Radiolab - The Primitive Streak

Episode Date: September 23, 2016

Last May, two research groups announced a breakthrough: they each grew human embryos, in the lab, longer than ever before. In doing so, they witnessed a period of human development no one had ever seen. But in the process, they crashed up against something called the '14-day rule,' a guideline set over 30 years ago that dictates what we do, and possibly how we feel, about human embryos in the lab. On this episode, join producer Molly Webster as she peers down at our very own origins, and wonders: what do we do now? This piece was produced by Molly Webster and Annie McEwen, with help from Matt Kielty. Special thanks goes to the Bioethics Research Library at Georgetown University; Omar Sultan Haque, Kevin Fitzgerald, SJ, and Josephine Johnston; Charlie McCarthy; Elizabeth Lockett, Mark Hill, and Robert Cork; plus, Eric Boodman, Lauren Morello, and Martin Pera. Producer's note about the image: Check out the super cool picture that's running with this piece. Scientist Gist Croft sent it to me a couple of weeks after my visit to the Rockefeller lab: it’s an image of the very embryo I looked at under the microscope - a twelve-day old human embryo - but with all the detail highlighted using fluorescent dye. (When I looked in person, we were using a light microscope that showed everything in black and white, with not nearly that precision.) The neon green bits are what's called the epiblast, the clump of cells from which the entire human body develops. See how it looks like it's pulling apart in to two? The scientists don’t know for sure, but they think this embryo might have been on it's way to becoming TWO embryos. Twinning! In action! Support Radiolab by becoming a member today at Radiolab.org/donate.    

Wait, you're listening. Okay. All right. You're listening to Radio Lab. Radio Lab. From W-N-Y-S. See? We're going to start with a conversation that I had with Jad a few weeks ago.

Okay. So I like medical stories. This I know about you. This you know. And so I read this website called statenews.com, which does sort of really, it's like a new website out of Boston. It's new, right? And basically it's this collection of really amazing, like, medical reporters.

And I will click on stories that look interesting. And there was one about, we've just grown embryos, human embryos, for a long time in a lab. And that was when I read the phrase, the 14-day rule for the first time. And it was that apparently there's this thing that you can't grow an embryo in a lab past 14 days. Huh. Which I didn't even know you could grow an embryo in a lab at all. Right, right. Or that people were or that, I mean, I guess I knew IVF happened.

Sure. Like test tube babies. How long, in the average IVF situation, how long is an embryo in a dish for? And then I realized I didn't actually even know that either. So then I just spun out. So like the whole article is just interesting to me because I was like, I don't know about any of this. Right, right. I'm Molly Webster.

Oh, and I'm Robert Krollwich. This is Radio Lab? And today on Radio Lab, we're going to zip down a wormhole into another universe. And Robert, you're coming with me. Okay, tell me about this universe before I buy a ticket. Okay, you're going to want to buy a ticket because in this universe are twins and souls and mice and something called a primitive streak. And they're all gathered together around a certain rule.

Oh, and remind me again what the rule was? Well, so you know how you can fertilize an egg? You get an egg in a sperm and you put them together. Yes. Fertilizes the egg. Right. And then the egg, the fertilized egg, it multiplies, multiplies cell divides. So a scientist could take it to watch it grow to learn about human development.

But then they have to stop at day 14. That's the rule. Is this a medical kind of thing or science limitation? It is, it's medical. It's all those things. It's medical and it's science. And there's like philosophy and ethics and obviously religion. And we're going to tell it to.

Yeah, you're buying it now, right? I see. The whole chivalve. I have water. Okay. I'll take a sip. Okay. We're going to begin with this guy, Leroy Walters.

Okay. He was an ethicist at Georgetown University, now retired. And to me, he is sort of the father of the 14-day rule. I never thought of myself as the father of the 14-day rule. But he is. He totally is. Well, we shouldn't forget the context of 73. All right.

So, 1973. Leroy has recently graduated with a doctorate in ethics from Yale University and settling into his job. And at the time, medicine and ethics were a sort of collision course. Yes. Yes. Mm-hmm. Good evening. January 1973. In a landmark ruling, the Supreme Court today legalized abortion.

Roe v. Wade happens. It is clear, at least under present law, that an unworn fetus is not a, person within the meaning of the Constitution. But just six months after that decision, the issue of fetuses and research done with them. Fetal research became a hot topic. Some of the testimony in here is shocking. There were news reports of butchering and cutting up enough.

About dissecting fetuses, even an instance of decapitating fetuses. Oh, man. And then around the same time, used as human guinea pigs. Research involving human beings. A controversial Tuskegee syphilis study. News reports of the syphilis studies that were done. on African-American men without their knowledge.

