is tied down, and they cut a slit.
JAD: A tiny one right across an artery in the sheep's neck.
EDWARD DOLNICK: And our man, Arthur Koga ...
JAD: They have him ...
EDWARD DOLNICK: Put his arm on the table, and they cut open a vein of his. And now they take a skinny little metal tube and they run it between the two.
JAD: So that blood goes from the sheep's neck into the man's arm and back. And then they wait. And wait. And wait.
ROBERT: Well, how long would you think you'd have to wait for a madman to become sheep-like in his personality change?
EDWARD DOLNICK: Well, I guess they had waited for him to spring up from the table. And—but there is no baa-ing. There is no sudden coming to his senses, but nobody drops dead. And that counts as a success.
JAD: And they thought, "You know, maybe we're just not getting at this the right way."
EDWARD DOLNICK: Maybe there's some other experiment that if we did it properly, we could find out the answer to this question. What is in the blood that makes each person special?
JAD: And in fact, around that time ...
EDWARD DOLNICK: The eminent scientist of the day, this great figure ...
JAD: ... a guy by the name of Robert Boyle ...
EDWARD DOLNICK: ... proposed 16 experiments that they ought to do.
JAD: Now there are no records of the experimental results, but we can pretty much imagine how it went.
EDWARD DOLNICK: Number one, the blood of a cowardly dog.
JAD: Put that into a ...
EDWARD DOLNICK: Fierce dog.
JAD: Let's see if that makes the fierce dog ...
EDWARD DOLNICK: More tame. So they try that. And that doesn't work.
JAD: Okay.
EDWARD DOLNICK: Well, what if you took a dog that has a fabulous sense of smell, like a bloodhound, and you put his blood into some ordinary dog who couldn't find his way home? Will that dog suddenly have a fabulous sense of smell?
JAD: And that? No.

EDWARD DOLNICK: No. That didn't work.
JAD: Fine.
EDWARD DOLNICK: Suppose you have a dog taught to fetch and carry, or to dive after ducks, and you put his blood into a common ignoramus dog who doesn't know anything? Will the simpleton dog suddenly be pointing out ducks to his master?
JAD: And no.
EDWARD DOLNICK: No, it turns out. Boyle tries variation after variation of this, and to cut to the chase, none of them with any useful result.
JAD: And it was around this time, if you ask historians, that our general thinking about blood began to shift. We stopped seeing blood as this magical thing. There's no essence in there. It's just biology, really, you know, platelets, proteins, red blood cells. That's how we see blood now. And those experiments in 1666?
EDWARD DOLNICK: The experiments sound to us absolutely ludicrous.
JAD: And of course, they are.
EDWARD DOLNICK: Except they were on to something.
SAUL VILLEDA: She's transferring me, so that another one of her colleagues can also ...
LYNN LEVY: All right. Saul, can you hear me?
SAUL VILLEDA: Yeah, I can hear you.
LYNN: Sweet.
JAD: So recently, our producer Lynn Levy found out about some research, some new research that might make you think differently about those experiments back in 1666.
LYNN: Right. So I called up one of the researchers.
SAUL VILLEDA: So my name's Saul Villeda, and I'm a faculty fellow here at UCSF. So I just started my own lab.
LYNN: You have your own lab? Is it like—it's the Saul Lab?
SAUL VILLEDA: It's the Villeda Lab, yeah.
LYNN: You're still pretty young, right?
SAUL VILLEDA: Yeah. I'm 32.
LYNN: So Saul does experiments with mice.
JAD: Okay.
LYNN: And there's one thing that you need to know about mice, just to understand this whole thing.
JAD: Which is what?
SAUL VILLEDA: Mice really hate water.
LYNN: You throw them in the water ...
SAUL VILLEDA: They want to get out of there as fast as possible.
LYNN: See, there's a classic experiment that scientists have been doing for a while. There are a lot of variations. The idea is that you ...
SAUL VILLEDA: Take a big pool of water.
LYNN: And you build a maze in it.
SAUL VILLEDA: A water maze?
LYNN: You know, it's like a mouse-sized maze.
SAUL VILLEDA: And then we actually put a platform in the pool.
LYNN: Somewhere under the water. You know, the mouse can't see it, doesn't know it's there. If you were a mouse, and you stumble across this platform, you're like, "Oh, I can totally use this."
SAUL VILLEDA: To get out of the water.
LYNN: Which I don't like at all. So I'm very excited about this platform.
JAD: Because you can rest.
LYNN: You could rest.
JAD: So wait. Why do they do this to the mice?
LYNN: The point is, like, you want to see how fast the mice can learn and remember where the platform is.
JAD: So it's like a learning test.
LYNN: It's a learning and memory test. And what you do is ...
SAUL VILLEDA: You keep dropping them into the pool.
LYNN: Over and over, and you just see how long it takes them, you know, to learn where the platform is.
SAUL VILLEDA: Exactly.
LYNN: So what you notice if you do it a lot, this kind of experiment, is that there's a pattern that emerges. And it has to do with age.
SAUL VILLEDA: A young animal gets it. They figure it out much faster.
LYNN: Once they've done it a couple of times ...
SAUL VILLEDA: Let's say after, you know, the sixth or seventh time that you drop them in there.
LYNN: They're like, straight, stop, left, right.
SAUL VILLEDA: Got it.
LYNN: They go straight to it.
SAUL VILLEDA: But the old guys, they don't do that.
LYNN: So what does it look like if you drop an old mouse?

