Deliberately infecting humans with a parasite that can penetrate the brain and affect our behavior doesn't sound like the dream. Yet that is the ultimate aim of Prof. Oded Rechavi and Shahar Bracha from Tel Aviv University, with Lilach Sheiner of the University of Glasgow and a large international team.
The concept: to use engineered Toxoplasma gondii parasites to deliver drugs beyond the blood-brain barrier. T. gondii has few charms from our selfish perspective.
Cats are popular pets , but for some the small potential that they may carry toxoplasma is a deal-breaker. Although the sexual cycle of toxoplasma only occurs in cats , the chief source of toxoplasmis in humans isn't cat litters – it's eating undercooked meat of any terrestrial type from chicken to horse. Fish are not considered a competent biological host for T.
gondii, but because we filth up our waterways and seas with our waste, we have managed to infect the whole food chain . Long story short, toxoplasma has gone planetwide and somewhere from 2 to 3 billion people are believed to be infected. Unusually though not uniquely among parasites, toxoplasma can pass the blood-brain barrier that protects our brains against bad things in our blood.
How it does that is still under investigation . Once inside, the parasites encyst in the brain, nerves and muscles. In this dormant, inactive condition, the parasites don't reproduce and aren't vulnerable to drugs or our immune system.
They may stay there for the duration of the carrier's life, biologist Jonathan A. Rader has observed. The infected usually remain asymptomatic or suffer mild flu-like symptoms, unless the immune system becomes compromised.
Then they may reactivate and as the cysts rupture in the brain, even pose a threat to life. Famously, toxoplasma infection can lead to counterproductive behavioral effects. In rats and mice, infection is associated with, among other things, diminished fear and a morbid attraction to cat urine.
In humans, the evidence of toxoplasma's behavioral effect is sporadic but the parasite is anecdotally suspected to be associated with, inter alia, schizophrenia risk, suicide, road rage and entrepreneurial spirit . "Fear of failure would be less important in infected individuals, who are more willing than others to start their own business," explains a 2020 paper in the Journal Français d'Ophtalmologie . There is no categorical evidence that toxoplasma infection in the human drives our attachment to cats, though one paper claims that tests of 34 infected men and 134 uninfected men found that the toxo-carriers discovered they had an increased attraction to cats (i.
e., were less repelled by the smell of their pee). In any case, toxoplasma is suspected to be unhealthy for humans, and now Rechavi and the group propose a silver lining to this particular cloud.
Their study was published this month in the journal Nature Microbiology . Toxoplasma gondii is a one-celled animal that can invade cells in a vast range of animals. Previous work has proven that toxoplasma can be exploited to deliver proteins to cells to which it attaches.
Since T. gondii can pass the blood-brain barrier, the team proposes to mutate (generally alter/engineer) it to produce and secrete therapeutic molecules. As proof of concept, they engineered toxoplasmosis to produce a protein called MeCP2, a putative therapy for Rett syndrome (a genetic neurological disorder), and deliver it into mouse brains.
Specifically, they hoped the proteins would reach the nerve cells, or neurons. "The parasite has three distinct secretion systems and we 'hitched a ride' on two of them," Rechavi explained. "We did not intervene with the first system, which secretes proteins outside the neurons.
The second system 'shoots' a 'harpoon' into the neuron, to enable penetration. Once inside, the parasite forms a kind of cyst in which it continues to secrete proteins permanently. We engineered the parasite's DNA to make it produce and secrete the proteins we want, which have therapeutic potential.
" How do we know the proteins made by the engineered parasites reached the target? By multiple lines of evidence, including that when the proteins reached said target, the mouse brains glowed in the dark. Green. They glowed neon green.
To be clear, the researchers didn't start straight with animal studies. They started with cell models, organoids – "miniature brains" grown in petri dishes in the lab – then progressed to animal models. Meaning mice.
So far, they have demonstrated that engineered T. gondii can deliver the protein MeCP2 to mouse brains. Meanwhile, a company evocatively named Epeius (after the Greek warrior credited with conceptualizing the Trojan horse) has been founded in collaboration with Ramot, the Tel Aviv University technology transfer company, and with the University of Glasgow's research and innovation services, to work on making the parasite safer – because the way things are, it isn't.
This is why we call it a parasite and not a commensal occupant of our innards. The problem is the potential side effects. Actually, Rechavi professes himself to be less worried about toxoplasma's reported effects on humans, because it simply isn't proven, anecdotal cat pee aversion transitions notwithstanding.
"Not a lot of researchers focused on possible behavior aspects. But the parasite, if it causes disease, can be dangerous and we have to deal with that," he says in a phone interview. Most infectees may be asymptomatic, and that's why they chose T.
gondii as their go-to parasite for the research: it's relatively benign, except if one has a compromised immune system – so to move the research to human trials down the road, the parasite has to be made even safer than it is, he explains. "There are all sorts of ideas of how to do that," he says. "For example, to engineer parasites to be less virulent, or to create self-destruct mechanisms.
Or to take medicine against it when its work is done." Or to engineer the animal to be dependent on a chemical without which it cannot survive or procreate, then to deny it that chemical. Given toxo's bad rep, and the work ahead – including to nail down what it may actually do and not do to us – this will take time.
But Rechavi is optimistic, noting that gene therapy also took decades to become relevant, and it took a vast scientific effort. "Here too will have to be a community effort to make it useful," he says. And come that happy day, if our brains need a protein that the blood-brain barrier keeps out, we may yet welcome infection by an engineered version of this parasite that causes mice to run straight into the cat's embrace, and continue to wonder if it did the same to us.
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