There was the sterilization of... Two daughters had been sterilized without their informed concerns. Women with intellectual disabilities. Genetic engineering was coming into its own. You have all these questions swirling about, like, how we feel about the human body, whether or not we want to experiment on it, and what do we protect, and what don't we protect?

It's just sort of this whirlwind. And... You are about to see a... Then most relevant for our story? We are going to deliver her by Zerian Sex. On July 25th, 1978. Scientists in the UK. We are now incising the uterus itself.

Produced a child with the aid of in vitro fertilization. The first baby that was born from an embryo that was grown inside a tube. Baby Louise Brown. Baby's not open her eyes yet. Everyone in the world was fascinated. But there were people who predicted doom. What was the doom? That in vitro fertilization would lead to reproduction as a form of manufacture.

So the government was grappling with, we need more regulations or we need as a country to think about what our ethical guidelines are? Right. So the Department of Health Education and Welfare. And they put together something called the Ethics Advisory Board. A panel of doctors, laymen, academics. Even a Jesuit priest. To consider some fundamental moral and ethical questions.

Questions involved in test tube human fertilization. Its meetings and discussions open today. Now, as part of those meetings, the board will call on these expert witnesses, and one of those witnesses was our boy Leroy. Right. The staff director. And they asked Leroy, like, ethically, tell us what we should be thinking about when it comes to embryos. And how we are to regard them.

And he says, well, there's a spectrum. And on the one side, you could argue that human embryos should be protected from the time of fertilization forward. We shouldn't even be growing embryos in a lab at all. But then there's the other side. The most permissive position was that research could be done until about eight weeks. Because a fetus at about eight weeks. can have a reflex response to a stimulus.

And then... At some point, a committee member turns to Leroy and she says, where would you draw the line? He pauses and he says, well... Well, I would say for me, 14 days. Why 14? Well, Leroy had a couple different arguments. For one, before 14 days...

About 50% of early human embryos... are simply sloughed off. They're just sort of shed from the woman's uterus. And don't develop further. So the thinking was, if we're already losing 50% of them naturally. We don't have strong moral obligations toward early human embryos. I see. You can even pose it as a metaphysical question.

If these are important beings, why do 50% of them disappear? And we never have any knowledge of them. Argument number two? Early embryos can swel. split into two. As in twins. Or two separate embryos can recombine into one embryo.

Right. Like before 14 days an embryo doesn't know if it's one embryo or if it's like going to be one person or if it's going to be two people. So as Leroy put it, it doesn't have a biological identity. And that happens right around 14 days.

Argument number three. The primitive streak appears. The primitive streak appears. The primitive streak is the first index of an axis of the future body. People see it as like the body starting to organize itself. You might say it's the outline of the spinal cord that will develop later on. It's the first hint of like, shape.

All of those seem to kind of converge around 14 days. Eventually, the committee decides to take Leroy's suggestion and recommend that all research on human embryos be stopped at 14 days. With high expectations, we submitted the report to Secretary of Health Education and Welfare, Joseph Califano on May 4, 1979. And on July 19, 1979, before he could respond, Secretary Califano was fired by President Jimmy Carter. It was part of a whole cabinet shakeup. And so the report has been sitting on shelves.

gathering dust, and there has never been a formal response. It did end up becoming a guideline in the U.S. It's actually an international guideline, but we never actually needed it. Because 14 days... That was so far beyond the capacity of researchers to culture early embryos that it also seemed like a safe marker, a safe boundary. Because, and this is the interesting thing, With IVF, we're familiar with like days 0, 1, 2, 3, 4, 5, 6, which is about the time they put the embryo into the mother.

Uh-huh. So nobody had ever really seen how an embryo develops from day 7 through 14. Oh, interesting. You can't photograph it through the body for like various reasons. For one, no one ever knows they're pregnant that early. Like, when did you and your wife realize you were pregnant? It's like a month after the fertilization happens. Yeah, it's funny.

It's like when you, even if you're trying, you don't actually know for weeks until. Yeah. And it's so small that even if you did know, the way it attaches to the uterus, it sort of burrows in and you kind of can't see it. And at the same time, scientists are pretty sure that this is a very important moment in development. And they just can't get to it. Wait, wait a second. Life magazine 50 years ago published these gorgeous pictures. of a fertilized cell

and then beautiful little baby with eyes, you know, just... Yeah, but that, they have pictures of sperms and eggs, then there's a blank spot until at least three

and a half weeks. So that magazine spread... So life didn't show the first few, the second or third. No. Really? You're saying

that there is a place in the development of the human being that no scientist has seen? No. Ever? No.