SAUL VILLEDA: Oh ...

LYNN: According to Saul, no matter how many times you run an old mouse through the maze ...
SAUL VILLEDA: No matter what you do to them, they're just not getting better.
LYNN: So it's like, "Do I go left here? Right? I'm pretty sure it was right last time. Why did they make it like this?"

JAD: [laughs]
SAUL VILLEDA: It's really hard. But that's where the blood came in.
LYNN: So Saul had an idea that was kind of similar to Boyle's 350 years ago.
SAUL VILLEDA: This is 1600?
LYNN: Although Saul didn't actually know about any of those old experiments. I gave him a copy of the paper.
SAUL VILLEDA: That's crazy. I'm gonna keep this.
LYNN: Anyway, his new but old question was this ...
SAUL VILLEDA: Well, what happens if you mix young and old blood? Does this affect learning and memory?
LYNN: So one of the things he did was he took blood from an old mouse, who's—you know, they're really bad at learning where the platform is, and he put it into a young mouse, who's really good. Just sort of to see what would happen.
JAD: Wait. So he put old blood in young mice?
SAUL VILLEDA: Yes. And then we did all the tests.
LYNN: You know, drop them in the pool, the whole thing.
JAD: And what happened?
LYNN: Well, all of a sudden ...
SAUL VILLEDA: They did much worse. The young animal looked a lot more like an old guy.
LYNN: Suddenly, this young mouse was just wandering around the maze all confused, you know, like an old mouse.
SAUL VILLEDA: Not quite as bad, but pretty close.
LYNN: No idea where he is, no idea where the platform is.
SAUL VILLEDA: The old blood really did impair learning and memory.
ROBERT: Wow!
SAUL VILLEDA: Isn't that crazy?
ROBERT: Yeah. What's—is there something in the blood that would change the mental state of the recipient?
JAD: What was the blood doing?
SAUL VILLEDA: A good question. So we ...
LYNN: Saul and his collaborators also did another experiment to get at that very question. And in this one, there were young mice who got old blood, but there were also old mice who got young blood.
SAUL VILLEDA: It went both ways, yeah.
LYNN: And at the end of the experiment, instead of looking at behavior ...
SAUL VILLEDA: We looked at the brain.
LYNN: See, they were looking at a part of the brain that specializes in learning and memory, and they were looking for a very specific thing.
SAUL VILLEDA: Brand new baby neurons.
LYNN: See, when you're young, as you learn things, your brain makes lots and lots of baby neurons, but as you get older ...
ROBERT: Not so much.
LYNN: Not so much. So Saul and his collaborators, they took all these mice, you know, old mice who got young blood, young mice who got old blood, sliced their brains real thin.
SAUL VILLEDA: Thinner than a slice of paper.
LYNN: And went hunting for baby neurons.
SAUL VILLEDA: So I counted all of these in a microscope, right? So literally with a little clicker, I just ...
LYNN: So wait, you're clicking every time you see a new ...
SAUL VILLEDA: A new neuron. Like, click, click, click, click, click.
LYNN: Apparently, when you zoom in on one of these little neurons ...
SAUL VILLEDA: They look like little trees, really, when you're looking at them.
LYNN: So little tree, click. Little tree, click.
SAUL VILLEDA: Over hours and hours and hours.
LYNN: Until finally one night, pretty late ...
SAUL VILLEDA: It was, I think, one or two in the morning.
LYNN: ... he gets his first look at the results.
SAUL VILLEDA: In a young animal, it was about a 25 percent decrease in those baby neurons.
LYNN: Was it dramatic?
SAUL VILLEDA: Oh yeah. I mean, you could see it.
LYNN: Just by looking. So it seems like somehow, when he gave the youngsters this old blood, the old blood was preventing baby neurons from forming.

JAD: Huh.

