Should We Study Human Embryos Beyond 14 Days?

To talk about pregnancy, we should first talk about frogs.

Frogs spawn hundreds of eggs in water that is teeming with parasites and predators. In some species these eggs grow at breakneck speed, transforming from one fertilized cell to the 40 million that make up an independently swimming tadpole in about two days. Errors are common. Most do not survive.

We have evolved a different strategy. We devote all of our reproductive energies to one embryo (usually). But we lose them all the same. Despite years of study, we don’t fully understand why as many as 30% of pregnancies fail or why some women suffer more misfortune than others.

A nine to ten week-old human embryo

Thanks to IVF, the days leading up to implantation are well-studied. With IVF, at around seven days post fertilization, healthy embryos are squirted into the potential mother’s uterus in the hopes that they will burrow into the lining and grow. If successful, the embryo dives in and disappears.

Scientists describe the period that immediately follows as a black box. What little we do know is based on donated and preserved human embryos made available through institutions like the Carnegie Collection, started in the early 1900s, and the cultured embryos of animals–mice, chicks, the rare large mammal, and a few non-human primates.

But humans are not frogs or mice or monkeys, and so to understand human development, we have to study humans. It’s no easy task. The newly implanted embryo is like a grain of sand embedded in a pillow locked in a box—impossible to observe. Unless that is, you can get an embryo to develop not in a uterus, but in a dish.

Limits

This summer two collaborating laboratories did just that. Headed by Ali Brivanlou, a professor at Rockefeller University, and Magdalena Zernicka-Goetz, a professor at the University of Cambridge, they published in Nature and Nature Cell Biology the first ever images of live human embryos cultured to days ten, 11, 12, and 13.

Embryos at this stage usually die if not nestled in the uterine wall. “This is a stage that is difficult to study in mice,” Zernicka-Goetz says. “It is next to impossible to study in humans.” But this time, the researchers had created a sufficient surrogate—a little shelter that allowed the human embryos to be bathed in just the right solution. They watched them grow. The previous record had been nine days. Most groups could not get past seven.

A human embryo at 12 days of development

“We discovered, in the human embryo, a population of cells that nobody else has ever seen in any other animal. Not knowing that this is part of our anatomy—at the beginning of the 21st century—is a little bit, how shall I say, embarrassing,” Brivanlou says. Mouse studies had left them so ill-prepared that according to Brivanlou, “it should no longer be qualified as the closest model to humans.”

Brivanlou thinks that embryonic self-organization may continue well past 13–14 days post-fertilization, though he cannot be sure. When the embryo reached 13 days, his lab stopped the experiment. The embryos were frozen for reasons of research ethics. They had bumped up against the 14-day rule.

Origins

The 14-day rule is an ethical line past which cultured human embryos are not to continue developing outside the body. It is protected by law in 12 countries, including the United Kingdom, and acts as a guideline in five, including the United States.

The rule was created shortly after the birth of Louise Brown, the first IVF baby, in 1978. An ethics advisory board was called to make broader recommendations for the treatment of human embryos in research and in IVF clinics. Leroy Walters, then the director of the Center for Bioethics at Georgetown University’s Kennedy Institute, was on the advisory board at the time. “We were all pondering, well, what would be a good upper limit? For a variety of reasons we came to a consensus that 14 days was a reasonable limit, even though that was way beyond what anyone had been able to achieve.”

One of those reasons was that pre-implantation embryos are regularly discarded by the human body. In the language of the report, “not every meeting of sperm and ovum results in the production of a viable embryo. One study estimates that…only 37% of fertilized human eggs survive to be delivered as live infants.”

Another consideration, Walters says, was that “embryos before the completion of implantation can split into two and give rise to twins, or more rarely, two embryos with different genomes can combine into a single hybrid embryo.” Some argued, how could an embryo at this stage represent a person if it could become two people or two could become one?

Fourteen days is also about the time when a human embryo elongates and develops a line called the primitive streak, which marks a channel where the spinal cord will eventually grow, Brivanlou says. “In other words, it’s that moment in your life—actually the most important moment in your life, not divorce, or marriage or kids—it’s that moment where you separate your head away from your butt.”

