Ali Brivanlou slides open a glass door at the Rockefeller University in New York to show off his latest experiments probing the mysteries of the human embryo.
"As you can see, all my lab is glass just to make sure there is nothing that happens in some dark rooms that gives people some weird ideas," says Brivanlou, perhaps only half joking.
Brivanlou knows that some of his research makes some people uncomfortable. That's one reason he has agreed to give me a look at what's going on.
His lab and one other discovered how to keep human embryos alive in lab dishes longer than ever before at least 14 days. That has triggered an international debate about a long-standing convention (one that's legally binding in some countries, though not in the U.S.) that prohibits studying human embryos that have developed beyond the two-week stage.
And in other experiments, he's using human stem cells to create entities that resemble certain aspects of primitive embryos. Though Brivanlou doesn't think these "embryoids" would be capable of developing into fully formed embryos, their creation has stirred debate about whether embryoids should be subject to the 14-day rule.
Brivanlou says he welcomes these debates. But he hopes society can reach a consensus to permit his work to continue, so he can answer some of humanity's most fundamental questions.
"If I can provide a glimpse of, 'Where did we come from? What happened to us, for us to get here?' I think that, to me, is a strong enough rationale to continue pushing this," he says.
For decades, scientists thought the longest an embryo could survive outside the womb was only about a week. But Brivanlou's lab, and one in Britain, announced last year in the journals Nature and Nature Cell Biology that they had kept human embryos alive for two weeks for the first time.
That enabled the scientists to study living human embryos at a crucial point in their development, a time when they're usually hidden in a woman's womb.
"Women don't even know they are pregnant at that stage. So it has always been a big black box," Brivanlou says.
Gist Croft, a stem cell biologist in Brivanlou's lab, shows me some samples, starting with one that's 12 days old.
"So you can see this with the naked eye," Croft says, pointing to a dish. "In the middle of this well, if you look down, there's a little white speck it looks like a grain of sand or a piece of dust."
Under a microscope, the embryo looks like a fragile ball of overlapping bubbles shimmering in a silvery light with thin hairlike structures extending from all sides.
Croft and Brivanlou explain that those willowy structures are what embryos would normally extend at this stage to search for a place to implant inside the uterus. Scientists used to think embryos could do that only if they were receiving instructions from the mother's body.
"The amazing thing is that it's doing its thing without any information from mom," Brivanlou says. "It just has all the information already in it. That was mind-blowing to me."
The embryos they managed to keep alive in the lab dish beyond seven days of development have also started secreting hormones and organizing themselves to form the cells needed to create all the tissues and organs in the human body.
The two scientists think studying embryos at this and later stages could lead to discoveries that might point to new ways to stop miscarriages, treat infertility and prevent birth defects.
"The only way to understand what goes wrong is to understand what happens normally, or as normally as we can, so we can prevent all of this," Brivanlou says.
The 14-day cutoff
But Brivanlou isn't keeping these embryos alive longer than 14 days because of the rule.
"The decision about pulling the plug was probably the toughest decision I've made in my scientific career," he says. "It was sad for me."
The 14-day rule was developed decades ago to avoid raising too many ethical questions about experimenting on human embryos.
Two weeks is usually the moment when the central nervous system starts to appear in the embryo in a structure known as the "primitive streak."
It's also roughly the stage at which an embryo can no longer split into twins. The idea behind the rule is, that's when an embryo becomes a unique individual.
But the rule was initiated when no one thought it would ever be possible to keep embryos growing in a lab beyond two weeks. Brivanlou thinks it's time to rethink the 14-day rule.
"This is the moment," he says.
Scientists, bioethicists and others are debating the issue in the U.S., Britain and other countries. The rule is law in Britain and other countries and incorporated into widely followed guidelines in the United States.
Insoo Hyun, a bioethicist at Case Western Reserve University, advocates revisiting the rule. It would allow more research to be done on embryos that are destined to be destroyed anyway, he says embryos donated by couples who have finished infertility treatment.
"Given that it has to be destroyed," Hyun says, "some would argue that it's best to get as much information as possible scientifically from it before you destroy it."
But others find it morally repugnant to use human embryos for research at any stage of their development and argue that lifting the 14-day rule would make matters worse.
"Pushing it beyond 14 days only aggravates what is the primary problem, which is using human life in its earliest stages solely for experimental purposes," says Dr. Daniel Sulmasy, a Georgetown University bioethicist.
The idea of extending the 14-day rule even makes some people who support embryo research queasy, especially without first finding another clear stopping point.