Really? Yeah. So this is this kind of period which in the textbook you will find describe as a black box. Which brings us to Magdalena. So I'm Magdalena, Jernica Gets, at the University of Cambridge in UK. Okay, great. She for years had been trying to figure out how to grow embryos during this period. But for those experiments.

And the problem was at this point, the embryo is beginning to attach to the mother's uterus, and so it just needs certain things from the mother. and if you try and grow it in a dish, it just shrivels up and dies. Yes, yes. So at the time, we were trying really scratch our heads and come up with the most enriching environment we could imagine. Like maybe I can recreate that really warm, cozy home, but in a dish without the mom.

Interesting. So it's like experimenting. Like what is the right bath that the growing embryo needs to sort of get what it needs? Yeah, and they decided that while they were still trying to figure it out, they would just do it on mice embryos first. And so she started essentially just coming up with, like, chemistry concoctions. They started with the gel. Which was of particular elasticity, sort of gloppy and gooey,

and then they tossed in a serum made from human placentas. Added some hormones, like progesterone, along with fibroblast growth factors. And, of course, a dash of... Slamin, fibroenectin. This sounds like someone would sell this as like a face cream or something. They even tried serum from... That's placentas. That actually really didn't work.

It was not so good as the serum from the human placenta. Oh, really? Yes. For five years, they put stuff in, they pulled stuff out, they tried everything. Until they ended up with something that, at least on mice, seemed to work really well. So they thought, okay, maybe it's time we try this with human embryos. We took two embryos, just two human. Put them in a dish with their chemical concoction and amazingly, it worked. One of them did make it.

To 13 days, the other one didn't. But one made it, right? Suddenly they had an embryo that was growing happily into day eight, day nine, day 10, day 11. And they were able to see all of these moments in human development. that no one had ever seen before. And guess what, Robert? Yeah. I got to see them too.

You did? I did. Do you want to come? Of course I want to come. Okay, good. We should go right now. We are going to go, but we're going to actually have to take a break first. Oh, God.

So we'll be back in a bit. Okay. Hi, this is Lizzie from Arlington, Texas. Radio Lab is supported in part by the Alfred P. Sloan Foundation, enhancing public understanding of science and technology in the modern world. More information about Sloan at D. www.sloan.org. Okay, we're back.

I am Robert Krollwitch. I'm Molly Webster. This is Radio Lab, and today, the 14-day rule. Last we left you, we had just met a woman who managed to grow a human embryo in a lab right up to the 14-day line. And now we get to see it, right? That's what you promise. Yes. One earphone on, one earphone off.

Good look. Good luck. Lucky enough for me. There is an embryology lab right here in New York, Rockefeller University. Hi, how are you? It's nice to meet you. Run by this guy. So you're a radio scientist. Ali Brivenloo. I fake being a scientist. Ali's team, building off of Magdalena's work, they were also growing human embryos in the lab to the 14-day mark. So we invited me up to see them.

Today, you would realize that your eyes are seeing something that no other human beings has ever seen, except the group in this lab. And obviously Magda's lab. How many people are in this lab that you think saw it? I think we're a total of 25. So then I'll be like 26. So Ali has to step out of the room? I'm excited. Thank you, Ali. And he passes me off to the guy that runs, like, the human embryology research at the lab.

Guestcroft. And a lab technician. Chichilla Pellegrini. Chichilia Pellegrini. Yes. Okay. We go into the lab. We're walking through a cool lab.

It's very big and everyone's looking at me. Lots of benches and microscopes and people pipetting. And so, a fridge. There's a little sticky note on the fridge that says, Experiment 27, embryos here. And so we keep them in the tip-off. And Chichelia pulls out like a plastic box that has a blue bottom and like a white opaque top.

The lid just came off. And inside there was kind of like a microscope slide and the embryos were attached to that. But there was condensation on it so we had to wait like 10 minutes. I got weirdly nervous. But eventually you look down into this like little square well. Oh, okay. It's like 10 millimeters by 10 millimeters, and it has a little bit of liquid in it.

And then inside that liquid. Wow, this is a human embryo. Yeah. How big is a, how big is an embryo? Oh, my God, it's so small. It's like we talk about 14 days, and in my mind I do imagine a tiny little human. Is it even human-like at that point? The tiny dot right there.

