Research Ideas and Outcomes :
Research Idea
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Corresponding author: Vixey Foxwish Douglas (fox@vixeyfoxwishdouglas.com)
Academic editor: Editorial Secretary
Received: 07 Aug 2024 | Accepted: 11 Dec 2024 | Published: 19 Dec 2024
© 2024 Vixey Douglas
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Douglas V (2024) North American red fox rabies immunity gene drive for safer (sub)urban rewilding. Research Ideas and Outcomes 10: e134189. https://doi.org/10.3897/rio.10.e134189
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Animal-transmitted diseases such as rabies represent a barrier to successful rewilding and threaten continued human-wildlife co-existence. In North America, population growth and human settlement expansion lead to encounters with wild mammals which have the potential to transmit rabies to domestic dogs and humans. The recent development of gene drives mediated by CRISPR-Cas9 allows for ecosystem engineering at unprecedented scales given the potential to spread new traits through wild populations with biased inheritance exceeding the pattern of classical Mendelian dominant genes. This study of a possible red fox rabies immunity gene drive project contributes a novel proposal to the existing academic conversation about suitable applications of gene drive technology in wild animal populations, such as projects to fight malaria and Lyme disease. Noting the unique characteristics of rabies, such as the dire mortality rate in humans once symptoms arise, as well as the tendency for rabid wild animals to lose their fear of humans, it appears to be a suitable target for eventual eradication via gene drive to spread immunity through wild mammal reservoir populations. Introducing heritable rabies immunity into North American red fox populations through gene drive represents a strategy to both battle rabies and adjust the ecology of (sub)urban environments. Given this review of the project's possible implementation and expected outcomes, providing inherited rabies immunity to wild red fox populations in North America via gene drive appears both feasible and sensible. Similar projects may be used to eradicate comparable infectious diseases from other wild animal populations, with likely benefits to human patients, wildlife and ecosystems.
policy development, gene drive, CRISPR, wildlife management, rewilding, human dimensions, species interactions, urban ecology, evolutionary biology, zoonotic disease, rabies, mammals, red foxes, co-evolution, predator-prey interactions, veterinary medicine, biomedical engineering
Rewilding explores new ways in which flourishing wildlife populations can co-exist with human civilisation, yet the risk of zoonotic disease transmission represents a barrier to successful rewilding projects. Gene drive has the potential to eradicate perilous zoonotic diseases, such as rabies or Lyme disease, in their wild animal reservoir populations. Targeting rabies in North American red foxes may be a suitable pilot project of this nature.
This paper explores the use of gene drive to combat zoonotic disease by evaluating detailed methods and possible downstream benefits of providing heritable rabies immunity to wild red fox populations in North America.
Rewilding represents the attempt to discover new ways in which human civilisation and wildlife can amicably co-exist. As human population growth in North America combines with preferences for low-density housing to expand the geographic area covered by cities and suburbs, wildlife biologists can seek ways in which wild mammals can thrive amid human settlement in order to prevent habitat loss as landscapes change. In her work Rambunctious Garden: Saving Nature in a Post-Wild World, Emma Marris cautions against limiting the definition of nature to ‘pristine wilderness’ to avoid an outcome where ‘urban, suburban and rural citizens believe there is no nature where they live; that is it far away and not their concern. They can lose the ability to have spiritual and aesthetic experiences in more humble natural settings.’ She urges readers to encompass ‘human-dominated lands’ within the societal view of nature, ‘making the most of every scrap of land’ (
Urban and suburban parks, landscaped neighbourhoods and gardens that provide sustenance for small herbivores, such as rodents and rabbits, represent possible artificial ecosystems that could support mesocarnivore predators in the absence of severe human-wildlife conflict in the rabies-free United Kingdom (
