The Aedes aegypti mosquito, which can carry devastating diseases, was recently engineered by a biotech company to have a genetic "kill switch" intended to crash the local population in the Florida Keys.
Decades of efforts to eradicate the disease-carrying Aedes aegypti mosquito from the Keys and other tropical locales have had limited impact. Since the advent of pesticides, homes and neighborhoods have been drenched with them, but after each spraying, the mosquito population quickly bounces back, and the pesticides have to be sprayed over and over. But thanks to genetic engineering, new approaches are underway that could possibly prove safer, cheaper and more effective than any pesticide.
One of those approaches involves, ironically, releasing more mosquitoes in the Florida Keys.
The kill-switch will ensure that the female offspring die before they reach maturity and thus, be unable to reproduce.
British biotech company Oxitec has engineered male mosquitoes to have a genetic "kill-switch" that could potentially crash the local population of Aedes aegypti, at least in the short-term. The modified males that are being released are intended to mate with wild females.
Males don't bite; it's the female that's deadly, always seeking out blood to gorge on to help mature her eggs. After settling her filament-thin legs on her prey, she sinks a needlelike proboscis into the skin and sucks the blood until her translucent belly is bloated and glowing red.
The kill-switch will ensure that the female offspring die before they reach maturity and thus, be unable to reproduce. In some experiments using genetically modified mosquitoes, the small number of females that survived were rendered unable to bite. The modification prevented the proboscis, the sickle-like needle that pierces the skin, from forming properly. But this isn't the case with Oxitec's mosquitoes; in the Oxitec release, the females simply die off before they can mate.
The modified mosquitoes are the second genetically engineered insect to be released in the U.S. by Oxitec. The first was a modified diamondback moth, an agricultural pest that doesn't bite humans. But with the mosquitoes, there are many questions about the long-term effects on wild ecosystems, other species in the food chain, and human health. With the Keys initiative, there has been vociferous opposition from environmental groups and some local residents, but some scientists and public health experts say that genetically modified insects pose less of a risk than the diseases they carry and the powerful, indiscriminant pesticides used to combat them.
Oxitec spent a decade developing the technology and engaging in a massive public education campaign before beginning the field test in April. Eventually, the company will release 750,000 of the insects from six locations on three islands of the Florida Keys. Although the release has been approved by the Environmental Protection Agency, the Florida Department of Agriculture and Consumer Services, and the Florida Keys Mosquito Control District, the company was never able to obtain unanimous approval among local residents, some of whom worry that the experiment could cause irreversible damage to the ecosystem.
The company has already begun distributing multiple blue and white boxes containing the eggs of thousands of the mosquitoes which, when water is added, will hatch legions of modified males.
There are a number of techniques available to genetically engineer animals and plants to minimize disease and maximize crop yields. According to Kevin Gorman, chief development officer for Oxitec, the company's mosquitoes were altered by injecting genetic material into the eggs, testing them, then re-injecting them if not enough of the new genes were incorporated into the developing embryos. "We insert genes, but take nothing away," he says.
Gorman points out that the Oxitec mosquitoes will only pass the kill-switch genes on to some of their offspring, and that they will die out fairly quickly. They should temporarily lessen diseases by reducing the local population of Aedes aegypti, but to have a long-term effect, repeated introductions of the altered mosquitoes would have to take place.
Critics say the Oxitec experiment is a precursor to a far more consequential, and more troubling development: the introduction of gene drives in modified species that aggressively tilt inheritance factors in a decided direction.
Gene Drives
Gene drives coupled with the recent development of the gene-editing technique, CRISPR-Cas9, promise to be far more targeted and powerful than previous gene altering efforts. Gene drives override the normal laws of inheritance by harnessing natural processes involved in reproduction. The technique targets small sections of the animal's DNA and replaces it with an altered allele, or trait-determining snippet. Normally, when two members of a species mate, the offspring have a 50 percent chance of receiving an allele because they will receive one from each parent. But in a gene drive, each offspring ends up getting two copies of a desired allele from a single parent—the modified parent. The method "drives" the modified DNA into up to 100 percent of the animals' offspring.
