What is a gene drive?

As part of its $50 million mouse control package, announced in May, the NSW Government yesterday committed $1.8 million to “breakthrough genetic biocontrol research” – a three-year program to identify “fast-acting gene drives”. What does that mean?

Sometimes a population of animals becomes problematically large, leading to rampant disease or plague: reference the current mouse plague. One way of curbing the population is to use genetic technology, such as a gene drive.

A gene drive is a process that pushes certain genes to be inherited in populations when two organisms breed.

There are different types of gene drives, but all of them are aimed at either decreasing a population, or removing unfavourable genes from a population.

How do animals normally inherit genes?

Like humans, most animals inherit half their chromosomes from their father and the other half from their mother. Each chromosome carries alleles, which is a form of a gene that’s responsible for making a protein. These proteins are what shape our physical traits.

When we inherit two chromosomes, we get two alleles, as well. Together, these two gene forms determine our characteristics, or phenotype. Sometimes the alleles will make the exact same protein and other times they make slightly different proteins – this is why we can have dominant and recessive traits, because two different proteins are trying to determine our characteristics.

Sometimes, if there are two alleles, one can ‘rescue’ the other if it isn’t working properly, by making enough useful proteins.

Confusingly, we often talk about a gene as the pair of alleles together, but technically you can have one, two or even more alleles, depending on how many chromosomes there are, and it’s still colloquially called a gene.

Our parents also have two alleles, but only pass one on to us, which means we have a 50% chance of inheriting either of their alleles. The ratios of characteristics are a bit different, though, because we need to consider both of the alleles together. This is called “Mendelian inheritance”.

Gene drives are designed to disrupt these relatively balanced ratios and make one gene or allele over- or under- represented.

Using a gene drive to push sterility

This isn’t novel science.

Sterile fruit flies were released in South Australia to help decrease damaging fruit fly populations, and sterile mozzies have been tested as a control against malaria.

As a starting point, let’s look at the basics of how sex determination works.

In the same way as humans, many animals determine biological sex broadly with X and Y chromosomes (there are lots of exceptions to this, but we’ll stick with this form, or it gets pretty complex).

In general, two X chromosomes (XX) determines a female and X and Y (XY) chromosomes determine a male. Females produce eggs, which always carry an X chromosome, and males produce sperm, which can be an X or a Y. That means the father is ‘responsible’ for sex determination – there’s a 50% chance either way.

But X and Y chromosomes don’t look the same. In fact, the Y chromosome is much smaller than the X, which means it technically carries less genetic information, and you won’t always get two alleles in a group.

For example, alleles carried on the X chromosomes might only have a pair if they are matched with another X chromosome, and not a Y. In the latter case, there might only be one allele determining our characteristics, or one allele might ‘override’ other genes. This is why males and females develop differently.

This makes them an excellent target for genetic modification that affects only one sex.

In the case of a gene drive, you could make small changes to one of the chromosomes in order to make the organism sterile – and you could choose whether this happens to the male or the female.

Female sterility

The NSW Government’s investment is fast-tracking a gene drive technology that will cause female mice to be infertile. This characteristic would spread through mice breeding with each other – except only some of them can breed, so those population inheritance ratios get mucked up.

“So effectively it just uses the natural mating processes to spread a gene though a population that will cause what we are trying to cause, [which is] female [mouse] infertility,” says Professor Paul Thomas of the University of Adelaide, who will lead the research.

“We have modelled it already and that should cause the population to crash over time.

“This boost of funding will enable us to move much faster on these projects.”

That means the genes they are investigating will only affect alleles on X chromosomes – more specifically, the alleles on the X chromosome that determine female development, which aren’t found on the Y chromosomes. Males are still able to develop, thanks to their normal Ys, but females don’t become fertile in the same way because of the altered genes.

For each succeeding generation, a portion of the female mice won’t be able to produce more babies, and each generation will see the population decrease.

Another way the research team might achieve female sterility is to change genes in male mice that seek out and destroy sperm with X chromosomes. This method is called “X-shredder”.

Both methods shift the population away from 50% males to females.

These are still relatively early days, though.

“The funding will enable us to test each of these strategies and come up with the one that we think is the most promising, that we can then take forward to the next level of testing,” says Thomas.

How is the gene changed?

This can happen in two ways: selective breeding or gene modification. Selective breeding is laborious and random, so many gene drives are started by editing a gene directly – that way there are no off-target mutations that change other characteristics. It’s even harder to do when you are trying to get sterility genes in the population.

But a popular method of achieving the gene drive is through use of CRISPR technology. This is a very precise way of specifically targeting and altering an allele – for context, it can target just 20 units of DNA out of the 2.5 billion units that mice have.

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What is CRISPR?

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The CRISPR mechanisms search the genome of the organism for target alleles – in this case, ones that affect female development. When found, the allele is altered. In males, this would only target one allele – the one on the X chromosomes.

However, in the female offspring they have, the process can happen again, in real time, instead of in a lab. Because of this, both X chromosomes will be altered, and no proteins can be made that help the female develop properly. This can happen generation after generation.

Using CRISPR technology and older methods of gene editing on an organism means that it’s classed as a genetically modified organism in Australia. Some people can feel worried about this type of biotechnology. It’s always important to weigh up the risks.

Mitigating risk

Great caution should always be taken when implementing population-control methods, because things can get out of hand without a proper understanding of how a changed population will affect the ecosystem.

“We know bio-controls can go incredibly well, but then other experiments – like the introduction of cane toads – can be pretty bad,” says Andrew Cox, CEO of the Invasive Species Council.

“The risk is that we could create an even worse type of rodent, so there needs to be a lot of caution around this.

“Given all the unknowns it’s important that a lot of research goes into this.”

One way of making the best predictions is to use mathematical models to determine the many possible outcomes. Massive mouse plagues are still damaging, so both sides need to be considered.

“It’s about solving a problem that can often seem insurmountable,” says Cox. “Everyone’s suffering the latest mouse plague, but we know there’ll be another one in years to come.

“Doing nothing creates environmental, social and economic impacts, and while everything has a risk, are the upsides worth the potential negative consequences?”