Starting in May, 2021, the first trial group of genetically modified mosquitoes was released in the United States, sparking controversy and making history [1, 2]. The goal was to lower the number of mosquito-transmitted viral disease cases, such as Zika and dengue, by significantly decreasing the female mosquito vector population. The target species for population reduction was the invasive Aedes aegypti, which naturally comprised around 4% of the mosquito population in the Florida Keys release location. Aedes aegypti is responsible for nearly all mosquito-borne virus transmissions in the same area [3, 4].
This unprecedented experiment has been met with significant residential [5] and scientific [6] protest coupled with ethical concerns, marking it as an important case study in the fields of biological control mechanisms and outside-lab experimentation. Concerns include the prospect of engineered genes becoming ubiquitous in the natural mosquito population, the possible lasting effects of genetic engineering, and the fact that laws and regulations are failing to match pace with this rapidly-evolving field.
The Science:
The genetic alteration used in the Florida Keys trial employed ‘gene drive’ technology, a method designed to spread gene alterations through a population at higher-than-normal rates than observed in typical inheritance [7]. For instance, instead of only half of an individual’s offspring carrying any one of the given parents’ genes, 100% of the offspring would inherit said gene under control of a gene drive [7, 8]. The gene drive itself is a genetic sequence inserted into the DNA; it is composed of the novel gene, the code for an enzyme that can cut DNA (Cas9), and a DNA sequence that denotes where the enzyme should cut. When a gene-drive-containing DNA strand is in the presence of a wild-type DNA strand, the produced enzyme from the altered strand will ‘cut’ the wild-type DNA and insert a copy of the novel gene, resulting in two strands of DNA containing both the gene drive and the desired novel gene [9].
The target gene drive in the Florida Keys Experiment inserted code for the production of lethal toxin during mosquito embryonic development. However, many genes are activated differently in males and females due to splicing (or ‘editing’) of the code. For instance, imagine a bead necklace representing the little bits of code making up a gene. Females may take every third bead off, allowing for a different product than the original necklace, whereas males may leave it as is, producing a different end result than females from the same starting sequence.
Only female mosquitoes can serve as vectors for disease transmission. As a result, the target inserted gene is designed to be lethal to only females, leading to a significant reduction in population and subsequent disease transmission.
In males, the inserted gene was spliced in a way that deactivated the gene, preventing toxin production during embryonic development and enabling male carriers to grow to adulthood. In females, the inserted gene for toxin production was left mostly untouched, and therefore allowed for toxin production and female embryonic termination. Given that only males survive to reproductive maturity, this gene drive led to a heavily skewed adult male-to-female Aedes aegypti sex ratio. The resulting drop in the number of females caused a drop in viral transmission cases.
Over multiple generations, descendents of females who never inherited the gene drive will gradually reassert themselves as the majority within the population, leading back to a balanced male-female ratio, and the infection rate will rebound [7]. Thus, although the actual effect of this mosquito experiment is multi-generational, it is theoretically only temporary.
The specific gene chosen for insertion is also important to the overall gene drive’s effectiveness. Some genes are more prone to mutation than others; in other words, they are ‘less conserved’. Generally, ancestral genes tend to be more rigid in their construction, since they have had longer to achieve near-maximum efficiency. The vast majority of random mutations affecting them will be deleterious, and thus, not passed on [10, 11]. Resistance to a gene drive can only result from a mutation in its target sequence; a beneficial natural mutation can grant immunity to a gene drive and thus become dominant over time in the population.
The Florida Keys Mosquito Experiment managed to minimize the chances of creating immunity by choosing a highly conserved gene (the doublesex gene). A natural mutation in the sequence that would prevent the targeted gene-drive alteration will likely be lethal, putting genetically modified organisms between a rock and a hard place where either mutating or not mutating are both likely deadly.
Ethical, Scientific, and Residential Concerns
Naturally, there are a plethora of ethical concerns when altering the genomes of millions of individual organisms with the goal of extermination. Unlike selective breeding, which gave us dogs from wolves [12] and corn from ancestral maize, genetic editing involves the introduction of completely new and artificial genes to a population that did not previously possess them. This is an altogether different story from selective breeding and man-made evolutionary pressures.
In effect, gene-editing technology amounts to rewriting fragments of the essence of a species – a power that expands the god-like authority humans claim over species and our natural environment. While humans can destroy habitat, drive species to extinction with hunting, and keep entire populations in captivity, genetically altering a species changes the very code of its existence, and can be seen as a much more permanent invasion of that animal’s fundamental nature.
Since there is a vast amount still not understood about the functioning of genetics, perhaps the amount of failure and evolutionary experimentation needed to understand this supernatural authority at the expense of genetically-functioning organisms is a line that humans shouldn’t cross. Perhaps, as suggested by several organizations, it could inadvertently lead to the degradation or collapse of our entire, delicately balanced biosphere ecology [13, 14].
The potential for good to be achieved with genetic editing is also a significant part of the conversation. For the first time, the Mosquito Experiment shows the viability and potential good of a genetic solution to a real-world problem. If expanded, perhaps genetic editing could be used to manage other pests and invasive species. Perhaps it could even be used to provide widespread customized gene therapy in humans [15], curing people of genetic diseases presently considered incurable.