In the case of gene drive mosquitoes, the modified males will mate with wild females. Upon fertilization of the egg, the offspring will start off with one copy of the targeted allele from each parent. But an enzyme, called Cas9, is introduced and acts as a kind of molecular scissors to cut, or damage, the "wild" allele. Then the developing embryo's genetic repair mechanisms kick in and, to repair the damage, copy the undamaged allele from the modified parent. In this way, the offspring ends up with two copies of the modified allele, and it will pass the modification on to virtually all of its progeny.
There is some debate among researchers and others about what constitutes a gene drive, but leaders in the nascent field, such as Andrea Crisanti, generally agree that the defining factor is the heritability of a change introduced into a species. A gene drive is not a particular gene or suite of genes, but a program that proliferates in a species because it is inherited by virtually all offspring.
An illustration of how gene drives spread an altered gene through a population.
Mariuswalter, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons
Of the experts who spoke with Leaps.org for this article, there was disagreement on whether the Oxitec mosquitoes carry a gene drive, but Gorman says they don't because they carry no inheritance advantage. The mosquitoes have baked-in limitations on their potential impact on the tropical ecosystem because the kill-switch should only temporarily affect the local population of Aedes aegypti. The modified mosquitoes will die pretty quickly. But modified organisms that do carry gene drives have the potential to spread widely and persist for an unknown period of time.
Since it has such a reproductive advantage, animals modified by CRISPR and carrying gene drives can quickly replace wild species that compete with them. On the other hand, if the gene drive carries a kill-switch, it can theoretically cause a whole species to collapse.
This makes many people uneasy in an age of mass extinctions, when animals and ecosystems are already under extreme stress due to climate change and the ceaseless destruction of their habitats. Ecosystems are intricate, delicately balanced mosaics where one animal's competitor is another animal's food. The interconnectedness of nature is only partially understood and still contains many mysteries as to what effects human intervention could eventually cause.
But there's a compelling case to be made for the use of gene drives in general. Economies throughout the world are often based on the ecosystem and its animals, which rely on a natural food chain that was evolved over billions of years. But diseases carried by mosquitoes and other animals cause massive damage, both economically and in terms of human suffering.
Malaria alone is a case in point. In 2019, the World Health Organization reported 229 million cases of malaria, which led to 449,000 deaths worldwide. Over 70 percent of those deaths were in children under the age of 12. Efforts to combat malaria-carrying mosquitoes rely on fogging the home with chemical pesticides and sleeping under pesticide-soaked nets, and while this has reduced the occurrence of malaria in recent years, the result is nowhere near as effective as eradicating the Anopheles gambiae mosquito that carries the disease.
Pesticides, a known carcinogen for animals and humans, are a blunt instrument, says Anthony Shelton, a biologist and entomologist at Cornell University. "There are no pesticides so specific that they just get the animal you want to target. They get pollinators. They get predators and parasites. They negatively affect the ecosystem, and they get into our bodies." And it's not uncommon for insects to develop resistance to pesticides, necessitating the continuous development of new, more powerful chemicals to control them.
"The harm of insecticides is not debatable," says Shelton. With gene drives, the potential harm is less clear.
Shelton also points out that although genetic modification sounds radical, people have been altering the genes of animals since before recorded history, through the selective breeding of farm and domesticated animals. While critics of genetic modification decry the possibility of changing the trajectory of evolution in animals, "We've been doing it for centuries," says Shelton. "Gene drives are just a much faster way to do what we've been doing all along."
Still, one might argue that farms are closed experiments, because animals enclosed within farms don't mate with wild animals. This limits the impact of human changes on the larger ecosystem. And getting new genes to work their way through multiple generations in longer-lived animals through breeding can take centuries, which imposes the element of time to ascertain the relative benefits of any introduced change. Gene drives fast-forward change in ways that have never been harnessed before.
