Biology subjects

Hay, B.

Publications and source records attributed to Hay, B..

5 recordsLinked to original sources

bioRxiv2025

The LAST mile: Evaluating genetic biocontrol as a supplemental tool for eradicating invasive rodents on islands

Invasive rodents cause severe ecosystem degradation on islands and can be challenging to eradicate. Current best-practices rely heavily on the application of toxic oral baits and have led to successful eradications and remarkable recoveries of native flora and fauna. Yet this single method is not universally applicable. Reliance on a single method limits further eradication success in situations where toxicants cannot be used or remnant populations persist after application. Genetic biocontrol offers a suite of new solutions to potentially improve outcomes in the critical "last mile" of eradication. These approaches involve the release of genetically modified individuals of the target species to reduce population fitness over time. These include self-limiting approaches which require multiple releases and self-sustaining mechanisms (i.e., select gene-drive systems) which could theoretically collapse populations after a single release. While gene drive systems have received significant attention, their development in vertebrates remains technically challenging, and their ecological and regulatory implications are still in active debate. In contrast, some non-drive genetic biocontrol approaches, such as Y-linked editors, fsRIDL, and Gravid Lethal, offer self-limiting alternatives that may be more immediately deployable. These approaches could be used to supplement toxicant-based methods and may also have reduced environmental risks and regulatory barriers. To evaluate the potential of these tools, we developed an individual-based model simulating the eradication of house mice (Mus musculus) on a 125ha island with an initial population of 11,000 individuals. We tested various combinations of genetic biocontrol release and effort strategies to understand tradeoffs between required effort and uncertainty for achieving successful eradication. Under certain effort strategies, we found that the Gravid Lethal approach performed the best, achieving eradication in less than 2.3 years with intensive release effort and monitoring. Our findings suggest that integrating non-drive genetic biocontrol into adaptive management frameworks could enhance the effectiveness and feasibility of rodent eradication programs. These tools are not replacements for toxicants but may serve as critical supplements--particularly in the "last mile" of eradication. Further stakeholder engagement is needed to assess the ecological, ethical, and logistical dimensions of deploying these technologies in real-world settings.

ecology↗

bioRxiv2025

Metabolic rewiring of cancer cells induces metastasis via ERK5 but triggers recognition by NK cells

Metastasis is largely controlled by Natural Killer (NK) cell-mediated immune surveillance. To colonize new environments, cancer cells undergo epithelial to mesenchymal transition (EMT), which allows them to detach and migrate. EMT is fueled by fatty acid oxidation (FAO), which partially replaces glycolytic-based tumor metabolism. Whether metabolic rewiring affects the targeting of cancer cells by NK cells remains unknown. Here, we show that forcing solid cancer cells to perform FAO by inhibiting pyruvate dehydrogenase kinase 1 with dichloroacetate (DCA) activates extracellular signal-regulated kinase-5 (ERK5), triggering EMT and tumor cell migration and invasion. Concomitantly, FAO induces the expression of ligands that mediate NK cell recognition. Consequently, NK cells better infiltrated DCA-treated 3D tumor spheroids, where they exerted their cytotoxic effects. DCA-treated cells showed increased migration in a zebrafish model, whereas metastasis from mammary cancer cells grafted into immune-deficient mice was enhanced by DCA. These migrating/metastatic cells are preferentially killed by NK cells, which strongly limit their invasive potential. Hence, FAO promotes both metastasis and NK-mediated tumor surveillance, highlighting the Achilles heel of metastatic cells, which may offer new therapeutic opportunities. TeaserMetastasis recognition and killing by immune cells, such as NK cells, requires a metabolic shift that relies on lipid metabolism.

cancer biology↗

bioRxiv2024

Allele Sails: launching traits and fates into wild populations with DNA sequence modifiers