LYNN: Now in the old mice ...
SAUL VILLEDA: Normally, in an old animal, you're hard-pressed to find a handful of these cells.
LYNN: But after the old guys had been filled up with this young blood ...
SAUL VILLEDA: All of a sudden, we were getting, you know, maybe two or three times as many new neurons as we had seen before.
ROBERT: Two or three times as many?
SAUL VILLEDA: And they looked better. They looked longer, and they looked a lot more like the young neurons did.
ROBERT: Jad?
JAD: [laughs]
ROBERT: Come a little closer.
JAD: Stay away from me!
ROBERT: So does this mean what it sounds like it means? Like, I get the young blood and suddenly I can finish the day with my gloves, umbrella, and my keys all in my right hand pockets?
JAD: You mean instead of losing them on the 1 Train?
ROBERT: Yeah.
LYNN: Maybe, but we're not at all ready to say that yet.
SAUL VILLEDA: Not yet.
LYNN: This is really new stuff. There's a lot more work that needs to be done before we know, like, really even what it means. But it does seem possible, right?

LYNN: I feel like if you come out with a result that says yes, you can find—you can do the water maze better if you're full of young blood, like ...
SAUL VILLEDA: Crazy, right?
LYNN: Yeah. It's crazy and it freaks me out a little bit. Like, I feel like old women are gonna be buying vials of baby blood.
SAUL VILLEDA: You sound like my mother.

LYNN: [laughs]

SAUL VILLEDA: My mother is this—on a good day, five foot Latin lady. She's from Guatemala, and she's loud and excited, and she sounds just like you, just in Spanish.
LYNN: Oh!
SAUL VILLEDA: She's like, "Mijo, be careful. Be careful!"
LYNN: Because?
SAUL VILLEDA: Well, she's worried that all of a sudden, 16-year-olds are gonna go missing. [laughs]
LYNN: Don't you worry about that? That seems to be ...
SAUL VILLEDA: No.
LYNN: That does seem to be the logical extension of this, though.
SAUL VILLEDA: Oh, man. You really do sound like my mom.
ROBERT: But they are at least sure that it is the introduction of the new blood that is the agent of change here?
LYNN: Yeah, pretty sure. Because this isn't the only study. There have actually been a bunch of studies in the past several years that have come out with similar results for different parts of the body. Like, the skeletal muscle can repair itself better when there's young blood in the mix. Actually, the heart, there was a really recent study at Harvard. Amy Wager is one of the people who worked on it. I went to visit her at her lab in Cambridge.
LYNN: I'm from WNYC Radio in New York.
LYNN: And one of Amy's assistants, Danica, showed me this tiny little vial.
LYNN: Wow, this is really frozen.
DANICA: It's minus 80 degrees Celsius.
LYNN: It had a protein in it that they got out of the blood, a very special protein.
LYNN: Oh boy.
LYNN: Called GDF11.
LYNN: So you've just opened the freezer, and it's crusted in ice. And you're taking out a little red box. What do you got?
DANICA: That's what it looks like. GDF11 in a vial. So it's basically the purified protein that we keep at minus 80.
LYNN: So they think that the clear stuff in this vial, it does something kind of amazing, because when you get older, your heart tends to get bigger, which is not—you don't want that. It doesn't work as well. You want it to stay small. So what these Harvard people did is they took these old, enlarged mouse hearts and bathed them in young blood, and they shrunk back down to be like young heart size. And they think that very important protein is the mechanism. That's the key.
LYNN: It looks like absolutely nothing.
DANICA: Exactly. That's pretty much it. So you can see the frozen liquid at the bottom. That's really it.
LYNN: So that's a very important little thing in that vial that looks like nothing.
DANICA: Exactly. It regenerates many systems, so—yep.
LYNN: So that's the research being done in Boston, right?
JAD: Uh-huh.
LYNN: It's beeping because it's angry?
DANICA: Yes. Going up in temperature, so ...
LYNN: But then you talk to the guys, to Saul and the guy he's working with, they're looking at 600 proteins right now, trying to figure out which one might be—might be implicated, or which ones might be implicated. And if you were to talk about all the proteins in your blood, if you include all the splices and little variant proteins, there could be up to 100,000 of them.
JAD: Wow!
LYNN: Yeah.
JAD: So there's 100,000 different agents in there doing something?
LYNN: Yeah.
JAD: Producer Lynn Levy.
[ANSWERING MACHINE: Start of message.]
[CHRISTIEN TINSLEY: Hi, this is Christien Tinsley.]
[INGER TORNBERG: This is Inger Hagglund Tornberg in Sweden.]
[JAMES SHAPIRO: Hi, this is Jim Shapiro.]
[CHRISTIEN TINSLEY: Gonna start reading the credits for Radiolab.]
[INGER TORNBERG: Radiolab is supported in part ...]
[JAMES SHAPIRO: By the National Science Foundation, and ...]
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[INGER TORNBERG: Enhancing public understanding of science and technology in the modern world.]
[JAMES SHAPIRO: More information about Sloan at www.sloan.org.]
[CHRISTIEN TINSLEY: I know you guys were thinking about the Dracula version. I don't think I can do it, but let me—I'll give it a shot. Radiolab is produced by WNYC and distributed by NPR.]

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