No, is just the little white dot. Holy crap, it's really small. That's like a grain of sand. Yeah, it's about that size. And it looks like, I kept also thinking that it looked like, if you took a sheet of typing paper, and you took a pin, and you poked a hole in the paper, and a little pinpoint of light came through,

that's what it looks like that. I cannot believe that goes into a five-foot-nine tall human being. So that was a day 12 embryo we were looking at with our naked eye, but Gist and Chichilia also took me over to this badass microscope. What do I? I don't want to break anything. Yeah, you're not going to break it. I'll show you how to do it.

So we could look at a bunch of images and see the development of an embryo day by day. Starting with... Day eight. You see right here, like you have the embryo mass. What is it look like? It looks very lunar to me. Blown out gray sphere that has, like, modeled surfaces,

but inside of it are hundreds and hundreds and hundreds of cells. There's trophactoderm. primitive endoderm, and there's epiplast. There were, like, three different types of cells, but to me, it, like, looked like a simple structure. And then... This is the same embryo the next day? Wait, is this day nine? Oh, whoa, it looks totally different.

So it starts to get a little more complex. Now we can see nuclei. Is that what all those bright spots are? Yeah. There's a nucleus. There's a nucleus. Huh. And can we switch from 9 to 10?

Mm-hmm. So what are those, like, oil droplet-looking things? Those look like oil droplets, don't they? Now there are these, like, six? spherical balls around the edges and it could be any number of things, but guess things they might be fat, like lipid? And the embryo, it starts forming like the asymmetry, like you see things move to different areas of the cell. It makes a hollow shell inside. And then your inner gut cavity, that starts to form.

There's all of a sudden a new cell type we've never seen, a yolk sac true vectorum cells. So a totally new type of cell no one's ever seen before. So we don't know where it comes from and neither does anyone else. And then day 11. I get excited every time you open one of them. Okay, day 11. Day 11 didn't really look that different to me. Day 12?

Day 12 has a lot more going on. That's the origin of the placenta. Cool. Day 13, there's all this brightness at the bottom in the upper left-hand corner. These could be epiblast cells. Do you remind me again, the epiblast is? That is the cell type from which the entire body eventually emerges. Gist says those are the cells that all of the body comes from.

Like all the other stuff is mostly just support. Oh, wow. So it's like the primal, like primordial cells. It's foundational cells. Yeah. Yeah. So I actually got there on day 13 of the experiment. So all of the embryos were just sort of waiting to get to day 14.

And so that was it. So let's shut this down and get this guy back in the incubator. And then I was just sort of spit back out into the real. world. Are they learning fantastically new amazing things based on this? Well, like the, the, the big takeaway that both of the groups had was that this embryo grew for another week without any maternal input, and it grew basically as it should have grown. Which was mind-blowing to me and to all of my colleagues that the human embryo will behave in a self-organizing manner in a complete absence of maternal inputs, at least for 14 days.

Like, I think they always thought, even if they got the chemistry right, there'd be some sort of system breakdown because it wasn't getting input from the mom. Interesting. I always keep thinking of it as like the anti-mothersday message. The embryo doesn't need you. Happy Mother's Day. But the one pro-mom thing is by the end, in between day, like 12 to 14, it became clear that it started needing maternal input. I see. Like what? Do they know? Well, so they, this is the part that was cool. It was like, they saw that the embryo started

forming tunnels and pathways for the mom to like infiltrate. So there were little tubes and pathways that formed where like nerve attachment could happen and like circulation. So it prepares itself in this week for the mom and the connection. That's really cool. It's like it's like hooking itself up to the network in a way. I know. It's funny. It's like coming online is like like a human being. Yeah, that's a good way to put it. Yeah. That's cool.

The other cool thing was Gist told me that right around day 10 along the edges of the embryo, this hormone shows up that your body doesn't have before. It's called like a gonadotrophin. So you know when you take a pregnancy test, the thing it's reading is that hormone. Oh, is that he thinks like the embryo broadcasting? Yes. It's like boom, boom, boom, boom, boom, boom, boom. like out to the rest of the body. Like, I'm here, I'm here, look at this hormone.

Wow, that's super cool. What does it like to look through a microscope and see day eight when we've been stopped at day seven since the 1970s or day nine or day ten? It's hard to describe it. When people receive the digital image of the Hubble telescope, those first few eyes who are getting it in their screens, I guess it has to be something very similar to that.