The unique thing about gene drives, Shelton says, is that they only affect the targeted species, because those animals will only breed with their own species. Although the Oxitec mosquitoes are modified but not imbued with a gene drive, they illustrate the point. Aedes aegypti will only mate with its own species, and not with any of the other 3,000 varieties of mosquito. According to Shelton, "If they were to disappear, it would have no effect on the fish, bats and birds that feed on them." But should gene drives become widely used, this won't always be true of animals that play a larger part in the food chain. This will be especially true if gene drives are used in mammals.
One factor, cited by both proponents of gene drives and those who want a complete moratorium on them, is that once a gene drive is released into the wild, animals tend to evolve strategies to resist them. In a 2017 article in Nature, Philip Messer, a population geneticist at Cornell, says that gene drives create "the ideal conditions for resistant organisms to flourish."
Sometimes, when CRISPR is used and the Cas9 enzyme cuts an allele soon after egg fertilization, the animal's repair mechanism, rather than creating a straight copy of the desired allele, inserts random DNA letters. The gene drive won't recognize the new sequence, and the change will slip through. In this way, nature has a way of overriding gene drives.
In caged experiments using CRISPR-modified mosquitoes, while the gene drive initially worked, resistance has developed fairly rapidly. Scientists working for Target Malaria, the massive anti-malaria enterprise funded by the Bill and Melinda Gates Foundation, are now working on developing a new version of a gene drive that is not so vulnerable to genetic resistance. But cage conditions are not representative of complex natural ecosystems, and to figure out how a modified species is going to affect the big picture, ultimately they will have to be tested in the wild.
Because there are so many unknowns, such testing is just too dangerous to undertake, according to environmentalists such as Dana Perls of the Friends of the Earth, an international consortium of environmental organizations headquartered in Amsterdam. "There's no safe way to experiment in the wild," she says. "Extinction is permanent, and to drive any species to extinction could have major environmental problems. At a time when we're seeing species disappearing at a high rate, we need to focus on safe processes and a slow approach rather than assume there's a silver bullet."
She cites a number of possible harmful outcomes from genetic modification, including the possible creation of dangerous hybrids that could be more effective at spreading disease and more resistant to pesticides. She points to a 2019 paper in Scientific Reports in which Yale researchers suggested there's evidence that genetically modified species can interbreed with organisms outside their own species. The researchers claimed that when Oxitec tested its modified Aedes aegypti mosquitoes in Brazil, the release resulted in a dangerous hybrid due to the altered animals breeding with two other varieties of mosquito. They suggested that the hybrid mosquito was more robust than the original gene drive mosquitoes.
The paper contributed to breathless headlines in the media and made a big splash with the anti-GMO community. However, it turned out that when other scientists reviewed the data, they found it didn't support the authors' claims. In a short time, the editors of Nature ran an Editorial Expression of Concern for the article, noting that of the insects examined by the researchers, none of them contained the transgenes of the released mosquitoes. Among multiple concerns, Nature found that the researchers didn't follow the released population for more than a short time, and that previous work from the same authors had shown that after a short time, transgenes would have faded from the population.
Of course, unintended consequences are always a concern any time we interfere with nature, says Michael Montague, a senior scholar at Johns Hopkins University's Center for Health Security. "Unpredictability is part of living in the world," he says. Still, he's relatively comfortable with the limited Florida Keys release.
"Even if one type of mosquito was eliminated in the Keys, the ecosystem wouldn't notice," he says. This is because of the thousands of other species of mosquito. He says that while the Keys initiative is ultimately a test, "Oxitec has done their due diligence."
Montague addressed another concern voiced by Perls. The Oxitec mosquitoes were developed so that the female larvae will only hatch in water containing the antibiotic tetracycline. Perls and others caution that, because of the widespread use of antibiotics, the drug inevitably makes its way into the water system, and could be present in the standing pools of water that mosquitoes mate and lay their eggs in.
It's highly unlikely that tetracycline would exist in concentrations high enough to make any difference, says Montague. "But even if it did happen, and the modified females hatched out and mated with wild males, many of their offspring would inherit the modification and only be able to hatch in tetracycline-laced water. The worst-case scenario would be that the pest control didn't work. Net effect: Zero," he says.
