February 8, 2019, by Brigitte Nerlich
Mice, dice and copycats: Metaphors for gene drives in mammals
When you hear the word ‘gene drive’, you will either be baffled or you will think about mosquitoes, engineered to eradicate insect-born disease like malaria, Dengue fever, or Zika for example. But gene drive research has now moved from insects to mammals.
On the 23rd of January, researchers at University of California, San Diego, led by Kimberly Cooper, announced that they had developed a method for controlling inheritance in mice using the gene-editing tool CRISPR Cas9.
Such a method, generally called ‘gene drive’, had, so far, only been demonstrated in insects, not mammals. Hannah A. Grunwald, Valentino M. Gantz, Gunnar Poplawski, Xiang-ru S. Xu, Ethan Bier, and Kimberly L. Cooper, published their paper on ‘Supermendelian inheritance’ in Nature on the 23rd. Two press releases were issued on that day, one by UC San Diego (UCSD) (which was used widely, e.g. by Science Daily), and another syndicated by the Press Association.
Grant Jacobs, a computational biologist and science communicator, published a blog post the following day, which is worth a read, as it provides a clear and detailed explanation of this achievement. He explains: “A gene drive is the informal name given to a process where a genetic variation is set up so that it will be inherited more often in the offspring than it would by chance. In a gene drive each generation has a better than 50% chance of inheriting the new variant, so over time the chosen variant becomes the dominant variant of that gene in the population.” Jacobs goes on to tease out what the new research demonstrates and does not demonstrate, what it has achieved and what its limitations are.
Another good overview of the background to this research can be found in a Nature News article published on 6 July 2018, together with a Science article from 13 July 2018. These articles appeared at the time of the submission of a pre-peer-reviewed version of the paper on the preprint server bioRxiv.
Mice and models
The Science article summarises the research as follows: “The team from the University of California, San Diego, used the genome editor CRISPR to put a gene in the mice that modifies their coat colors. But they also engineered these same mice to pass on the genes that create CRISPR itself so that progeny edit their own genomes to carry the coat color–modifying gene. When they mated an engineered mouse to a normal one, it should have created a pup with the coat color–modifying gene in one of two chromosomes. But because the pup also inherited CRISPR, it altered the unmodified chromosome passed down from the normal parent so that it, too, had the gene.”
The scientists did not set out to find a way of eradicating diseases or pests, in this case rodents, but to demonstrate ways in which gene drives can be used to bias inheritance in order to “transform the use of rodent models in basic and biomedical research” (Nature article), to “make mammals models of complex human genetic diseases, like arthritis and cancer, that are not currently possible” (Press Association, 23, January), to control “the inheritance of multiple genes in mice” (Cooper quoted in City News Service, 23 January), and even to understand “the mechanisms of evolution” (UCSD, Press release, 23 January) and of the ”origins of mammalian diversity” (ibid.).
As a secondary outcome it my “decrease the time, cost and number of animals needed to advance biomedical research on human diseases and to understand other types of complex genetic traits” (ibid.).
How was this new research reported after the official publication? To see what is out there, I consulted the news database Nexis and downloaded all articles published in English Language News between 23 and 28 January. After removing duplicates, there were, astonishingly only nine items left, and of these only four were published in mainstream newspapers, of which Ian Sample’s article for The Guardian was the most interesting. One article by Cooper herself appeared in The Conversation on the 24th of January (republished in MENA English, Middle East and North Africa Financial Network). Others mainly reproduced what the two press releases (UCSD and Press Association) had said.
In this blog post I’ll pick out a few metaphors used in this coverage, but I will not cover ethical legal and social aspects in any detail. This will have to wait for a bigger and more detailed study.
Loading dice and flipping coins
The first two words of the Nature title, “Super-Mendelian inheritance mediated by CRISPR–Cas9 in the female mouse germline”, are already slightly metaphorical or rather hyperbolic and point to a nexus of metaphors explicating how inheritance works and is reworked in gene drives. The phrase ‘supermendelian inheritance’ had previously been employed to report on research on gene drives in mosquitoes.
One of the most used phrases (see Press Association, 23 January) was that of ‘increasing the odds’. This was in the context of using a specially designed gene drive to increase the chance of mouse offspring to inherit two copies of a mutation causing them to be born with white instead of black fur. But how does this work? To understand this, we have to go back to the beginnings of genetics.
The Press Association article explains: “Under normal circumstances, genes come in pairs, on inherited from each parent. Gregor Mendel, the ‘Father of Genetics’, discovered this fundamental principle of heredity in the 19th century as he experimented with pea plants. It means an offspring has an equal chance of inheriting a particular genetic variation, or mutation, form either its mother or father. A gene drive loads the dice, making it more likely that the offspring will be born with a chosen trait, such as fur colour.”
In her Conversation article, Cooper has provided one of the most detailed explanations of this type of inheritance . Here she talks about ‘uber-inheritance’, which ‘boosts the odds’ of a trait or several being inherited. To explain things, she uses the analogy of flipping or tossing a coin: “Each animal has two versions of each gene. Each parent will pass only one version to each offspring. Inheritance of different genetic traits is therefore a bit like a coin toss where a particular version is inherited 50 percent of the time.” This gets us to the uber- or supermendelian aspect of the research:
“Creating a mouse that inherited mutated versions of three disease-causing genes from each parent has the same likelihood as six simultaneously flipped coins all landing on ‘heads.’ But what if the coins could be unevenly weighted so that they have a higher probability of falling heads up?
