September 27, 2019, by Brigitte Nerlich

The microbe/gene drive communication confusion

Last week I wrote a post about how genetic modification and/or gene drive are used when managing disease transmitting insects. I want to come back to this topic today and talk about another difference, which, yet again, confused me. I hope that these efforts of disentangling stuff also help other people trying to understand and talk about the complex issue of ‘gene drive’.

When reading up on gene drives for last week’s post, I found out something that I didn’t know before (one of many many things I don’t know!).

I read the following and became puzzled: “It may not be immediately obvious, but the gene in ‘gene drive’ need not be a gene at all – it can be a microbe. All organisms exist not just with their own genomes, but also with the genomes of all their associated microbes – the ‘hologenome.’ Spread of a microbial genome through a population by inheritance can also be thought of as gene drive. By this definition, the first gene drive that has been deployed in mosquito populations for disease control is a bacterial symbiont known as Wolbachia. Wolbachia is a bacterium that infects up to 70 percent of all known insect species, where it hijacks the insect reproduction to spread itself through the population.” (And further below you’ll find out why Wolbachia is useful to manage those insect populations that it has, so far, not hijacked)

I had heard about Wolbachia before, but always thought it was not gene drive. For example, Wolbachia bacteria are used by the World Mosquito Project (see here article by O’Neill et al., 2019; see also Flores and O’Neill, 2018), funded by the Gates Foundation, which aims to eliminate diseases transmitted by the mosquito Aedes aegyti (such as dengue and Zika, for example). By contrast, another project, Target Malaria, targets other species of mosquito and does research into gene drive together with Imperial College.

Gene drives and Wolbachia

In order to understand the link or not between Wolbachia bacteria and gene drive we need to understand gene drives and Wolbachia.

What is a gene drive? I almost want to say: Please don’t ask, as it’s quite complicated, at least to me! But: according to the Royal Society, “[g]ene drives are systems that bias the inheritance of a particular DNA sequence. They can be used to increase the persistence of an introduced trait that would otherwise disappear from a population very rapidly because the introduced trait puts the organism at a disadvantage. They can also spread a desired trait through a population. Many such systems occur naturally, and these are inspiring the development of new gene drives using synthetic biology techniques. Synthetic gene drives use genome editing technologies, such as CRISPR/Cas9, to increase the probability that a particular gene is inherited from 50% to up to 100%.”

A gene drive cheats on normal inheritance (it’s indeed a ‘selfish’ gene), as it “can copy-and-paste a specific DNA sequence from the chromosome carrying it to the other chromosome, ensuring it is always passed to the offspring. Over multiple generations, the gene rapidly spreads through a population” (see here).

A gene drive sort of hacks the gene and stacks the odds in favour of a certain outcome. (For a slightly longer and more user-friendly explanation of gene drive, consult the Genetics Unzipped podcast here).

What is Wolbachia? Here is a good video. And a blogger, talking about this topic in the context of the World Mosquito Project, summarises nicely how Wolbachia works:

Wolbachia is a genus of Gram-negative endosymbiotic bacteria that is naturally present in many insects, such as in the fruitfly Drosophila melanogaster. However, it is absent from Aedes aegypti (the yellow fever mosquito) and some other medically important mosquito species. Experimental infection of mosquitoes with this bacteria [sic] have been demonstrated to have multiple effects. One of the traits of Wolbachia is a gene drive-like attribute, called cytoplasmic incompatibility, where uninfected female mosquitoes that mate with infected male mosquitoes will not produce any offspring from the mating (italics added). Given that Aedes aegypti typically only uses the semen of the first male it mates with, that sterilization has a large effect on fecundity, and consequently mosquito population numbers. This attribute is utilized by the company MosquitoMate to control invasive Aedes albopictus in the US. Cytoplasmic incompatibility is beneficial for the spread of Wolbachia because infected females can successfully reproduce, even if they mate with infected male mosquitoes, providing a relative fitness benefit to infected mosquitoes, driving Wolbachia through the population. However, there is a slight fitness cost associated with the infection itself, which keeps the bacterium from completely infecting every individual in the population.”

So, the bacterium is ‘driven’ through a population, but not by hacking into the mechanism of genetic inheritance, as a gene drive does, as far as I can make out. Hence, this process has ‘gene drive-like’ properties, but is not really a gene drive.

A very recent article (Jones et al., 2019) on public attitudes to gene drives in agriculture in the US puts Wolbachia and gene drives into historical context and points out:

“Strategies involving mass release of modified insects for area-wide pest management have a long history and extend well beyond gene drives. Some of these technologies have historically been deployed in agriculture without much public attention. For example, mass release of radiation-sterilized insects has occurred for over 60 years to disrupt mating and suppress certain pest populations. Analogous approaches using genetic engineering include self-limiting conditional, dominant lethal systems such as RIDL [Release of Insects carrying a Dominant Lethal, BN], or, more recently, the demonstration of a CRISPR-based precision-guided sexing and sterility system. Modern biological control methods are also being pursued, notably the use of Wolbachia bacterial infections to bias reproduction in suppression or replacement strategies. Like gene drives, Wolbachia-based approaches have the potential for self-sustaining spread (at least within a local area) but, unlike gene drives, do not use genetic engineering. This latter feature has been portrayed as an advantage by proponents, who have described it as a ‘natural’ method for insect control.” (Italics added) (Note the word ‘lethal’, highlighted in my previous post, turns out to be a jargon term)

Questions for science/gene drive communication

So, Wolbachia-based insect control is on the one hand grounded in something ‘natural’, while on the other hand the self-sustaining spread through an insect population is ‘like’ a gene drive which can be seen as ‘unnatural’, I suppose, as it’s based on genetic engineering (which, however, can be inspired by and exploit natural processes….).

How should we then talk about gene drive and gene drive-like ways of managing disease transmitting insect populations (and other creatures, even mammals)? Do we say one is more natural or less natural than the other, and if so, on what grounds?

We also have to ask ourselves whether to say that Wolbachia is a gene drive, albeit a microbial one, or that it only acts like a gene drive, or better leave the phrase ‘gene drive’ out altogether…

And again, as in the last post, one has to ask, what do we have to know before we decide what type of intervention to use? Do we need an understanding of cells, genes, Mendelian inheritance, evolution, probability, ecology, genetic engineering, synthetic biology, CRISPR – some of these or all of the above? I really don’t know!

Image: Wolbachia, Wikimedia Commons

Posted in GMOsScienceScience Communicationsynthetic biology