As for comparing GMO mosquitoes with insecticides, Montague says, "We 100 percent know insecticides have a harmful effect on human health, whereas modified [male] mosquitoes don't bite humans. They're essentially a chemical-free insecticide, and if there were to be some harmful effect on human health, it would have to be some complicated, convoluted effect" that no one has predicted.
It's not clear, though, given the transitory nature of self-limiting genetically modified insects, whether any effects on the ecosystem would be long-lasting. Certainly in the case of the Oxitec mosquitoes, any effect on the environment would likely be subtle. However, there are other species that are far more important to the food chain, and humans have been greatly impacting them for centuries, sometimes with disastrous effects.
The world's oceans are particularly vulnerable to the effects of human actions. "Codfish used to dominate the North Atlantic ecosystem," says Montague, but due to overfishing, there were huge changes to that ecosystem, including the expansion of their prey—lobsters, crabs and shrimp. The whole system got out of balance." The fish illustrate the international nature of the issues related to gene drives, because wild species have few boundaries and a change in one region can easily spread far and wide.
On the other hand, gene drives can be used for beneficial purposes beyond eliminating disease-carrying species. They could also be used to combat invasive species, fight crop-destroying insects, promote biodiversity, and give a leg up to endangered species that would otherwise die out.
Today nearly 90 percent of the world's islands have been invaded by disease-carrying rodents that have over-multiplied and are driving other island species to extinction. Common rodents such as rats and mice normally encounter a large number of predators in mainland territories, and this controls their numbers. Once they are introduced into island ecosystems, however, they have few predators and often become invasive. Because of this, they are a prevalent cause of the extinction of both animals and plants globally. The primary way to combat them has been to spread powerful toxicants that, when ingested, cause death. Not only has this inhumane practice had limited impact, the toxicants can be eaten by untargeted species and are toxic to humans.
The Genetic Biocontrol of Invasive Rodents program (GBIRd), an international consortium of scientists, ethicists, regulatory experts, sociologists, conservationists and others, is exploring the possible development of a genetically modified mouse that could be introduced to islands where rodents are invasive. Similar to the Oxitec mosquitoes, the mice would carry a modification that results in the appearance of only one sex, and they would also carry a gene drive. Theoretically, once they mate with the wild mice, all of the surviving offspring would be either male or female, and the species would disappear from the islands, giving other, threatened species an opportunity to revive.
GBIRd is moving slowly by design and is currently focused on asking if a genetically engineered mouse should be developed. The program is a potential model for how gene drives can be ethically developed with maximum foresight and the least impact on complex ecosystems. By first releasing a genetically engineered mouse on an island — likely years from now — the impact would naturally be contained within a limited locale.
Regulating GM Insects
While multiple agencies in the U.S. were involved in approving the release of the Oxitec mosquitoes, most experts agree that there is not a straightforward path to regulating genetically modified organisms released into the environment. Clearly, international regulation is needed as genetically modified organisms are released into open environments like the air and the ocean.
The United Nations' Convention on Biological Diversity, which oversees environmental issues at an international level, recently met to continue a process of hammering out voluntary protocols concerning gene drives. Multiple nations have already signed on to already-established protocols, but the United States has not and, according to Montague, is not expected to. "The U.S. will never be signatory to CBD agreements because agricultural companies are huge businesses" that may not see them as in their best interests, he says. Bans or limitations on the release of genetically modified organisms could limit crop yields, for example, thereby limiting profits.
Even if every nation signed on to international regulations of gene drives, cooperation is voluntary. The regulations wouldn't prevent bad actors from using the technology in nefarious ways, such as developing gene drives that can be used as weapons, according to Perls. An example would be unleashing a genetically modified invasive insect to destroy the crops of enemy nations. Or the releasing of a swarm of disease-carrying insects. But in this scenario, it would be very hard to limit the genetically modified species to a specific environment, and the bad actors could be unleashing disaster on themselves.
Because of the risks of misuse, scientists disagree on whether to openly share their gene drive research with others. But Montague believes that there should be a universal registry of gene drives, because "one gene drive can mess up another one. Two groups using the same species should know about each other," he says.