This development of individuality, of head and butt separation, is a key rationale behind the rule. But is it the correct goalpost? In the same issue as the report documenting the first 13-day human embryo culture, Nature published a commentary calling on scientists and ethicists to reconsider the 14-day rule: “In light of the evolving science and its potential benefits, it is important that regulators and concerned citizens reflect on the nature of the restriction and re-evaluate its pros and cons.”

Pushing past 14 days to, say, 21 or 28 days could help doctors understand and possibly prevent and treat a vast swath of medical problems, including infertility, pregnancy loss, spina bifida, cancer, and various diseases of aging. It would likely lead to improved stem cell therapies for today’s intractable diseases, such as diabetes, Parkinson’s, and multiple sclerosis. Other tantalizing possibilities include better understanding of fetal alcohol syndrome, potential causes of autism, how and why some chemicals affect development, and the strange and heartbreaking birth defects caused by the Zika virus.

The researchers have already learned a great deal by watching embryos develop up to 13 days. “I almost fell off my chair,” Brivanlou recalls—not just because he was witnessing something so few had ever seen, but because what he saw was so surprising.

“I always believed that the minute the embryo attaches to the uterine wall, the interactions between the embryonic tissue and the maternal tissue will have to coordinate so that everything happens within the correct timing. What we saw here was that at least for the first 13 days or so, all the information that is necessary and sufficient to generate all the cell types is actually within the embryo, not from outside.”

It was like the human embryo was a snowflake, creating a mesmerizingly complex structure from itself alone. “That to me was one of those amazing moments in my scientific career,” Brivanlou says.

Loss

Perhaps the most immediately apparent benefit of pushing past the 14-day limit is in better understanding and preventing early pregnancy loss. Early pregnancy loss, commonly called miscarriage, is when a pregnancy spontaneously terminates during the first 13 weeks. While most pregnancies that fail that early are never known, about 10% of known pregnancies result in early pregnancy loss and one-third of pregnancies result in miscarriage for women over 40, according to the American College of Obstetricians and Gynecologists. For those trying to get pregnant through IVF, 70% of conceptions fail.

Because of the risk of miscarriage, women are often counseled by friends and the internet not to announce a new pregnancy until around the third month. But not talking about it doesn’t make less common, nor does it erase the experience. Miscarriage can cause enormous emotional stress to women and their families.

Maria Dunlap lives in the western U.S. with her husband and two naturally conceived, biological children. Her first pregnancy, though, didn’t go as hoped. She and her husband had quickly become pregnant, but at about seven weeks, she began to bleed and realized that she was suffering a miscarriage.

Ten (left) and 11 (right) day-old human embryos

“The emotional toll was extremely heavy and way crazier than I thought it would be. When I was going to the grocery store I couldn’t even walk down the aisles that had baby supplies because I would just cry.”

Charlotte Emery lives in South Carolina with her husband and three biological children—a daughter and twin boys. She had several miscarriages before she was diagnosed with a genetic blood clotting disorder. She talks about the toll of miscarriage on her previous relationship. “We went into opposite corners of life…There becomes this whole emotional roller coaster where you are looking at your partner, and you are saying oh, well, it’s us, it’s you, it’s everything. We just grew apart in a big bad way.”

Just up the coast, Erica Kim lives in suburban Virginia with her husband and two adopted children. She has suffered four pregnancy losses, spent an estimated $75,000 of personal money trying to conceive through scientific means, and had zero live births. Erica says she can talk openly about her experiences only because of support from family and professional therapy. “When you are unable to do something that is so fundamental to the human body and mammals, all mammals, to procreate, to have your own offspring…Unless you are superhuman and don’t have emotions, anyone who goes through that suffers keenly. I think I developed PTSD from pregnancy loss.”

Limbo

Of course Dunlap, Kim, and Emery’s pregnancies had progressed beyond 14 days, long enough that the women were aware they were pregnant. Many women share the same experience, nurturing embryos that will never progress to a live birth. In cases of natural conception, nonviable embryos are flushed away in monthly menses; with IVF, unused embryos may be frozen or destroyed.

It’s important to remember how many fertilized eggs are discarded by human bodies, even before a woman knows she is pregnant—and well past 14 days, says University of Manchester bioethicist John Harris. “If God or nature regards embryos essentially as expendable in order for healthy human adults first to come to term as embryos and then to grow up, it is unclear to me why we should have a rule as restrictive as the 14-day rule,” he says. “What I think we need is a much clearer discussion about when and why the emerging human individual becomes morally significant—becomes the sort of thing that could have rights or interests.”