Hank Greely, a Stanford University bioethicist, worries that going beyond 14 days could "really draws into question whether we're using humans or things that are well along the path to humans purely as guinea pigs and purely as experimental animals."
Embryo alternative: "Embryoids"
So as that debate continues, Brivanlou and his colleagues are trying to develop another approach. The scientists are attempting to coax human embryonic stem cells to organize themselves into entities that resemble human embryos. They are also using induced pluripotent stem (iPS) cells, which are cells that behave like embryonic stem cells, but can be made from any cell in the body.
Brivanlou's lab has already shown that these "embryo-like structures" or "embryoids" can create the three fundamental cell types in the human body.
But the scientists have only been able to go so far using flat lab dishes. So the researchers are now trying to grow these embryonic-like structures in three dimensions by placing stem cells in a gel.
"Essentially, we're trying to, in a way, to re-create a human embryo in a dish starting from stem cells," says Mijo Simunovic, another of Brivanlou's colleagues.
In early experiments, Simunovic says, he has been able to get stem cells to "spontaneously" form a ball with a "cavity in its center." That's significant because that's what early human embryos do in the uterus.
Simunovic says it's unclear how close these structures could become to human embryos entities that have the capability to develop into babies.
"At the moment, we don't know. That's something that's very hot for us right now to try to understand," Simunovic says.
Simunovic argues the scientists are not "ethically limited to studying these cells and studying these structures" by the 14-day rule.
There's a debate about that, however.
"At what point is your model of an embryo basically an embryo?" asks Hyun, especially when the model seems to have "almost like this inner, budding life."
"Are we creating life that, in the right circumstances, if you were to transfer this to the womb it would continue its journey?" he asks.
Dr. George Daley, the dean of the Harvard Medical School and a leading stem cell researcher, says scientists have been preparing for the day when stem-cell research might raise such questions.
"I think what prospects people are concerned about are the kinds of dystopian worlds that were written about by Aldous Huxley in Brave New World," Daley says. "Where human reproduction is done on a highly mechanized scale in a petri dish."
Daley stresses scientists are nowhere near that, and may never get there. But science moves quickly. So Daley says it's important scientists move carefully with close ethical scrutiny.
The latest guidelines issued by the International Society for Stem Cell Research call for intensive ethical review, Daley notes.
Brivanlou acknowledges that some of his experiments have produced early signs of the primitive streak. But that's a very long way from being able to develop a spinal cord, or flesh and bones, let alone a brain. He dismisses the notion that the research on embryoids would ever lead to scientists creating humans in a lab dish.
"They will not get up start walking around. I can assure you that," he says, noting that full human embryonic development is a highly complex process that requires just the right mix of the biology, physics, geometry and other factors.
Nevertheless, Brivanlou says all of his experiments go through many layers of review. And he's convinced the research should continue.
"It would be a travesty," he says, "to decide that, somehow, ignorance is bliss."
RACHEL MARTIN, HOST:
Scientists doing embryo research are facing some sensitive questions over a new generation of scientific experiments, questions like how long should scientists be allowed to keep human embryos alive in their labs to study them? And should entities that they create from stem cells resembling human embryos be treated the same way? NPR's health correspondent Rob Stein visited a lab that's at the forefront of this provocative research, and he brings us now the first of two reports.
ROB STEIN, BYLINE: So what are we going to see first?
ALI BRIVANLOU: A human embryo that is attached and grown for 13 days in a petri dish.
STEIN: Ali Brivanlou runs the lab at The Rockefeller University in midtown Manhattan.
So this is an embryo that - where you were able to keep it alive in the laboratory...
BRIVANLOU: Exactly.
STEIN: ...Up until day...
BRIVANLOU: Day 13.
STEIN: And had it been done before?
BRIVANLOU: Never.
STEIN: For decades, scientists thought the longest an embryo could survive outside the womb was only about half that long - only about a week tops. So this is the first time scientists can actually see living human embryos at this crucial stage of development and study them at a time when they're usually hidden in a woman's womb.
BRIVANLOU: And women don't even know they are pregnant at that stage, so it has always been a big black box.
STEIN: Brivanlou arranged for one of his colleagues to show me.
BRIVANLOU: I ask him to make sure that he has a real sample for you to see with your own eyes so that you can appreciate the beauty in their own glory. It's really one of the most beautiful things I have ever seen in my life.
STEIN: Brivanlou's colleague Gist Croft pulls out some samples. Turns out, he's going to show me several embryos, starting with one that's 12 days old.