A modified, non-natural world with less suffering is already the generally preferred outcome in human society, as demonstrated by the presence of healthcare systems and the general rejection of Social Darwinism in humans. The emerging ideology of compassionate conservation may soon extend significant consideration to the well-being of non-human animals, i.e. ‘all harms to wild animals should be minimised wherever and to the extent possible’ in wildlife biology research projects (
If failing to save a drowning child when we could have done so makes us responsible for that child’s death, then acquiring the ability to mitigate animal suffering renders us morally responsible if we choose not to. […]. Three weeks ago I rescued a limping stray cat. Had she not received care and antibiotics, she would likely have lost the ability to hunt and slowly starved due to her badly infected wound. How is that stray cat different from an ocelot cub stricken with a screwworm infection, which is unimaginably more painful? We didn’t deliberately create either, but we can do something about the stray cat, but cannot aid the ocelot. Of course, that will not be true for much longer: we eradicated the screwworm from North America with sterile insect technique, and with gene drive could do the same for South America. Should we? […] since we are now developing the power to intervene, it becomes a moral issue where previously it was not (
Assisted colonisation, ecological replacement, biocontrol, gene drives and veterinary medicine as applied to wildlife populations represent emerging, sometimes conflicting approaches that reshape the suite of available choices by which civilisation can interface with the natural world. This research proposal explores the hypothetical use of gene drive technology in North American red foxes to provide heritable, population-wide rabies immunity, such that wild red foxes would no longer serve as a reservoir of the rabies virus and would present no risk of rabies transmission to other species. With examples of human-red fox co-existence in situations where there is no risk of rabies transmission, the rabies-free islands of the United Kingdom and Japan are examined as test cases of what rewilding outcomes could be possible in a post-rabies North America (
This theoretical study explores existing literature while also contributing original ideas to advance this field of study. For such a transformative biotechnology as gene drive, academic research necessarily precedes field tests of the intervention. A review of existing strategies to counter rabies revealed various shortcomings of extant methods used to fight this virus. Given recent developments in gene drive research proposals, further study of the situation of red fox rabies carriers in North America suggested that it could be beneficial to use gene drive to provide North American red foxes with heritable immunity to rabies as a pilot project towards eventual continent-wide or global rabies eradication via immunising other wildlife reservoirs similarly. Downstream ecological consequences of the intervention were also assessed by researching red fox diet and interactions with other species in complex food web relationships. Here, we consider the possibility of a gene drive for heritable rabies immunity in North American red foxes and propose that it may be highly beneficial.
Rabies represents a dire threat to the health and safety of wild animals and humans wherever these populations co-exist. The neurotropic rabies virus (family Rhabdoviridae, genus Lyssavirus) is notorious for the near 100% fatality rate in humans once symptoms occur, such that prevention of transmission is strongly preferred, as post-exposure prophylactic treatment may be inaccessible or fail to save a patient (
The rabies virus presents a key barrier to the rewilding of urban and suburban communities with wild mammals (birds, fish, reptiles and amphibians do not carry rabies; all mammals are susceptible) in that rabies symptoms include aggression, staggering and behavioural changes, for example, ‘Rabid wild animals may lose their natural fear of humans, and display unusual behavior [...] an animal that is usually only seen at night may be seen wandering in the daytime’ (
Seeing nocturnal animals during the day has been known for years to be a surefire way of telling whether or not an animal is rabid and, therefore, infected with rabies. In this day and age, however, it is not unusual to see a great number of nocturnal animals out and about during the daylight hours. In some ways, it’s a kind of evolution. They have learned to stay awake at the best times to find food. Humans mean food [...] you will find nuisance wildlife and scavengers. These animals are doing whatever they need to do in order to survive (
Unless rabies eradication is achieved, any rewilding of urban and suburban areas with wild mammals can only be expected to increase human-wildlife conflict and humans’ fears of encountering rabid wild mammals.
