How Has Embryo Research Changed?

Growing a human out of a Petri dish might sound like a scene taken straight from a movie, but is it really? Dr. Ali Brivanlou conducted a 13-day experiment in 2015 that would change the fate of human embryo experimentation. His team at Rockefeller University placed several human embryos into culture dishes and observed their growth through the earliest phases of development. On the last day, however, Brivanlou was faced with a tough decision as to whether to continue the experiment or bring it to a halt. That day, Brivanlou ended the experiment, leaving the developments that occurred after a mystery.

Brivanlou followed the 14-day rule, which is an ethical guideline that limits further in vitro studies on human embryos 14 days after fertilization. Day 14 is when the embryo develops primitive streaks, marking the embryonic development of body axes, and begins distinguishing the head from the tail and the left from the right. In this phase, not only do the cells become specialized, but the embryo is individualized, meaning identical twins can no longer form.

First proposed over 40 years ago, the 14-day rule has acted as an essential limit for embryonic research. The International Society for Stem Cell Research (ISSCR) released its first set of guidelines for embryonic research in 2006, establishing the rule in the scientific world. However, on May 26, the ISSR updated its guidelines and relaxed the well-known 14-day rule, allowing embryos to be cultivated beyond two weeks.

Magdalena Zernicka-Goetz’s team at the University of Cambridge, which achieved the same feat as Brivanlou, set out on their mission in 2013 to grow human embryos for longer than seven days, the maximum duration researchers could grow an embryo at that time. The researchers sought to understand what occurs beyond the blastocyst stage, characterized by the rapid division of cells around day five. Zernicka-Goetz’s team perfected a mixture of hormones and growth factors in 2016 to do so.

Zernicka-Goetz’s group investigated gene expression in the cells while the embryos developed. Her group analyzed 4,820 cells from 16 embryos from day five, when the embryo is usually implanted in the womb, to day 11, the stages of development that prepare for gastrulation. Gastrulation is the essential embryonic phase when the embryo is reorganized from a ball of cells, known as the blastula, into a multi-layered organism. Results from single-cell RNA sequencing revealed the inactive and active genes as embryonic cells transition from totipotency, when the cell type is undetermined, to pluripotency, a differentiated state.

Both Zernicka-Goetz’s group and Brivanlou’s group experimented with human embryos with aneuploid cells, cells that have an abnormal number of chromosomes and are associated with at least half of pregnancy losses. Results from Zernicka-Goetz’s experiment showed that embryos diagnosed early with some kind of aneuploidy could still grow to be healthy. Similarly, Brivanlou’s group examined gene expression in the embryo from early developmental phases, discovering that aneuploid cells were erased. These cells either grew into supporting tissue or were selected for apoptosis, or cell death. In vitro fertilization (IVF) clinics assess aspects of an embryo’s genetic health, including aneuploidy, by examining only a few of its cells. But, discoveries from both groups indicate that the common practice of diagnosing aneuploidy in IVF embryos may have led to many embryos in IVF clinics being incorrectly labeled as unhealthy.

As a result of these advancements, some ethicists and academics now argue that the decade-old rule is outdated and needs to be revised. Researchers express that extending the limit could provide a better understanding of human development in the third week and beyond, which is synonymous with comprehending the reason for some pregnancy failures. With the relaxed limit, researchers could study gastrulation, a stage between days 14 to 22, and gain insight into the body’s primary pattern and organ production. Brivanlou aims to reveal the genetics behind a four-chambered beating heart and to unveil the genetic blueprint that converts stem cells to brain cells, which occurs after week two. Understanding these developments is crucial to developing treatments for neurodevelopmental disorders and common congenital heart defects. These concerns and goals have led the ISSCR to loosen the 14-day rule but not completely replace or extend the limit. Instead, embryos that reach this point would be monitored closely and subjected to many stages of evaluation to determine whether the experiment should be terminated or not.

The first 3D stem model of embryos developed by Jianping Fu, a biomedical engineer at the University of Michigan in Ann Arbor, only showed early evidence of a primitive streak. Since then, model embryos have become so complex that they can now imitate early embryonic phases such as implantation, gastrulation, primitive stages of the brain, and development of the heart and spinal cord. Not only may these sophisticated models be used to research embryonic development instead of actual human embryos, but they may also be used to produce functional cells, such as neurons, that could be inserted into patients in the future.

However, as the models become more sophisticated, they are bound to spark ethical debates. What if their neurons begin sending messages or their heart cells start beating? What if they surpass simple imitation and function normally without any restraints?

The ISSCR’s decision to partially lift the 14-day rule was met with mixed results. Some critics say that the ISSCR was irresponsible in relaxing the limit without providing a new limit, as it could be seen as giving full approval for embryonic research. Some researchers also argue that removing the limit could break the trust between the public and the scientific community regarding embryo research. Meanwhile, others insist that research is progressing so rapidly that drawing another limit will be difficult and pointless because it will inevitably be overcome. Some scientists, including Brivanlou, agree with the decision and believe that research beyond day 14 provides enormous benefits, as it could save lives one day. Additionally, relaxing this hard barrier is not unethical because it might reveal how miscarriages and birth abnormalities occur. Moreover, many believe that the ISCRR’s new guidelines could pave the way for the genetic engineering of humans. Perhaps when these lab-grown embryos become more developed, they could be used to examine the consequences of genetically editing babies and creating human-animal hybrids.

Science is advancing now faster than ever, and rules from decades before are holding it back. Changing the old ways and allowing science to run its course will prove advantageous for us. The future of embryo research, genetic engineering, and other fields depend on our success with removing these limits on research.