Why Human Embryos?

(February 26th, 2016) The world collectively held its breath, when a UK research group received permission to genetically manipulate human embryos. What’s the rationale behind the group’s experiments?

Just a few weeks ago, the Human Fertilisation and Embryology Authority (HFEA) granted a research group from the Francis Crick Institute in London a license to alter the genetic make-up of human embryos using a technique known as CRISPR/Cas9. Despite the fact that these embryos will never pass the blastocyst stage and will never reach full-term gestation, this work has raised immense controversy. Lab Times decided to investigate why the group needs to use human embryos in their experiments.

For over ten years, team leader Kathy Niakan has been trying to understand the early stages of embryo development. The researcher knows the first challenge faced by the embryo is the formation of the blastocyst, where 20 very special cells – called epiblast cells – hold the key to embryo development but exactly what genes are relevant for this stage is still a mystery. “Our work is to understand the function of the genes that are responsible for setting aside these 20 epiblast cells vs. the placental or the yolk sac cells,” said the researcher at a recent press conference.

However, after identifying that many essential genes are expressed in a different way in human vs. mice embryos, the team reached the conclusion they could not continue to use the mouse as a model organism. The crucial question – and trigger for this work - then became whether the differences between humans and mice could explain the incredible losses that occur from fertilisation to implantation in humans? After all, it’s well known that humans are incredibly bad at reproducing and it’s estimated that only 25% of fertilised embryos will implant, whereas mice can have an almost 100% efficiency in reproduction.

Using CRISPR/Cas9, their first target is to eliminate a gene called Oct4, which seems to be expressed exclusively in the epiblast. The prediction is that these genetically modified embryos will simply fail to develop the epiblast and it will be impossible to derive embryonic stem cells. “One of the assays we could use”, explained Niakan, “is derivation of human embryonic stem cells, to determine if the Oct4 gene is important in the development of a proper epiblast.”

If all goes well, the first stage will be completed with the analysis of a further two or three genes also uniquely expressed in human embryos and with, as yet, unknown functions. With success rates over 80% in mouse embryos, the team is not anticipating any major problems transferring the CRISPR/Cas9 system to human embryos. After all, as Oct4 is highly conserved between mice and humans, it will be possible to target the same areas to optimise the technique.

When asked about what this work could bring in the future, the answer was less clear. “If we discover some fundamental differences between mouse and human, allowing human embryos to be more like the mouse, maybe we could dramatically improve fertility, but we don’t know what’s possible,” said Niakan. “Our focus is on providing a much deeper insight into the function of genes involved in the development of blastocyst, and that information could help developmental biologists and stem cell biologists to understand better those early stages.”

The team is hoping to start these experiments as soon as possible but they have to wait until they get enough embryos donated via their links with IVF clinics throughout the UK. They estimate about 20 to 30 zygotes for each gene they would like to target, to have a sufficient number of replicates.

Alex Reis

Photo: Human blastocyst (NIH/J. Conaghan)

Last Changes: 03.02.2016