In continental Europe, efforts to vaccinate domestic dogs against rabies, while allowing red foxes to persist as a confirmed rabies reservoir, suggest that human rabies cases are ultimately the result of wild canids transmitting the virus to domestic dogs who then infect humans, given that people with presumed rabies exposure had seldom been directly exposed to foxes (
In high biodiversity areas, distribution of bait laden with live rabies vaccine intended for consumption by wildlife presents unexpected risks, as a set dosage that protects one species, jackals, may induce rabies in another, such as baboons (
While a gene drive in North American red foxes to confer heritable rabies immunity is a radical idea, the Latin root word radix, a root, is the etymological origin of the word ‘radical’ applied as a modern pejorative (
Red foxes immunised against rabies via gene drive would not necessarily be any less red fox by nature. A genomic region encoding antibodies to the rabies virus could conceivably be isolated from a red fox with acquired immunity such that there would be no transfer of DNA across species aside from the introduction of the CRISPR-based gene drive system. Beyond such a bespoke approach, proof-of-concept research exists on the expression of functional human antibodies within transgenic research animals such as mice, rats, rabbits, chickens and cows (
The gene drive against zoonotic disease concept is explained by researcher Kevin Esvelt with respect to a similar proposal to modify white-footed mice on Nantucket with antibodies to confer resistance to Lyme disease in order to reduce transmission to humans via ticks, using mouse DNA from Lyme-resistant mice: ‘Our idea is since most ticks are infected by white-footed mice, if we could immunize the mice, then you would break the cycle of transmission. Ticks would no longer be infected. People wouldn’t get disease’ (
An engineered gene drive involving CRISPR-Cas9 components would qualify as an artificial instance of the widespread natural phenomenon known as horizontal gene transfer, in which genetic material is moved across lineages rather than solely from parents to offspring (
In terms of research methodology, the red fox rabies immunity gene drive proposal may work as follows: first, it is already routine practice that North American red fox ambassador animals approved by the USDA are administered the rabies vaccine tested and approved in domestic dogs (
Captive-raised young red foxes have been released into wild populations via ‘soft release’ strategies in which they have the option of relying on humans for food or gradually adapting to hunting and foraging on their own (
Red Fox Rabies Immunity Inheritance featuring Mendelian Dominance in the absence of Gene Drive. This figure shows patterns of heritable immunity without the use of gene drive to accelerate spread through a wild population. Labels refer to P: parental, F1: first filial and F2: second filial generations. I: immunity allele, w: wild-type allele.
Red Fox Rabies Immunity Inheritance featuring Gene Drive to go beyond the Mendelian Dominance baseline pattern. This figure shows patterns of heritable immunity with the use of gene drive to accelerate spread through a wild population. Labels refer to P: parental, F1: first filial and F2: second filial generations. D: gene drive allele, w: wild-type allele. n.b.: germline cells may be homozygous DD giving rise to only D-carrying gametes in drive-carrying individuals with Dw (not shown) somatic cells.
Beyond the aforementioned considerations, it is also important to address the question of whether this project could be achieved prior to substantial further discoveries and upgrades concerning gene drive technology. Numerous technical barriers exist that would have to be decisively surmounted for this project to make its way out of literature and into the real world. For instance, random mutations may occur that end up disabling the resulting single guide RNA necessary to target the Cas9 machinery to the suitable spot when making a second copy of the desired rabies antibody gene and CRISPR-Cas9 system. The system might induce genetic editing at originally untargeted locations due to an sgRNA mutation that led to reaching a new sequence instead. Engaging in double-strand DNA breaks and calling DNA repair machinery to the right spot in the genome may incur a fitness cost for an animal that might not even encounter the rabies virus in its particular lifetime. Across enough instances of this situation, a new mutant allele that sufficed to disable the gene drive system might find its way to the forefront of the genetics of a population. Strategies, such as guide RNA multiplexing, a haplolethal homing drive and so forth, may help reduce the formation and effects of resistance alleles, though these existing approaches may not suffice to clear all hurdles that could arise in complex mammals, such as red foxes (