Many researchers point out that, for the embryos they work with, the alternative to allowing them to develop further is usually destruction. “The only human embryos we study are ones discarded from the IVF clinic that would never be allowed to develop into babies,” Zernicka-Goetz says. “It is believed that 70% of these would fail in their development. To work on these embryos, we have full agreement of the donor couples.”

Today, over five million babies owe their existence to IVF, and one of the results of those successes are the embryos that remain frozen, hundreds of thousands of which are in the U.S. alone. Many patients will ultimately choose to donate their unused embryos for scientific research. In other cases, healthy IVF embryos are given to infertile couples for the creation of children. Maria Dunlap knows one of these babies. “I actually have a girlfriend here who adopted IVF embryos from somebody else who was done having their kids and had a bunch of extra embryos. And now she has a two-year-old daughter who plays with my son.”

But this alternative is rare, and some U.S. studies show that women and couples hesitate to hand over their embryos to strangers for the purpose of creating a child. Erica Kim’s experience affirms the sentiment. “We felt uneasy donating them to another couple that would potentially raise our biological child.”

For Dunlap, the challenge is reconciling her faith with the advances that research could provide. “If a person believes that even an embryo at day one is already a human being—even if it is just presenting as a cluster of cells—then you have to follow the logic through and say, well now it’s not OK to destroy that, day one, day nine, day 14. From a science perspective, I love the idea of learning more about what you could do to prevent people from losing pregnancies at any stage. I am very pro-science. But then I’m super, super pro-baby.”

Debate

Some critics view calls to re-evaluate the 14-day rule as a pernicious moving of the goalposts. How meaningful can they be, the line of reasoning goes, if scientists want to change rules as soon as they bump up against them?

“There were disagreements about the rationale and validity of the 14-day rule before this point, but no one in the research community really pushed the issue because it was not particularly important,” says Glenn Cohen, a Harvard bioethicist. “There is nothing wrong with pragmatic necessity driving us to start a re-examination process.”

Revision is not necessarily a bad thing, says Debra Mathews of the Johns Hopkins Berman Institute of Bioethics. Plus, scientists are not the only ones whose views may change. “There are many processes wherein we make a decision, we collect information, and we revise our decision. I don’t think that’s actually a problem. When Louise Brown, the first IVF baby, was born—the uproar! And now 2% of babies born in the US are born by IVF.”

The potential for scientific advancements should be considered when determining the ethics of human embryo research, Mathews says. “It’s weighing social, moral, ethical concerns against the value of the science.”

For those who oppose human embryo research at any stage, such arguments may seem irrelevant. “Young human beings, especially in their unique vulnerability during early stages of development, are ‘ends’ in themselves, entitled to unconditional respect and protection, not ‘means’ to be utilized to achieve other goals, even when those goals may be lofty and high-minded,” says Father Tad Pacholczyk, director of education at the National Catholic Bioethics Center.

Stacy Trasancos, an author and mother with advanced degrees in chemistry and theology, says that, as a Catholic, she believes an embryo at any stage is deserving of full human rights. “We oppose any kind of research that uses human lives as research products or commodities,” Trasancos says. “We come back to the extreme case—would you do it with two-year-olds?” Regarding the argument that embryos are naturally discarded from the body, and miscarriage is common, “there’s a difference in a natural death and intentional killing,” she says.

Researchers know that any change could be contentious, and they are clear that they do not want any change without a transparent public conversation. “My job right now is to make sure that the debate is initiated,” Brivanlou says. “This is too important of a topic to leave it in the hands of scientists alone. In fact, scientists should be ex officio sitting on the sidelines, ready to answer questions required to make a decision but not necessarily be part of the decision itself.” Trasancos agrees that the conversation is important. “I do think there needs to be an all-encompassing conversation,” she says. “It’s about the dignity of human life.”

Brivanlou is similarly reverent, using words like “beautiful” and “mesmerizing” to describe what he sees in his research. “I have you tell you one of the toughest decisions in my life was when I had to pull the plug after this whole thing, because I realized that this Pandora’s box has not even been explored—not even a piece of dust of it has been explored yet.”