Ultimately, the decision of whether and when to release gene drives into nature rests with not one group, but with society as a whole. This includes not only diverse experts and regulatory bodies, but the general public, a group Oxitec spent considerable time and resources interacting with for their Florida Keys project. In the end, they gained approval for the initiative by a majority of Keys residents, but never gained a total consensus.
There's no escaping the fact that the use of gene drives is a nascent field, and even geneticists and regulators are still grapping with the best ways to develop, oversee, regulate, and control them. Much more data is needed to fully ascertain its risks and benefits.
Experts agree that the Oxitec venture isn't likely to have a noticeable effect on the larger ecosystem unless something truly catastrophic goes wrong. But following the GMO mosquitoes over time will give scientists more real-world data about the long-term effects of genetically altered species. If the release doesn't work, nothing about the ecosystem will change and Aedes aegypti will continue to be a menace to human health. But if something goes horribly wrong, it could hinder the field for years, if not forever.
On the other hand, if the Oxitec mosquitoes and other early initiatives achieve their goals of reducing disease, increasing crop yields, and protecting biodiversity, in the words of Anthony Shelton, "Maybe, 25 to 50 years from now, people will wonder what all the fuss was about."
Correction: The original version of this article mistakenly stated that the modified Oxitec mosquitoes would not be able to form a proper proboscis to bite humans. That is true for some modified mosquitoes but not the Oxitec ones, whose female offspring die off before they reach maturity. Additionally, the Oxitec release was not approved by the FDA and CDC, as originally stated. The FDA and CDC withdrew their role and passed the oversight to other regulatory entities.
Today's podcast episode features Doug Drysdale, CEO of Cybin, a company that is leading innovations in psilocybin, mushrooms that may help people with anxiety and depression.
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These mushrooms have been used for religious, spiritual and medicinal purposes for thousands of years, but only in the past several decades have scientists brought psychedelics into the lab to enhance them and maximize their therapeutic value.
Today’s podcast guest, Doug Drysdale, is doing important work to lead this effort. Drysdale is the CEO of a company called Cybin that has figured out how to make psilocybin more potent, so it can be administered in smaller doses without side effects.
The natural form of psilocybin has been studied increasingly in the realm of mental health. Taking doses of these mushrooms appears to help people with anxiety and depression by spurring the development of connections in the brain, an example of neuroplasticity. The process basically shifts the adult brain from being fairly rigid like dried clay into a malleable substance like warm wax - the state of change that's constantly underway in the developing brains of children.
Neuroplasticity in adults seems to unlock some of our default ways of of thinking, the habitual thought patterns that’ve been associated with various mental health problems. Some promising research suggests that psilocybin causes a reset of sorts. It makes way for new, healthier thought patterns.
So what is Drysdale’s secret weapon to bring even more therapeutic value to psilocybin? It’s a process called deuteration. It focuses on the hydrogen atoms in psilocybin. These atoms are very light and don’t stick very well to carbon, which is another atom in psilocybin. As a result, our bodies can easily breaks down the bonds between the hydrogen and carbon atoms. For many people, that means psilocybin gets cleared from the body too quickly, before it can have a therapeutic benefit.
In deuteration, scientists do something simple but ingenious: they replace the hydrogen atoms with a molecule called deuterium. It’s twice as heavy as hydrogen and forms tighter bonds with the carbon. Because these pairs are so rock-steady, they slow down the rate at which psilocybin is metabolized, so it has more sustained effects on our brains.
Cybin isn’t Drysdale’s first go around at this - far from it. He has over 30 years of experience in the healthcare sector. During this time he’s raised around $4 billion of both public and private capital, and has been named Ernst and Young Entrepreneur of the Year. Before Cybin, he was the founding CEO of a pharmaceutical company called Alvogen, leading it from inception to around $500 million in revenues, across 35 countries. Drysdale has also been the head of mergers and acquisitions at Actavis Group, leading 15 corporate acquisitions across three continents.
In this episode, Drysdale walks us through the promising research of his current company, Cybin, and the different therapies he’s developing for anxiety and depression based not just on psilocybin but another psychedelic compound found in plants called DMT. He explains how they seem to have such powerful effects on the brain, as well as the potential for psychedelics to eventually support other use cases, including helping us strive toward higher levels of well-being. He goes on to discuss his views on mindfulness and lifestyle factors - such as optimal nutrition - that could help bring out hte best in psychedelics.