Regarding the timeline for this project from an initial release of gene drive carriers to the widespread permeation of heritable rabies immunity throughout wild red fox populations, it is important to recall that gene drives work more quickly in species with shorter generation times. Though the exact months involved vary by latitude and climate, red foxes mate in late winter and give birth, 52-53 days later in early spring, to litters that average four or five kits (
Before making persistent genetic changes in populations of wild mammals that act as reservoirs for the rabies virus, it may be judicious with respect to public opinion and research feasibility to act first in a domestic animal species whose genetic material could be manipulated as an advance trial for this proposed intervention. In particular, since most human deaths caused by rabies globally occur due to contact with dogs, a project to develop a gene drive for heritable rabies immunity in domestic dogs would have immense export value while also potentially providing a source of well-characterised antibodies for use in transgenic red foxes for the North American first trial project in the wild, based on existing prior research into similar endeavours (
While rabies exacts its deadliest human toll via transmission from wild dogs in India, cultural and economic barriers suggest that this is not the ideal place for western scientists to trial a radical new technology for the first time (
In the rabies-free United Kingdom per
Both town and country foxes will have what is described as a ‘flight distance’: a distance that the wild fox will put between itself and you, in the knowledge that if you were to become hostile it would have enough space to get away. In the countryside, the flight distance may be a couple of fields, whilst in an urban setting only ten feet or so, for the urban fox seems more able to live in a closer proximity with man; perhaps […] urban foxes are persecuted to a lesser degree than rural ones (
As the absence of rabies allows United Kingdom red foxes to colonise backyard gardens and city parks in daylight without inducing humans’ fear of a rabid wild mammal, research indicates food deliberately supplied by householders was 60% of the red fox diet by volume in Bristol and weekly human-sourced scraps ranged from 4.7–8.9 kg in Oxford red fox territories (
Rewilding projects may be assessed in terms of what baseline they seek to restore. Two developed countries where red foxes pose no risk of rabies transmission to humans, the UK and Japan, already provide glimpses of what scenes a rabies-free, post-rewilding North America could allow (
The rewilding of suburban and urban North America with rabies-immune red foxes may have downstream ecological effects that promote environmental sustainability and support the persistence of biodiversity in native fauna. Feral cats and unaccompanied roaming outdoor domestic cats predate native bird species in vast numbers; the late deep ecologist Pentti Linkola, honoured with the epithet ‘the last man of the deep wild’, lamented that ‘man’s relationship with nature has never been more deranged, reckless and hypocritical than it is with the cat: when it comes to defending the cat, many environmentalists turn cunning and deceitful’, as favouritism for cats may cause humans to underestimate the threat that roaming outdoor cats pose to native avian species and to oppose any conservation efforts that directly combat the threats posed by cats (
In the New Yorker’s profile of Esvelt’s proposal for the white-footed mouse gene drive to prevent Lyme disease zoonotic transmission to humans, the article laments that ‘in communities throughout the Northeast, the fear of ticks has changed the nature of summer itself — few parents these days would permit a child to run barefoot through the grass or wander blithely into the woods’ as there is ‘currently no approved Lyme vaccine for humans’ such that pre-emptive transmission prevention is strongly preferred over post-infection treatment strategies (
The continued existence of numerous North American private sanctuaries with tame ambassador animals (Howler’s Inn, Bearizona, Adirondack Wildlife Refuge, Wild Hearts Exotic Animals, Wild Wonders, Animal Wonders etc.) supported by patrons and/or visitors suggests that people place substantial economic value on encountering wildlife in-person and will travel distances to do so, in the event that their cities and suburbs are largely devoid of the opportunity to sight wild mammal mesocarnivores, such as foxes and coyotes. As for the cliché correlation of tree-lined streets and higher property values, it may also be the case that cities and suburbs with a wider variety of fauna (not just wild canid mesocarnivore, but avian as well, in the event that the hypothesised fox-cat-bird ecological cascading predator control interaction proposed in this paper works in practice) would experience higher home prices. Local residents could enjoy the sight of their outdoor dog frolicking with a wild fox without reason for fear if fox-originated rabies transmission were impossible (
Long term maintenance of this rewilding strategy could include local trial releases on islands, daisy gene drive variants and otherwise self-limiting refined gene drive systems in subregions for locally informed control and post-intervention compensatory feedback, as well as non-invasive DNA monitoring via collection of hair, urine, scat and carrion samples (