Population-scale genome editing can be used to alter the composition or fate of wild populations. One approach to achieving these aims utilizes a synthetic gene drive element--a multi-gene cassette--to bring about an increase in the frequency of an existing allele. However, the use of gene drives is complicated by the multiple scientific, regulatory, and social issues associated with transgene persistence and gene flow. Alternatives in which transgenes are not driven could potentially avoid some of these issues. Here we propose an approach to population scale gene editing using a system we refer to as an Allele Sail. An Allele Sail consists of a genome editor (the Wind) that introduces DNA sequence edits (the Sail) at one or more sites, resulting in progeny that are viable and fertile. The editor, such as a sequence-specific nuclease, or a prime- or base-editor, is inherited in a Mendelian fashion. Meanwhile, the edits it creates experience an arithmetic, Super-Mendelian increase in frequency. We explore this system using agent-based modeling, and identify contexts in which a single, low frequency release of an editor brings edits to a very high frequency. We also identify conditions in which manipulation of sex determination can be used to bring about population suppression. Current regulatory frameworks often distinguish between transgenics as genetically modified organisms (GMOs), and their edited non-transgenic progeny as non-GMO. In this context an Allele Sail provides a path to alter traits and fates of wild populations in ways that may be considered more acceptable.

synthetic biology↗

bioRxiv2023

Cleave and Rescue gamete killers create conditions for gene drive in plants

Gene drive elements promote the spread of linked traits, even when their presence confers a fitness cost to carriers, and can be used to change the composition or fate of wild populations. Cleave and Rescue (ClvR) drive elements sit at a fixed chromosomal position and include a DNA sequence-modifying enzyme such as Cas9/gRNAs (the Cleaver/Toxin) that disrupts endogenous versions of an essential gene, and a recoded version of the essential gene resistant to cleavage (the Rescue/Antidote). ClvR spreads by creating conditions in which those lacking ClvR die because they lack functional versions of the essential gene. We demonstrate the essential features of ClvR gene drive in the plant Arabidopsis thaliana through killing of gametes that fail to inherit a ClvR that targets the essential gene YKT61, whose expression is required in male and female gametes for their survival. Resistant (uncleavable but functional) alleles, which can slow or prevent drive, were not observed. Modeling shows plant ClvRs are likely to be robust to certain failure modes and can be used to rapidly drive population modification or suppression. Possible applications in plant breeding, weed control, and conservation are discussed.

genetics↗

bioRxiv2021

Gene drive that results in addiction to a temperature sensitive version of an essential gene triggers population collapse in Drosophila

One strategy for population suppression seeks to use gene drive to spread genes that confer conditional lethality or sterility, providing a way of combining population modification with suppression. Stimuli of potential interest could be introduced by humans, such as an otherwise benign virus or chemical, or occur naturally on a seasonal basis, such as a change in temperature. Cleave and Rescue (ClvR) selfish genetic elements use Cas9 and gRNAs to disrupt endogenous versions of an essential gene, while also including a Rescue version of the essential gene resistant to disruption. ClvR spreads by creating loss-of-function alleles of the essential gene that select against those lacking it, resulting in populations in which the Rescue provides the only source of essential gene function. In consequence, if function of the Rescue, a kind of Trojan horse now omnipresent in a population, is condition-dependent, so too will be the survival of that population. To test this idea we created a ClvR in Drosophila in which Rescue activity of an essential gene, dribble, requires splicing of a temperature-sensitive intein (TS-ClvRdbe). This element spreads to transgene fixation at 23{degrees}C, but when populations now dependent on Ts-ClvRdbe are shifted to 29{degrees}C death and sterility result in a rapid population crash. These results show that conditional population elimination can be achieved. A similar logic, in which Rescue activity is conditional, could also be used in HEG-based drive, and to bring about suppression and/or killing of specific individuals in response to other stimuli.. SIGNIFICANCE STATEMENTGene drive can be used to spread traits of interest through wild populations. In some contexts the goal is to suppress or eliminate the population. In principle, one way to achieve this goal is if the trait being spread confers on carriers conditional lethality in response to an environmental stimulus that is either introduced by humans into the target area at a specific time (a virus, otherwise benign chemical; a kind of species-specific insecticide), or that occurs naturally on a seasonal basis, such as a change in temperature. Here we show that ClvR selfish elements can be used to spread a gene that confers lethality and sterility in response to increased temperature, demonstrating that conditional population elimination can be achieved.

genetics↗