In no small way, the controversy surrounding the Mosquito Experiment is raising ethical questions about the field’s application in everyday life.
In a more focused sense, there is also no perfect way to predict the effect of taking a sledgehammer to the Aedes aegypti population within the ecosystem. While results are likely to be small (as the population comprises only 4% of all mosquitos in the region), they will affect the entire ecosystem in some small and still unknown ways [16]. Several organizations caution tampering with a species’s genetics and subsequent prevalence without having a strong idea of the ecological implications, despite that this complexity can be nearly impossible to fully map [13, 14].
There are both scientific and residential concerns about the experiment as well. While the chances of viable mutations to the doublesex gene are low, a similar experiment in Brazil found that a small proportion of genetically modified mosquitoes seemed capable of breeding and siring offspring. These offspring seemed to be equally – or possibly even more capable – of carrying diseases than their unaltered predecessors [6].
Future application/use:
In the future, genetic modifiers to mosquitoes will likely become more common. Aedes aegypti is relatively cold-intolerant and has a range limited to temperate regions [5]. As climate change continues raising average winter temperatures across the US, it is likely that the range of Aedes aegypti will expand northward. This migration may be followed by the use of more genetic control factors in the future [17] in more northern regions of the US to prevent mosquito-viral transmissions. It’s also possible that genetic control factors will be applied to other species globally.
Given the expected increase of the Aedes aegypti species and the long-term benefits of gene modification in other applications, it is likely genetic alteration will become more prevalent, despite its yet unresolved ethical implications.
Citations:
“In Florida Keys, a Controversial Project Releases Genetically Modified Mosquitoes.” The Washington Post, Washington Post Company, 4 May 2021, www.washingtonpost.com/health/in-florida-keys-a-controversial-project-releases-genetically-modified-mosquitoes/2021/04/30/0e094238-a860-11eb-8c1a-56f0cb4ff3b5_story.html.
Lisa Palmer • June 4, et al. “Genetically Modified MOSQUITO Sparks a Controversy in Florida.” Yale E360, e360.yale.edu/features/genetically_modified_mosquito_sparks_a_controversy_in_florida.
https://www3.paho.org/hq/index.php?option=com_content&view=article&id=12861:2016-zika-evolved-from-emergency-into-long-term-public-health-challenge&Itemid=1926&lang=en
“Vector-Borne Diseases.” World Health Organization, World Health Organization, www.who.int/news-room/fact-sheets/detail/vector-borne-diseases.
“Aedes Aegypti - Factsheet for Experts.” European Centre for Disease Prevention and Control, 1 June 2021, www.ecdc.europa.eu/en/disease-vectors/facts/mosquito-factsheets/aedes-aegypti.
(www.dw.com), Deutsche Welle. “Genetically Modified Mosquitoes Breed in Brazil: DW: 13.09.2019.” DW.COM, www.dw.com/en/genetically-modified-mosquitoes-breed-in-brazil/a-50414340.
Scudellari, Megan. “Self-Destructing Mosquitoes and Sterilized Rodents: the Promise of Gene Drives.” Nature News, Nature Publishing Group, 9 July 2019, www.nature.com/articles/d41586-019-02087-5.
Ktmoelle. “Gene Drives.” Ktmoelle, 14 Mar. 2019, askabiologist.asu.edu/gene-drives.
Coffey, Donavyn. “What Is a Gene Drive?” LiveScience, Purch, 17 Apr. 2020, www.livescience.com/gene-drive.html.
Luo, Hao, et al. “Evolutionary Conservation Analysis between the Essential and Nonessential Genes in Bacterial Genomes.” Nature News, Nature Publishing Group, 14 Aug. 2015, www.nature.com/articles/srep13210.
Bergmiller, Tobias, et al. “Patterns of Evolutionary Conservation of Essential Genes Correlate with Their Compensability.” PLOS Genetics, Public Library of Science, journals.plos.org/plosgenetics/article?id=10.1371%2Fjournal.pgen.1002803.
Yong, Ed. “A New Origin Story for Dogs.” The Atlantic, Atlantic Media Company, 16 June 2021, www.theatlantic.com/science/archive/2016/06/the-origin-of-dogs/484976/.
Animal Biotechnology: Science Based Concerns. National Academy Press, 2002.
Ministerie van Economische Zaken, Landbouw en Innovatie. “Consequences of Gmos for Biodiversity.” Biotechnology | Government.nl, Ministerie Van Algemene Zaken, 30 July 2018, www.government.nl/topics/biotechnology/consequences-of-gmos-for-biodiversity.
Center for Biologics Evaluation and Research. “What Is Gene Therapy?” U.S. Food and Drug Administration, FDA, www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/what-gene-therapy.
Weintraub, Karen. “The First Genetically Modified Mosquitoes Released in the U.S. to Buzz in the Florida Keys.” USA Today, Gannett Satellite Information Network, 2 May 2021, www.usatoday.com/story/news/health/2021/04/29/genetically-modified-mosquitoes-released-florida-keys-first-us/4876624001/.
“Does ‘Global Warming’ Mean It's Warming Everywhere?: NOAA Climate.gov.” Does "Global Warming" Mean It's Warming Everywhere? | NOAA Climate.gov, 29 Oct. 2020, www.climate.gov/news-features/climate-qa/does-global-warming-mean-it%E2%80%99s-warming-everywhere.