While this rewilding via gene drive proposal does not seem inherently natural, the eradication of smallpox (and ongoing interventions against polio and COVID-19) represent precedents of humans opposing natural processes out of moral and ethical preferences to live in a less natural world with less suffering. It is seldom if ever argued sincerely that the eradication of smallpox or polio or tuberculosis should be considered ethically undesirable because the ‘species count’ of global biodiversity would decline by one or two or three in exchange for the elimination of mass suffering of sentient life. Per the ‘devil’s advocate’ thought experiment in which one attempts to imagine, predict and anticipate criticisms of what one would otherwise consider a moral and ethical good, opponents may argue that the rabies virus is part of the natural world, contributes to viral biodiversity and exerts pressure via natural selection to strengthen the red fox immune system (
Does this rewilding proposal seem natural? No, but that question is immaterial to whether or not it ought to be done, unless one indulges in the naturalistic fallacy with respect to ethical decision-making for animal populations, in which case veterinary medicine as a field of wildlife biology would not have any rationale to exist. Via the status quo of 'speciesism', North American wild red foxes are simply left behind and forgotten, save for the occasional vaccine-laden bait providing merely non-heritable immunity, when it comes to the distribution of economic resources and scientific research projects for rabies prevention and the alleviation of virus-caused suffering in mammals (
Prior to this paragraph, the omission of any scientific species name for ‘red’ foxes (whose common naturally occurring colour morphs also include silver and cross, with an even-broader colour palette achieved by artificial selection in captive-bred foxes) has been entirely intentional and perhaps even necessary, given the current dispute on red fox speciation (
Phylogenetically speaking, within tribe Vulpini (an intermediate taxonomic level between the family Canidae and the genus Vulpes corresponding to the ‘true foxes’), while arctic foxes (Vulpes lagopus) share overlapping habitats with North American red foxes (Vulpes vulpes or Vulpes fulva; contested) in both Alaska and Canada, it seems likely that arctic foxes as a rabies reservoir could only be directly impacted by a separate arctic fox gene drive in another project beyond the scope of this initial proposal (
There have been reports of hybrid fox kits occurring in the wild, but such matings (arctic x red) are not a common occurrence as the two species are natural enemies in the wild, with red foxes often killing and eating arctic fox kits as well as competing with them for food and territory. Hybrid foxes can come in several different colour mutations, depending on the colouration of the red and arctic parents. Hybrid foxes are quite uncommon in the exotic pet trade. They are born sterile, meaning they cannot reproduce (
However, patterns in sea ice surrounding eastern North America allowed an arctic fox to migrate from Spitsbergen, Norway to Ellesmere Island, Canada over 2,000 miles in 76 days (
With respect to raw calculations of resource allocation, with even non-heritable human rabies vaccination costing $750 per capita in the US, it may be orders of magnitude less expensive to use gene drives in red foxes and then all other wild mammal rabies reservoirs to eradicate the rabies virus entirely, as opposed to vaccinating over 8 billion humans (and counting, given that traditional rabies vaccination is not heritable) at a comparable per capita expense to yield the same ‘zero zoonotic rabies cases in humans’ and ‘better human-wildlife co-existence’ outcomes that could conceivably be reached without altering any non-human animals, albeit at an exorbitant cost to achieve global vaccination of humans against rabies (
In closing, reframing the bioethics issues of gene drive from solely anthropocentric concerns to the broader issues of animal ethics and deep ecology that rewilding entails, the following passage from
We need another and a wiser and perhaps a more mystical concept of animals. Remote from universal nature and living by complicated artifice, man in civilisation surveys the creatures through the glass of his knowledge and sees thereby a feather magnified and the whole image in distortion. We patronise them for their incompleteness, for their tragic fate of having taken form so far below ourselves. And therein we err and greatly err. For the animal shall not be measured by man. In a world older and more complete than ours, they move finished and complete, gifted with extensions of the senses we have lost or never attained, living by voices we shall never hear. They are not brethren, they are not underlings; they are other nations, caught with ourselves in the net of life and time, fellow prisoners of the splendour and travail of the earth.
