Scientific findings and medical benefits of embryo research

Early human embryos are microscopically small collections of cells that can also be created in the laboratory - for example as part of artificial fertilisation. Research with embryos can provide important insights into how human life develops in the first few days after fertilisation. These findings can be useful for recognising and treating diseases and making reproductive medicine safer.

Embryo research uses embryos that are just a few days old, which have been created as part of reproductive medical treatment and have not yet been transferred to the uterus. These embryos are often referred to as pre-embryos. These are microscopically small collections of cells that have emerged from the fertilisation of a human egg. For over 30 years, such early embryos can also be created "in vitro", i.e. in the laboratory, for example as part of artificial fertilisation. Embryo research is a recognised field of research and is practised internationally.

Under natural conditions ("in vivo"), the resulting embryo can implant in the uterus six to ten days after fertilisation of an egg by a sperm. During this phase, a multi-stage quality control process takes place in the body: it is determined whether the combination of maternal and paternal genetic material is functional and whether the embryo is able to undergo further development into a human individual. In the first few days after natural fertilisation, around every second embryo dies because it is unable to survive due to chromosomal maldistribution or mutations. It is assumed that only every third to fourth fertilised egg leads to a live birth under natural conditions. Even with in vitro fertilisation, only around one in four embryos is currently capable of full development.

Research into early human embryonic development provides important insights into human developmental biology. It is hoped that this will lead to new ways of avoiding or better treating infertility, miscarriages, premature births, genetic diseases or malformations in children.

During fertilisation, a sperm penetrates the egg in the woman's fallopian tube. The sperm and egg each have a set of chromosomes. In vitro, i.e. under artificial conditions in the laboratory, the sperm can either penetrate the egg cell independently or be injected. The union of egg and sperm results in a cell with a complete double set of chromosomes: the zygote. The respective parental genomes initially remain in the pronuclei, which are formed from the cell nuclei of the sperm and egg cell.

Cell division now begins. Observations in mouse embryos suggest that complete mixing of the parental chromosomes does not take place until the 2-cell stage. For this to happen, the membranes of the pronuclei must dissolve. The resulting cell nuclei contain both the maternal and the paternal chromosome set.

In the 4-cell stage, activation of the embryonic genome begins. This is essential for protein synthesis and the continuation of cell division. After a further cell division, the cells in the subsequent 8-cell stage gradually lose their totipotency due to the onset of differentiation and become pluripotent. Pluripotent cells have the potential to differentiate into all tissue types of the body. In contrast to totipotent cells, they can no longer develop into an independent organism.

If the cell sphere consists of 16 or 32 cells, it is referred to as a morula. This continues to divide and, under natural conditions, reaches the uterus around four days after fertilisation. Part of the cells move to the centre of the morula, while the other part remains outside. On day five, the embryo consists of around 60 to 100 cells. They become flatter and more compact and eventually form a hollow sphere consisting of two layers of cells, the blastocyst.

The embryo is usually transferred to the uterus at this stage during in vitro fertilisation (IVF). The special feature of IVF is that the human embryo is initially outside the body for up to six days and is therefore exposed to artificial growth conditions.

In order to continue growing, the blastocyst must implant in the uterine wall between day six and ten. Only in the uterus can the embryo develop into a foetus, which is referred to from day 70, when all organs and extremities are formed. Firstly, the gastrulation of the embryo begins after a few days: the cotyledons form. These eventually form the new human organism (also known as the "embryo proper"), while the surrounding cells form the egg membrane and placenta. The beginning of gastrulation can now also be induced under artificial conditions. The embryo reaches the stage of day eleven of natural development in vitro and is then around 0.3 millimetres in size.

In addition to fundamental questions about embryonic development and the early development of diseases, embryo research can also help to answer important questions in reproductive medicine. For example, it can help to better recognise and treat infertility, improve the survivability and healthy development of embryos and foetuses during pregnancy and prevent miscarriages and premature births.

One example of this is research into deviations in the number of chromosomes (aneuploidies) in early embryos in some or all of their cells. Aneuploidies are responsible for around a third of the miscarriages investigated and are therefore probably the most common cause of spontaneous termination of pregnancy. A better understanding of the causes of the high rate of aneuploidies in human embryos is necessary in order to be able to advise and treat couples who suffer from infertility or repeated miscarriages as a result.

Reproductive treatments have already been improved and made safer on the basis of international research findings. One example of this is elective single embryo transfer (eSET) in the context of artificial fertilisation. In this method, a larger number of eggs are fertilised and the embryo with the highest chance of development is transferred to the woman. In this way, risky multiple pregnancies occur much less frequently with almost the same chances of success. In the UK, these research findings have been systematically incorporated into an improvement in the quality of IVF treatment. The result is that within ten years, the number of multiple pregnancies and thus also serious premature birth risks for mother and child have been significantly reduced. In the UK, for example, the rate of twins per birth in IVF is around 10 per cent thanks to the eSET procedure, while in Sweden it is only 4 per cent. In Germany, where the procedure is banned, around one in five IVF treatments results in a twin pregnancy.

Due to their pluripotency, human stem cells from early embryos (hES cells) can develop into any cell type and form all tissue types of the organism. They therefore hold great potential for regenerative and personalised medicine. At the end of the 1990s, it was possible for the first time to obtain such stem cell lines from human embryonic cells. Since then, many hopes have been pinned on research with these cell lines, particularly for cell replacement therapy, i.e. the repair of damaged tissue. For example, clinical trials are currently being carried out to treat age-related macular degeneration, a form of severe visual impairment, using cell therapy. Research is also focussing on hES cells for the treatment of common diseases such as diabetes, arthrosis, heart attacks and strokes. The derivation of hES cells leads to the loss of the embryo in vitro and is currently prohibited in Germany. In Germany, however, the import of embryonic stem cells from other countries is possible within a narrow legal framework.

Some existing hES cell lines have been cultivated for years and have accumulated genetic and epigenetic changes in the process. They may also be contaminated with pathogens such as prions or mycoplasma. For clinical application, it would therefore be necessary to generate new hES cell lines under precisely defined conditions.

Another important field of medical research concerns the genetic correction of hereditary diseases by means of genome editing. Depending on the disease, there are two different approaches: the genetic correction of somatic cells or an intervention in the embryonic genome in vitro. Somatic gene therapy has been clinically trialled for many years. It is normally limited to the person to be treated, who is usually already ill.

When oocytes and sperm or their precursors are subjected to gene therapy, the germline is interfered with. These potentially also have an effect on subsequent generations, as the genetic modification can be passed on. The international scientific community largely agrees that germline interventions with the aim of inducing the birth of a human being are not currently justified due to the as yet unknown risks and possible alternatives such as somatic gene therapy, preimplantation genetic diagnosis and adoption. When twins were born in China in 2018 whose genetic material was deliberately altered during fertilisation using CRISPR/Cas9 gene scissors, this case therefore caused great outrage in the scientific community.

In order to at least be able to critically examine and evaluate the opportunities and risks of this form of gene therapy, it would be helpful to carry out corresponding basic research on germ and somatic cells as well as on early human embryos. In particular, the unintended effects still associated with the method (off-target effects), such as the loss of DNA sequences or chromosomes, could be better assessed and possibly prevented.

Published: May 2021