A certain ratio

CRISPR has become the go-to tool for gene editing in biological research, the development of biotechnology products and the treatment of diseases. While it gives high hopes for radical new medical treatments, some of the potential uses we may put it to have taken on an air of controversy.

A recent paper claims to demonstrate that CRISPR/Cas 9 editing can be used to bias the sex ratio in mammals. If it were extended for larger mammals it could have seismic effects on the economics of animal husbandry and agriculture.

The research was carried out by a team at the Sackler School of Medicine in Tel Aviv, with funding partly from by the European Research Council. The fact is has not drawn greater international attention is surprising.

The team under Dr IdoYosef and Professor Udi Qimron, say they have used a CRISPR technique on strains of mice to successfully bias the gender towards the female line.

The paper, ‘A genetic system for biasing the sex ratio in mice’ was published in August 2019 by the German based EMPO Reports and it appears to have slipped under the radar despite receiving some coverage in GEN Magazine.

Gender control

Yosef and his group outline work which appears to demonstrate for the first time in mammals that gender control with CRISPR Cas 9 editing protein is feasible.

They say the implications of the work in terms of farming and agricultural economics could be enormous ­– Yosef and two members of the team applied for a provisional patent in early January 2018, quite some time before their paper was approved for publication.

The paper claims proof of concept that the gender of a mammal can be genetically tilted one way – in this case towards the females.

The group describe how they created two genetically edited mouse lines and in the case of the maternal line, encoded a functional Cas9 protein on an autosomal chromosome. The paternal line was encoded with guide RNAs on the Y chromosome in such a way that they target three vital and specific genes (Atp5b, Cdc20 and Casp8) in the male line.

After fertilisation, the presence of both the ‘Y’ encoded guide RNAs from the paternal sperm and the Cas9 protein from the maternal egg was detected and with some deft experimental work proved that Cas9 from the maternal egg did target the genes vital to male embryo development.

The trend according to the paper was for the male embryos to self-destruct.

Professor Qimron said: “To date, there has been no accessible genetic way to regulate the sex ratio, which in nature is balanced at 50:50.”

“Our results pave the way for a genetic system that allows biased sex production of livestock’

Drawbacks?
There are some drawbacks though. A small percentage of males were actually born with defects so such a system cannot be approved in its present form. A more robust elimination system which kills all males in utero would need to be applied.

The work will attract interest in the farming industry where gender control in the dairy sector and the poultry industry might be desirable for efficiency and value.

It was also pointed out at the paper’s peer review stage, that any offspring produced this way would be gene modified, with all the complex legal and regulatory implications it implies.¹

In the past techniques, such as the sorting of sperm, have been used to bias sex selection, but there have not been any convenient genetic approaches.

However, the prevailing winds of genetic research suggests this is set to change. Indeed this is not the first time CRISPR has been considered as a mechanism for manipulating the gender balance in mammals.

In Australia, where they have serious pest control problems with rabbits and mice, they have studied the possibility of CRISPR gene modification to eradicate the problem.

A detailed look at the method and unforeseen problems it might create, was published in Proceedings of The Royal Society B in 2017.² They used an in-silico study to examine the effects and consequences of gender biasing in a large wild population.

The authors found that indeed, this system could be used to achieve eradication of ‘realistic’ pest population sizes. That term, ‘realistic’ population size, is a nod to the notion that population scale genetic modifications are most safely used on islands. This, the authors explain, is to minimise the risks associated with the unplanned dispersal or transport of modified genes. A happy coincidence of this important consideration is that invasive alien vertebrates are one of the major threats to island biodiversity and exotic rodents are likely responsible for the greatest number of extinctions and ecosystem changes on islands.

Ethical dilemma

From an economic point of view, the proposed applications from the Tel Aviv group may seem acceptable, and possibly even desirable in terms of animal welfare.

Although the system should also work for the economics of husbanding larger mammals, there is, as it were, an elephant in the room. If it works in ‘larger mammals’, then it could – could – work in humans. So, dare we extrapolate? If so, then the debate naturally moves to how, why and when we use it on ourselves – if we should at all. 

Even on an individual level this feels problematic. Could it, for example, create a ‘market’ in which parents will demand the choice in selecting the gender of their child? Add to that concerns of gender selection on a community or population level and the ethics of this definitely becomes troublesome.

Author

Dermot Martin is a freelance science writer

References

1. https://www.embopress.org/action/downloadSupplement?doi=10.15252/embr.201948269&file=embr201948269.reviewer_comments.pdf

2. https://royalsocietypublishing.org/doi/10.1098/rspb.2017.0799