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Creating life in the lab: in vitro gametogenesis (IVG) and synthetic human entities with embryo-like features (SHEEFs)

8 January 2018
By Dr Jess Buxton
Senior Lecturer in Medical Genetics, Kingston University London and Trustee, Progress Educational Trust
Appeared in BioNews 932

What exactly are SHEEFs and IVGs? How might they shed light on the mysteries of early embryo development, and offer new hope to those affected by infertility? These questions - as well as the more philosophical issue of whether SHEEFs 'challenge what it is to be human' - were the focus of the second session at the Progress Educational Trust's annual conference 'Crossing Frontiers: Moving the Boundaries of Human Reproduction' in London on 8 December 2017.

The session featured three presentations from world-leading experts: Professors Magdalena Zernicka-Goetz, Azim Surani and Robin Lovell-Badge. These were followed by a wide-ranging discussion, deftly chaired by Dr Helen O'Neill at University College London.

The topics covered perhaps require some introduction, given the astonishing pace of recent developments. Although the term SHEEFs (synthetic human entities with embryo-like features) surfaced in early 2017, the research leading to SHEEFs builds on years of scientific work.

In 1998, a US team reported the first successful isolation of human embryonic stem (ES) cells. This major breakthrough was followed by another in 2006, when Japanese researchers found that adult body cells grown in the lab can be returned to an embryonic state – resulting in so-called IPS (induced pluripotent stem) cells. Both ES and IPS cells are described as pluripotent – that is, they have the potential to grow into almost any of the 200-plus different types of cell found in our bodies. That includes sperm and egg cells, with the term in vitro gametogenesis (IVG) being used to describe the production of artificial gametes from pluripotent stem cells.

Recent studies are now bringing together new advances in stem cell biology and tissue engineering to recapitulate embryo development in the lab. Under the right growth conditions, both human and mouse ES cells can self-organise into structures called 'gastruloids' that show some of the features seen following gastrulation - the stage of early development at which embryos change from a blob of cells to something with a front, back, top and bottom.

The first speaker in the conference session, Professor Zernicka-Goetz at the University of Cambridge, in her talk on 'Building Embryo-Like Structures In Vitro' described her team's ground-breaking work in this area. She focused on the stage of development just before implantation of the embryo into the uterine wall, often described as a 'black box', because so little is known about this process.

Implantation occurs after the cells of the embryo (at this stage called a blastocyst) have differentiated into two populations: those that will form the tissues of the actual embryo, and those (the trophectoderm) that will form the placenta and associated tissues. Professor Zernicka-Goetz explained that implantation requires 'a partnership' of these embryonic and extra-embryonic tissues, and that a failure of this process is responsible for 30-70 percent of early pregnancy loss. Studying how these cells develop and interact during this crucial developmental stage could shed light on this problem, she said.

Professor Zernicka-Goetz's team recently managed to produce an embryo-like structure in the lab, by growing mouse ES cells and extra-embryonic trophoblast stem (TS) cells together in a 3D-scaffold. The study, published in Science last year, showed that the ES and TS cells can self-assemble into structures with a shape, organisation and cell population that closely resembles that of natural post-implantation embryos. This work paves the way for further experiments that should help prise open the black box – in mice at least.

Professor Surani at the University of Cambridge, gave the next presentation on generating germ cells. He reminded the audience that we have only recently started to understand the origins of human germ cell development, even though human primordial germ cells (hPGCs - the progenitor cells that give rise to the gametes) were seen in three week-old embryos around 100 years ago. Before then, in 1892, August Weismann was the first to articulate the idea that heritable information is transmitted only by germ cells, not by somatic cells – his 'germ plasm' theory of inheritance.

Professor Surani's team has been studying how PGCs develop into egg and sperm cells. This work could eventually lead to new treatments for infertility, as well as shedding light on this fundamental yet poorly understood developmental process. He described his group's recent experiments, in which they have grown hPGCs within 'gonadal organoids';, up to the equivalent stage reached in a 4 week old human embryo. Their next goal was to reach week 7-8, he said, as this is when sperm and egg producing cells become distinct. The team have also looked at the epigenetic marks present in the DNA of the lab-grown PGCs, to check that they are being erased and reset correctly.

In a subsequent article published in the Guardian newspaper, Professor Surani said the production of artificial gametes for treating infertility was likely to be 'at least a decade away' and stressed it would first be essential to show that lab-grown egg and sperm had gone through 'all of the right stages'.

The final talk in this session, 'Do SHEEFs Challenge What It Is to Be Human?' was given by Professor Lovell-Badge at the Francis Crick Institute. 'Probably not' was his succinct answer – but could SHEEFs challenge the 14 day rule? This is the legal and regulatory limit in the UK that restricts research on human embryos to the period before the 'primitive streak'; appears at the start of gastrulation. It is the faint band of cells marking the beginning of an embryo's head-to-tail axis.

Professor Lovell-Badge explained that the acronym SHEEFs (which encompasses human gastruloids) first appeared in an article published in eLife last March. It reviewed recent and possible future developments in the field, and considered the new ethical challenges SHEEFs may pose. They concluded that limits on such research should be based on 'the appearance of features or capacities that are associated with moral status', rather than defined developmental stages such as the appearance of the primitive streak. This approach, they argued, would allow for the regulation of work on other types of possible SHEEFs, such as a 3D printed post-gastrulation embryo.

Professor Lovell-Badge went on to consider the thorny issue of how the moral status of such entities might be assessed – the beginnings of a brain? An ability to feel pain? But, he pointed out, although both neural connectivity and the presence of pathways involved in perceiving pain could potentially be detected in a SHEEF, there is no way of testing for consciousness. He also asked how SHEEFs differ from teratomas, tumours that contain several types of tissue, which can occur either naturally or following injections of IPS and ES cells.

Overall, this fascinating session on cutting edge developments in reproductive science may have thrown up more questions than answers, but the opportunity it provided to engage with the researchers carrying out this work was invaluable.

Whether its new research on SHEEFs, IVGs or the potential ethical dilemmas they pose, BioNews will be continuing to cover developments in this field and other areas of genetics, assisted conception and embryo and stem cell science throughout 2018 – if you don't already receive the weekly email roundup of this free newsletter then you can do so here.

PET would like to thank the sponsor of this session, the Edwards and Steptoe Research Trust Fund, and the other sponsors of its conference - the Anne McLaren Memorial Trust Fund, the ART Institute of Washington, Ferring Pharmaceuticals, the London Women's Clinic and Vitrolife.

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