When I look inside of our own anatomy at the time where nobody knows that we even exist, is the same as looking at dimensions that we have never imagined we will ever see because we didn't even know they exist. But then, at day 14, you have to essentially embalm it. You, like, can make it stop growing. and freeze in the place that it's at. They call it fixing. But if they wanted to,

could they go past 14 days? Maybe, but Ali, he said that as they got closer to day 14, they noticed changes in the embryo that made it clear that it started needing more than just the current bath that it was in. Okay. But like, in Brevinlu says this too, and Magdalena says this,

it's like, every day feels like an accomplishment. You're like, oh, my gosh, it grew another day. And then you start, like, cheering it on. You're like, grow another day. Grow another day. Oh, my gosh, you're just. day 12 and it becomes like you're like championing it and then you're like okay stop you're done right and i felt like when i was standing there i was like oh that's abrupt because i wanted it to grow

grow grow grow grow grow but obviously i don't want it to grow grow too far so it was like go to day 15 and i'm like grow to day 16 and then i'm like when does the joy in my voice stop like this Eventually I'm going to hit a point where I'm like, that's uncomfortable. This is something that touches us in the root of our own definition of our being and existence and individuality. It becomes a little bit like a Pandora box. So, yes, you won't open it, but you have to be ready to see what's in it. If technology has now moved it a whole other week so we can go for 14 days, maybe it's pretty soon you can go a whole other week

and then a whole other week. Does that mean the rule's going to have to change? That is the conversation that's happening right now. Basically, once this research was published, there were commentaries and articles and columns about what do we do about the 14-day rule and there's conferences, there's a conference in Boston that's happening in the fall.

But what are your choices, though? Like, you could choose... He could do any number of things. It depends on where you sort of think. throw down a biological or moral marker that you feel comfortable with. Like, um, you could keep it at 14 days and sort of keep it around like this idea of twinning and the primitive streak. Uh, you could move it a week out to say to day 21 when there's interesting sort of neural folds and divisions that are starting to happen in the brain. You could go to eight weeks,

but it could also go back to zero. Oh, so there's no consensus on no, no, no, there's no consensus. And the scientists are the first to say, like, they don't want to make this decision they just think, like, maybe we should have this conversation as a group so the society decides, not us. So, yeah, and then... But it's just like, if you say that, like, it's as amazing as, like, the Hubble telescope, how does it feel when you're like, I've gotten this far, and now I have to end it?

So that's the toughest question you're going to ask me today. For me, for sure, it was important to stop the experiment where there was still a message that we could convey that would not offend people. This is more than just science. One of the greatest challenge in reproductive biology, especially in human reproductive biology, is to make sure that you don't offend people,

sense of identity, dignity, religion. And so, Ali, he finds himself trying to keep all of these different perspectives in his head all at once. So, for example, if the Catholic point of view is human origin's conception, then I have to respect also the Jewish point of view that says, you know what, is that heartbeat?

I also have to respect the Muslim point of view about the origin of human life, which surprisingly, for one, seems to be similar than the Jewish point of view. It's also heartbeat. I also have to respect the Buddhist point of view. And what about the Hindus? The Buddhist says,

if you don't cut the omical court in your life, independent, you're not a human being. You don't call an organ a human being because it's attached to you. A Hindu says, I don't know what you guys are talking about. There is no origin or end. We're circles within circles, within circles. I'm a butterfly today. I'm going to die and come back as a tiger. I'm going to die and come back as a human, die and come back as an elephant. What origin? A circle does not have an origin. So I am for the progress of science. I am for gaining knowledge. It's my job. It's the way I'm wired. As a human being, I satisfy our sense of curiosity.

And there is nothing more curious to me than our own origin. So then that would be like you would love to know like what happens on day 21. Absolutely. And I like to think that before I die, we will know what happens on day 21. This episode was produced by Annie McEwen with help from Matt Kielton. and Brenna Farrell and Simon Adler, and I actually think the entire radio lab staff had something to do with this episode. So thanks, guys.

And I want to thank the Research Library at Georgetown University. Thank you for listening. See you later. To play the message, press two. This is Leroy Walters. I'm a retired faculty member from Georgetown University, where I was part of the Kennedy Institute of Ethics

and the Philosophy Department. Radio Lab is produced by Jad Abumrod. Dylan Keith is our director of sound design. Soren Wheeler is senior editor. Jamie York is our senior producer. Our staff includes Simon Adler, Brenna Farrell, David Giebel, Matt Kielty, Robert Kralwich, Annie McEwan, Latif Nasser, Melissa O'Donnell, Ariane Wack, and Molly Webster. With help from Nigar Fatali,

Alexandra Lee Young, Charu Sinha, Persia Verlin, and W. Harry Fortuna. Our fact checkers are Eva Dasher and Michelle Harris. That's it.

Thanks. Bye. End of message.