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What is the germline?

21 December 2015
Appeared in BioNews 833

This year's annual conference of the Progress Educational Trust, titled 'From Three-Person IVF to Genome Editing: the Science and the Ethics of Engineering the Embryo', started with an invigorating talk from Professor Azim Surani, Director of Germline and Epigenomics Research at the Gurdon Institute, University of Cambridge.

He described the uniqueness of the germ-cell lineage – or germline – and how it comprises a link between successive generations. The sex cells – eggs and sperm – are derived from germline precursor cells and carry exactly half of the genetic contribution that future offspring receive. Once an egg is fertilised, the next line of germ cells – the so-called primordial germ cells – emerge, and so on down the line with each subsequent generation.

A newly formed embryo, although it includes an equal genetic contribution from the mother and the father, also undergoes early epigenetic modifications . These play a very important role in driving the differentiation of embryonic cells into all the types of cells that are needed for a fully functioning organism.

Current research has shown that around day 14, a pool of 50 cells become primordial germ cells under the control of around 160 key genes. Professor Surani's research group has shown that two transcription factors in particular – SOX17 and BLIMP1 – help determine whether an early embryonic cell will become either a germ cell or a somatic cell (with SOX17 determining a germline fate).

In the 19th century, the evolutionary biologist August Weismann described how germ cells are the determinants of genetic heredity and that the 'soma' – or somatic cells – cannot 'pass back' to the organism's germ cells any of the information acquired during their lifetime.

However, with the advent of induced pluripotent stem cells and by discovering which factors drive cells into becoming primordial germ cells, it is becoming possible to turn somatic cells into germ cells, and in this case, as Professor Surani explained, 'the Weismann barrier is broken'.

In fact, Professor Surani and his collaborator Professor Jacob Hanna form the Weizmann Institute in Israel have made great progress in this field, starting from reprogrammed skin cells, which they turned into induced pluripotent stem cells and then into primordial germ cells. Using this approach they have already created both human and mouse-induced germ cells (see BioNews 785).

At the close of his talk, Professor Surani alluded to the possibility of going one step further and using CRISPR/Cas9 genome editing to cut out and replace defective genes in these skin cells before they become stem cells and then, after checking that this has worked using genome sequencing, they could then be turned into 'healthy' germ cells for reproductive purposes.

At this stage, Dr Roger Highfield, Director of External Affairs at the Science Museum, who was chairing the session, took questions from the audience. The first questioner asked how soon we might see the birth of a baby from skin cells using this approach. Professor Surani replied that he would not want to make predictions and that an in vitro system, where individual cells function as predicted, would have to come first but added that 'research is going really fast'.

He went on to give some more details of how the technique might work. First, the primordial germ cells are created in culture. Then, when they are around five to six days old they could be injected into the testes or ovaries, where they would mature into sperm or eggs. Professor Surani explained that these could be used for IVF – with embryos containing edited genes or not – but noted that 'there are still a lot of details that need to be worked out'.

Professor Surani acknowledged that there are major ethical and scientific challenges ahead in following this approach, but argued that it could offer huge gains in knowledge about the human germline.   

Another crucial question was whether extending the 14-day rule for human embryo research would help us understand more about genome editing and germline development. Professor Surani said that understanding how human epiblast cells are primed to achieve a primordial germ cell fate would make a huge difference, and that going beyond the 14-day limit would really help this research.

CRISPR/Cas9 technology will be the drive for fascinating science and new discoveries. As Professor Sir Mark Walport, the government's Chief Scientific Adviser, said later in his keynote speech to the conference, the knowledge that we will gain – along with the responsibility to prevent suffering from life-threatening conditions – means that the UK should be leading such discussions about embryo engineering.

PET would like to thank the sponsors of its conference - Merck, the Edwards and Steptoe Research Trust Fund, Ferring Pharmaceuticals, the London Women's Clinic, the Medical Research Council and Wellcome Trust.
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Parallel Germ Lines ( - 19/02/2016)
Professor Surani's comments on human germ cells are extremely interesting when one considers artificial gametogenesis.  In particular, he highlights how recent research, including his own, is breaking down an item of biological orthodoxy: the watertight separation between somatic and germ lines of cells.  It is now demonstrable that somatic cells can be coaxed into becoming gamete progenitors that give rise to viable sperm, for example.

This is obviously very interesting and has significant ethical implications.  However, it is important to distinguish these issues from the legal and ethical issues arising in relation to embryonic or gametic genome editing, discussed in my own article, "The Distracting Genome" (BioNews-8 February).  The germ line in the sense described by Professor Surani is, I respectfully submit, normally limited to the life of the individual bearing those germ cells.  By contrast, international convention and European law is concerned with the integrity of the human genome at the population level: when it speaks of the germ "line" it is not referring to those cell lines, sequestered within human individuals, that are used in sexual reproduction, but, rather, with a "line" of inheritance connecting human generations through the medium of germ cells.  It will help debate on this issue greatly if these ideas are addressed separately.

As a footnote, I would suggest that Azim Surani's comments are nevertheless relevant where artificial gametes are concerned.  For example, were the use of artificial sperm to be tolerated for reproductive purposes, a potential loophole could open up, in the sense that some might argue that no "germ" line was involved (i.e. that these are "somatic gametes") and that restriction applicable to the "germ line" (e.g. the "germ line genetic inheritance of human beings") does not apply.  To avoid such debates, it would therefore be necessary to amend the law so as to deem such artificial gametes to belong to the "germ line".  In view of the fact that debate is currently being conducted using two different meanings, individual and inter-generational, I would suggest that distinct terms are adopted by anyone seeking to unpick these issues for purposes of ethical or legal debate.

Julian Hitchcock
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