Show links:
Doug Drysdale full bio
Doug Drysdale twitter
Cybin website
Cybin development pipeline
Cybin's promising phase 2 research on depression
Johns Hopkins psychedelics research and psilocybin research
Mets owner Steve Cohen invests in psychedelic therapies
Doug Drysdale, CEO of Cybin
Immune cells battle an infection.
Measuring immune resilience
The researchers measured immune resilience in two ways. The first is based on the relative quantities of two types of immune cells, CD4+ T cells and CD8+ T cells. CD4+ T cells coordinate the immune system’s response to pathogens and are often used to measure immune health (with higher levels typically suggesting a stronger immune system). However, in 2021, the researchers found that a low level of CD8+ T cells (which are responsible for killing damaged or infected cells) is also an important indicator of immune health. In fact, patients with high levels of CD4+ T cells and low levels of CD8+ T cells during SARS-CoV-2 and HIV infection were the least likely to develop severe COVID and AIDS.
Individuals with optimal levels of immune resilience were more likely to live longer.
In the same 2021 study, the researchers identified a second measure of immune resilience that involves two gene expression signatures correlated with an infected person’s risk of death. One of the signatures was linked to a higher risk of death; it includes genes related to inflammation — an essential process for jumpstarting the immune system but one that can cause considerable damage if left unbridled. The other signature was linked to a greater chance of survival; it includes genes related to keeping inflammation in check. These genes help the immune system mount a balanced immune response during infection and taper down the response after the threat is gone. The researchers found that participants who expressed the optimal combination of genes lived longer.
Immune resilience and longevity
The researchers assessed levels of immune resilience in nearly 50,000 participants of different ages and with various types of challenges to their immune systems, including acute infections, chronic diseases, and cancers. Their evaluation demonstrated that individuals with optimal levels of immune resilience were more likely to live longer, resist HIV and influenza infections, resist recurrence of skin cancer after kidney transplant, survive COVID infection, and survive sepsis.
However, a person’s immune resilience fluctuates all the time. Study participants who had optimal immune resilience before common symptomatic viral infections like a cold or the flu experienced a shift in their gene expression to poor immune resilience within 48 hours of symptom onset. As these people recovered from their infection, many gradually returned to the more favorable gene expression levels they had before. However, nearly 30% who once had optimal immune resilience did not fully regain that survival-associated profile by the end of the cold and flu season, even though they had recovered from their illness.
Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance.
This could suggest that the recovery phase varies among people and diseases. For example, young female sex workers who had many clients and did not use condoms — and thus were repeatedly exposed to sexually transmitted pathogens — had very low immune resilience. However, most of the sex workers who began reducing their exposure to sexually transmitted pathogens by using condoms and decreasing their number of sex partners experienced an improvement in immune resilience over the next 10 years.
Immune resilience and aging
The researchers found that the proportion of people with optimal immune resilience tended to be highest among the young and lowest among the elderly. The researchers suggest that, as people age, they are exposed to increasingly more health conditions (acute infections, chronic diseases, cancers, etc.) which challenge their immune systems to undergo a “respond-and-recover” cycle. During the response phase, CD8+ T cells and inflammatory gene expression increase, and during the recovery phase, they go back down.
However, over a lifetime of repeated challenges, the immune system is slower to recover, altering a person’s immune resilience. Intriguingly, some people who are 90+ years old still have optimal immune resilience, suggesting that these individuals’ immune systems have an exceptional capacity to control inflammation and rapidly restore proper immune balance despite the many respond-and-recover cycles that their immune systems have faced.
Public health ramifications could be significant. Immune cell and gene expression profile assessments are relatively simple to conduct, and being able to determine a person’s immune resilience can help identify whether someone is at greater risk for developing diseases, how they will respond to treatment, and whether, as well as to what extent, they will recover.
This article originally appeared on Big Think, home of the brightest minds and biggest ideas of all time.