by Constance Holman
PhD Student, AG Schmitz, Charité Medical Neurosciences
Science works (sometimes). It works by creating spectacular papers in prestigious journals like Nature or Science, and by concretely translating basic research into usable interventions for patients. At its very best, science works by bringing together people from all viewpoints, and finding ways to balance human greed for knowledge and advancement with the beliefs and values of the general public. Sometimes, it seems that examples of this are difficult to find. However, in the study of human development, there once was a time where when a prickly ethical issue turned into science at its best… only to become a moral conundrum once again.
Many readers of this issue may be familiar with developmental research performed on human embryos (HE); but many (including myself, before I got immersed in the topic) will not realize just how many aspects of science, society, and very complicated molecular biology these issues end up touching. A lot of this story rests on a single question: how can 14 days shape our understanding of what it means to be human? We will start at the beginning.
Or, at the very least, the single-cell stage.
Inner Space: The Final Frontier
Where do the cells used in HE research come from? During in vitro fertilization (IVF), oocytes and sperm are combined outside of the body to produce fertilized eggs. This process uses dozens of eggs (mothers are given medication to boost release of oocytes from the ovaries beforehand)., and several Several successfully fertilized eggs are implanted back into the body to increase chances of successful implantation and pregnancy. However, there are often still embryos “left over” from this process. Depending on national laws covering reproductive medicine, these are either frozen for future attempts, or set aside for research purposes.
Despite being only a tiny clump of cells at this point, human embryos (HEs) are more than worth their weight in gold (which is a good thing, because they weigh very little). For one thing, they provide a window into the very earliest days of human development, including things that can go wrong to induce early miscarriages. For another, they are full of totipotent cells, which can differentiate into any kind of human tissue. These are exciting not only for stem cell researchers trying to understand how cells eventually find their developmental destination, but also for patients with neurological conditions that could one day be treated with stem cell transplants.
However, it is also clear that there are extremely complicated ethical issues with this research [1,2]. Just scratching the surface, one can ask oneself whether, as some claim, true personhood begins at conception. Or implantation. Or 3 months (the time limit for abortions without extenuating circumstances in German and many other countries). Furthermore, research can lead to commodification (i.e. profit), for example, by patenting certain methods and techniques of extracting stem cells. Is this a morally acceptable with use of HEs? The list of ethical quandaries goes on.
Legality and Loopholes
Since the 1980s, when IVF first became widespread, countries around the world have been struggling to find solutions to the moral problems of working with HEs, or at the very least, compromises that satisfy all parties . At that time, committees formed at the national and international level to try and figure out working guidelines. In 2001, the UN came out with a set of guiding principles for work with HEs, eventually stating that it is the duty (emphasis mine) of every member state to discuss the ethical repercussions. The EU has similarly taken a fairly hands-off approach to governing work with HEs, leaving it to its member states to iron out the details . What is a forward-thinking country to do?
Germany has somewhat of a special legal situation, cobbled together by a set of national laws from the 1990s and early 2000s. First of all, it is a requirement that IVF in Germany is performed with as few HEs as possible. In fact, doctors are only allowed to implant 3 embryos at a time, decreasing the odds of successful pregnancy (though also decreasing the odds of multiple pregnancy- a “complication” with more cells involved). This means that there are necessarily fewer “extra” HEs. In fact, in the absence of exceptional circumstances (more on that below), German law entirely forbids the use of HEs for research. There is a loophole: HE stem cell lines may be imported from other countries, as long as they adhere to certain scientific/ethical standards of production, and as long as the research conducted with them is purely about fertility and reproduction. The federal government, through panels of experts, also decides whether researchers can use stem cells derived from HEs . Since 2002, 142 projects have been allowed, ranging from work on hepatitis virus characterization to implementing neural, pancreatic, or corneal cell transplants .
However, in countries with full-fledged biomedical research programs, German law is very much the exception. In the US, Canada, the UK, and most of the European Union, research on HEs is governed by the so-called 14 Day Rule. Simply put, fertilized HEs can be grown in labs and used in research for up to two weeks. This number is no accident, but rather was the product of a series of international meetings, consultations, and review in the 1980s [1,2].