The concept of stacking the odds in favor of one of the two versions of a gene underlies efforts to engineer gene drives. A gene drive is simply defined as a piece of DNA that is inherited more often than can be explained by random chance over several generations so that it sweeps through a population.”
Surprisingly, none of the articles on gene drive in mice used card analogies instead of dice or coin ones, despite the fact that card games can be used quite successfully to explain Mendelian inheritance – some people even talk about the card game of life!
Scissors and pens
To make their gene drive work, the Californian team used a now ubiquitous tool, namely a gene-editing tool called Crispr/Cas9. As quite a few articles said: “the system relies on ‘molecular scissors’ to make highly precise changes to DNA.” (Press Association, 23 January; The Conversation, 24 January)
One article in The Guardian was entitled “Scientists rewrite mice DNA so genes can be spread through species” – echoing older synthetic biology metaphors of rewriting the book of life. The article also puts this new research in the context of existing gene drive research using insects, where gene drives are used for “rewriting the genetic makeup of mosquitoes that carry the malaria parasite” (Ian Sample, 23 January).
Now we come to the special way in the researchers used gene-editing and to the fun name they chose for the molecular element that was employed. It was called ‘CopyCat’. This “was spliced into the gene for an enzyme controlling fur colour. Gene editing allowed CopyCat inserted into one copy of the inherited gene to be duplicated in the other during egg production in females. This increased the chances of CopyCat being passed on to the next generation.” (Press Association, 23 January)
In another article, CopyCat is called a “self-replicating DNA sequence” (UPI.com, 24 January). It was said to be “copying and pasting the same genetic coding from one chromosome to the other”. The article goes into more detail about the various mechanisms involved.
Donors and recipients
Crispr and CopyCat are used, it seems, between donor genes and recipient or target genes. As Cooper explains in The Conversation: “In a gene drive, a donor gene, which is the version we want to introduce into the animal, is engineered to use these components so that it can replace the non-engineered version, or the so-called recipient gene. When the non-engineered recipient gene is cut, the donor gene repairs the cut by copying itself into the recipient site so that there are two identical copies of the donor gene.
The donor gene therefore acts like the find and replace feature of a word processing program. The recipient gene is converted so that a mosquito, for example, would have two copies of the engineered donor gene to pass to its offspring.”
In the context of the new research, it turned out that the “donor gene was inherited as much as 86 percent of the time – a heavily weighted coin – compared to just the usual 50 percent.” This was relatively low though and only worked in females.
Selfish genes and cheating gene drives
Some articles also employ more creative metaphors. “Gene drives are pieces of DNA that cheat. They ‘copy and paste’ themselves from one genome copy to a target sequence in the other copy.” (New Scientist, 23 January).
This article also tells readers that some people call gene drives ‘active genetics’ (see also Scientific American). The term was apparently coined by two of Cooper’s colleagues, Valentino Gantz and Ethan Bier (see Scientific American, 28 January).
Such active gene drives are not only ‘super’ or ‘uber’, they are also selfish. As a Nature News article said: “Gene drives work by ensuring that a higher proportion of an organism’s offspring inherit a certain ‘selfish’ gene than would happen by chance, allowing a mutation or foreign gene to spread quickly through a population.” (6 July, 2018). I am starting to wonder whether there will ever by selfish self-driving gene drives…
Mice and ice-nine
The Scientific American article also quotes a scientist who framed gene drives more in scifi terms: “Fred Gould, an entomologist and evolutionary biologist at North Carolina State University, likens gene drives to the fictional substance ice-nine in Kurt Vonnegut’s novel Cat’s Cradle: a bizarre form of ice that freezes all other water it touches. Gene drives spread fast because they are sets of genetic elements that spontaneously copy themselves from a maternal chromosome to a matching paternal one or vice versa. In the process of copying itself, the gene drive can also add, delete or modify genes at its insertion point.”
Death and destruction
One short article published in The Times on the 24th of January, focuses on the possibility of using gene drives to eradicate disease carrying insects or invasive mammal species. It uses words like ‘wipe out’, ‘erase’, or ‘wreck’ (ecosystems). Such war metaphors were otherwise absent from the coverage of this particular research into mice, but are widely used when dealing with gene drives and insects.
Possibilities and responsibilities
However they framed it, most articles called this research ‘controversial’. It changes the ‘germline’ of mammals and one therefore has to proceed with extreme care, as this can “alter entire species” (Press Association, 23 January) and can lead to “unintended consequences” (ibid.).
Researchers and commentators alike expressed a need for caution, with everybody treading a fine line between excitement and restraint. One comment reported in the Financial Times summarises this quite well: “Bruce Whitelaw, professor of animal biotechnology at Edinburgh’s Roslin Institute who has also investigated gene drives in mice, said the UCSD project was ‘important as it both demonstrates mammalian gene drive for the first time and starts to clarify the aspects and limitations of the process’. He added: ‘The authors correctly state how this approach could make a huge positive . . . impact for laboratory animal use while pointing the way to the still far-off but feasible application in wild animals.’”
Scientific American pointed out: “For at least some time to come, these kinds of ‘active genetics’ technologies may be more useful as laboratory tools than as instruments for remaking nature.”
This means keeping, at present, an eye on ethics and responsibility in the context of labs and lab animal use, while also scanning ethical horizons for potential dangers ahead, especially with regard to using gene drives ‘in the wild’.
At the same time, it is also important to keep an eye on the language used, which, at the moment, seems to be quite restrained, mostly using metaphors for explanation not hype.