GIST CROFT: So you can see this with the naked eye. In the middle of this well, if you look down, there's a little white speck that looks like a grain of sand or a piece of dust in this well right here. I don't know if you can - can you see that?
STEIN: Yeah, it looks like a tiny little white translucent dot.
CROFT: That's it.
STEIN: Croft carefully places it on a big microscope and pulls a heavy black curtain closed.
CROFT: Would you like to look through the microscope?
STEIN: Yeah.
BRIVANLOU: OK.
STEIN: Croft helps me bring the embryo into focus.
Oh, yeah, I can see...
CROFT: Better?
STEIN: I can see the - oh, wow. Wow, that's, like, kind of beautiful.
It is quite stunning. It looks like a fragile ball of overlapping bubbles that's sort of shimmering in a silvery light, but it's also a little, well, funny looking.
So that looks like a (laughter) well, I mean, it kind of just looks like a - kind of a translucent hairy ball actually.
CROFT: Yes.
STEIN: Croft and Brivanlou get excited that I noticed what looked like little hairs reaching out from all sides because that's exactly what scientists would expect embryos to do at this stage if they were in the womb - search for just the right spot to nestle in.
CROFT: They're doing the reaching out and attaching that they normally do into uterus cells, but here they're doing it onto plastic.
STEIN: Wow, so they're behaving like they would - this embryo is behaving like it would if it was actually in the womb.
CROFT: That's right. It's reproducing certain key features of what it's normally doing in the womb.
STEIN: Scientists thought embryos could only do that sort of thing if they were getting instructions from their mother's body about what to do next - not all alone in some plastic dish.
BRIVANLOU: The amazing thing is that it's doing its thing without any information from mom - completely unexpected to me. It just has all the information already in it. That was mind-blowing to me.
STEIN: The embryos also start pumping out hormones and start organizing themselves, all by themselves, to form the cells needed to create all the tissues and organs that make up the human body. So Brivanlou and his colleagues think they could learn lots of things by studying them that could help stop miscarriages, treat infertility, prevent birth defects.
BRIVANLOU: The only way to understand what goes wrong is to understand what happens normally or as normally as we can so we can prevent all of this.
STEIN: But that would mean studying embryos beyond 14 days and Brivanlou can't keep these embryos alive any longer to keep studying them. Why? Because of a rule that says scientists should not conduct experiments on human embryos that are more than 14 days old. So Brivanlou decided he had no choice but to pull the plug on these experiments.
BRIVANLOU: The decision about pulling the plug was probably the toughest decision I've made in my scientific career. It was sad for me. It was sad.
STEIN: The 14-day rule was adopted decades ago to avoid raising too many ethical questions. It's a guideline in the U.S. but law in some other countries. Fourteen days is when the central nervous system starts forming, starting with something called the primitive streak. It's also usually when an embryo can't split into twins anymore. So the idea is that's when it truly becomes an individual. But that was before anyone thought it would ever be possible to go beyond two weeks. So Brivanlou says it's time to rethink the 14-day rule.
BRIVANLOU: It's time to reopen that debate. This is the moment. I think we are here. It would be a travesty to decide that somehow ignorance is bliss.
STEIN: And Brivanlou's not alone. There's a big debate about this going on in the United States, Britain and other countries. Insoo Hyun is a bioethicist at the Case Western Reserve University. He points out that these are embryos that were donated for research by couples who were finished with infertility treatments.
INSOO HYUN: You have to realize that with these embryos they are being used for research. That decision has been made. Now, the question is how long can you study them before they have to be destroyed? So given that it has to be destroyed, some would argue that it's best to get as much information as possible scientifically from it before you destroy it.
STEIN: Now, some people think it's morally repugnant to use human embryos for any kind of research at any stage of their development. And lifting the 14-day rule, that would just make matters worse. But the idea of extending the 14-day rule even makes some people who support embryo research uncomfortable, especially without first coming up with another clear stopping point. Hank Greely is a bioethicist at Stanford.
HANK GREELY: Unless there was something really important we could learn from doing research with human embryos, I wouldn't allow research beyond 14 days because at some point experimentation with it seems to really draw into question whether we're using humans or things that are well along the path to humans purely as guinea pigs and purely as experimental animals.
STEIN: So as that debate continues, Brivanlou and his colleagues are trying something else. They're using stem cells to create things that resemble primitive human embryos in their lab, but that's controversial too. Rob Stein, NPR News, New York.
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