14 days is special for several reasons. First, it is the time point when the primitive streak, the hallmark of gastrulation (see below) first appears. It is also the last point at which the embryo can split apart to become twins. If there was ever a time to define an “individual”, this is it (or so was the thinking at that time). The policy was not without its detractors, but was probably allowed to pass because, at the time, 14 days was considered blue sky thinking anyway- the longest that a HE had ever survived outside of the lab was a few days.
Pushing The Limit
Fast forward to in August 2016. In Nature and Nature Cell Biology, two different research groups report that they were able to have healthy HEs survive for 12-13 days [5,6]. Understandingly, the international research community had a meltdown.
On the one hand, it is now a moment of unparalleled optimism within the HE research community. Experiments which once seemed out of reach have suddenly sprung forward. And a lot can happen in two weeks! The embryo goes from a small blob of cells to a sophisticated flattened disc, with the beginnings of an attached placenta and architecture for blood perfusion . And experts contend that some of the most exciting developments are yet to come. No-one has ever properly seen human gastrulation (the division of the embryo into 3 layers, which will eventually become different organs) in humans, not to mention formation of the neural tube…  Yet clearly, we are not there yet, neither in terms of technology nor in the legal framework.
Many scientists are already pushing for an immediate extension of the 14 day rule, but this is unlikely to happen anytime soon. First, the negotiation of the original version took years to come into being. What’s more, it was based on moral and ethical arguments, rather than scientific extrapolation. Remember, at the time, keeping an embryo alive in a culture dish for any significant amount of time seemed ludicrous. The 14 day rule was an olive branch from the scientific community to the general public- a way of reassuring them that even when treading on morally shaky ground, researchers were willing to make a compromise to put the “best interests” of society first .
Now, negotiation of a time limit on HE research (if there should be a new one at all!) would be much more based on calculated scientific progress on maintaining and studying embryos in the lab. What’s more, proponents of an extension now have concrete examples of successful work with human tissue, including advances in pre-implantation diagnostics (checking embryos for specific genetic defects before returning them to the mother’s womb), stem cell extraction and more.
Despite this, any changes to the 14 day rule will likely be met with criticism. Foremost among these are the “slippery slope” arguments. The worry here is that extending HE research will open the floodgates for all manner of morally questionable practices involving germ cells and developing humans. We had a taste of this in late 2018 (see below). While such concerns are worth debating, they are perhaps (and more worryingly) indicative of a general crisis of confidence of scientific institutions as a whole . And due to recent international developments, this is likely to get worse before it gets better.
Science Gets Political
On the world stage, news about these breakthroughs could not have come at a more complicated time. In the US, one of the major powerhouses of biomedical research worldwide, debates over embryonic research and reproductive medicine have been subject to a political tug-of-war for decades. Under the Clinton administration, legislation similar to other countries using the 14 day rule was adopted. However, when George W. Bush came into power, restrictions on embryonic stem cell research were escalated, severely curtailing all work by federally funded groups. Obama and the Democratic Party struck back in 2009, once again opening the doors for embryonic research . However, in 2018, the Trump administration suddenly and without warning cut off funding of research groups working with fetal tissue . It is important to note that this research used human cells donated after abortion, but the message was clear: work on human development is in danger.
2018 provided another reason for society to start giving HE research some serious thought once again: the claims of the first human fetuses genetically altered with CRISPR technology . While many aspects of this story still need to be filled in, there is a growing sense of unease in the worldwide scientific community that research with embryos may not be as well under control as previously believed. On the one hand, the public and governmental regulatory bodies are somewhat on edge. On the other, what better time for us to all examine our scientific and moral rationales informing research with human cells?
The 14 day rule still stands. And, despite whatever may unravel stateside, it is will still likely stand for the coming months and years. In a world where “compromise” is increasingly a dirty word, perhaps the scientific community and the general public will actually take this as an opportunity to engage with one-another in a meaningful way. Two weeks is a long time. But whether it will ultimately be long enough remains to be seen…
 Cavaliere, BMC Med Ethics 2017
 Appleby and Brendenoord, EMBO Mol Med 2018
 Deglincerti et al., Nature 2016
 Shahbazi et al., Nat Cell Biol 2016
 Cyranoski, Nature 2018
Originally published in Charité Neurscience Newsletter, Spring 2019, Vol. 12, Issue 1