If Beston is correct that wildlife species are indeed other nations, then perhaps it is an ‘idea whose time has come’ for a novel foreign aid programme to continue the struggle to eradicate a notorious zoonotic disease for multiple ecological downstream benefits that could accrue to both wild mammal rabies reservoirs and those urbanites who seek to live in a post-rewilding North America alongside charismatic, sometimes approachable urban mesocarnivore neighbours, as well as recovering native bird populations.
Since rabies causes afflicted animals to lose their fear of humans and has a near 100% fatality rate in humans once symptoms occur, it is an ideal first disease to target for eradication by using gene drive to spread immunity in the wild mammal reservoir populations harbouring this virus, making rewilding more feasible. Animals may avoid vaccine-laden bait when alternative food sources are abundant, as in the case of some suburban/urban habitat niches.
Heritable rabies immunity may improve the ecology of urban and suburban habitats given the potential for red foxes to keep invasive feral cat populations in check in these ecosystems. This intervention represents a novel endeavour that may be applied to zoonotic diseases present in other wild populations, working towards healthier, more harmonious ecosystems. Using medical and veterinary resources to prevent disease in not only humans, but also wild non-human animals, represents progress within the compassionate conservation ethic for minimising wildlife suffering in the course of ecological management decisions.
This research concerning a rabies immunity gene drive in North American red foxes explores how spreading heritable, population-wide immunity to zoonotic diseases can reduce the risk of human-wildlife conflict and assist in safer (sub)urban rewilding as a win-win for animals suffering from infectious diseases and humans at risk of contracting these zoonotic diseases.
The Biomedical Engineering Department at Rensselaer Polytechnic Institute provided my core undergraduate training as an engineer with knowledge of problem solving strategies for challenges in the life sciences. Dr. Kevin Esvelt of the MIT Media Lab, an Associate Professor and the director of the Sculpting Evolution group, met with me in July 2014 for a discussion of applying CRISPR technology to achieve the inheritance pattern known as gene drive. His public work and insightful correspondence in the years that followed inspired me to create an educational animation about CRISPR-Cas9 and gene drives to help inform the public about this biotechnology, a project that developed from my studies with Professor Silvia Ruzanka from the RPI Electronic Arts faculty. In 2021, Dr. Esvelt also kindly provided encouragement and advice related to publishing this manuscript. Dr. T. J. Clark-Wolf of Utah State University, who was my instructor in the course Rewilding Animal Populations during his time as a PhD student at the University of Montana, provided early feedback in the development of this manuscript. Dr. Chad Bishop, UM's Department Chair of Wildlife Biology and my faculty advisor, provided support and guidance for my ambitions to contribute to this field of research. Dr. Douglas Emlen, my UM Professor in the course Genetics and Evolution, provided expert instruction and autographed my copies of two books that he authored, including our course textbook Evolution: Making Sense of Life. The 2023 McKinney Writing Contest at RPI, where I am currently a student, recognised this manuscript with First Prize in Undergraduate Academic Essay, encouraging me to persist in my efforts to develop and publish the paper. Thoughtful comments by technical editor Dr. Daniel Mietchen as well as helpful remarks by reviewer and gene drive scientist Dr. Jackson Champer enabled considerable additional edits and fixes to this research idea manuscript. In the illustrated food web, I included my original drawing of a specific feral cat character 'Pigeonfall' whose fur pattern design was created by the artist Jenna Meldrum.