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Rat neurons repair mouse brains — and restore sense of smell

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Two research teams have demonstrated that adding rat neurons to mouse brains that were missing crucial cells could help the organs to recover function1,2. The experiments could help scientists to better understand how different species’ brains develop, and even aid efforts to grow ‘chimeric’ pigs with human organs that could be used for transplantation in people.

Researchers have successfully generated hybrid, or chimeric, animals in the past. Among these have been mice with rat organs, including pancreases3, and mice with human neurons in their brains4. But no one had shown clearly whether rat neurons could be incorporated fully into a mouse’s brain circuits in such a way that they would become an essential part of controlling the host animal’s behaviour.

How neurons connect with one another, and fire, makes integrating cells from two species complicated, says Kristin Baldwin, a neuroscientist at Columbia University in New York City. “Neurons are not just Legos,” she says.

Early integration

In a paper published by one of the teams on 25 April in Cell1, Baldwin, molecular biologist Jun Wu at the University of Texas Southwestern Medical Center in Dallas and their colleagues attempted to test this by mixing rat and mouse neuronal cells very early in the mice’s development.

First, they engineered the genes in a group of mice in a way that destroyed some neurons in the animals’ olfactory systems. This disrupted the circuits linking olfactory neurons in the nose with higher brain regions, leaving the mice unable to use their sense of smell to find mini-cookies that the researchers had buried in various places throughout the animals’ cages.

But when the researchers injected rat stem cells into blastocysts — early-stage embryos — of mice engineered in this way, the cells filled the gaps in the brain circuits. And once the mice had grown into adults, they were able to find their cookies by smell. Killing the mouse neurons created “niches” for the rat cells to take up residence in various places inside the animals’ olfactory circuits, as well as elsewhere in their bodies, Baldwin says. Her group is now working on methods for replacing specific mouse neurons with rat cells in a more targeted way.

In a Cell paper published by the second team, also on 25 April2, Wu and his colleagues developed a more aggressive strategy for getting rat cells into a mouse’s brain. Using C-CRISPR, a genetic-editing tool that cuts genes in multiple places to ensure that they are fully inactivated, the researchers wiped out every trace of a gene called Hesx1 in a group of mouse blastocysts. This gene controls the development of the forebrain: a large region in the brain that coordinates much of an animal’s behaviour.

When the researchers allowed these blastocysts to develop into mice without forebrains, the animals died shortly after birth. But when Wu and his team injected rat stem cells into the blastocysts, the forebrains that developed were made entirely of rat cells. Once the mice had grown, they were healthy and seemed to act normally, although Wu says it would be difficult to determine whether there were any subtle behavioural differences between them and normal mice.

Hiro Nakauchi, a stem cell biologist at Stanford University in California, agrees that it would be hard to establish this. Researchers in his laboratory once tried making mice ‘smarter’ by giving them rat brain cells, but they abandoned the effort when they realized that the differences between rodents with and without the cells were too minor to detect statistically without testing the behaviours of a large number of hybrid animals. Still, Nakauchi says that the new papers are meticulous analyses of chimeric animals’ brains — something he is excited about. “This is what I have been awaiting,” he says.

‘Fascinating biology’

Wu and Baldwin say that their research addresses some long-standing concerns about developing chimaeras, particularly for the purpose of transplanting tissue or organs from animals such as pigs into people. Aside from ethical considerations, there is the concern that the human body will reject a transplanted chimeric organ. But because the teams added the rat cells so early in the mice’s development — long before the embryos had formed an immune system — the animals’ bodies never learnt to recognize the cells as foreign and never attacked them.

Another concern is a mismatch in the developmental rates of species. However, the teams found that the mouse brains developed at the same rate as they would normally, rather than at the slower pace at which a rat usually develops.

“There’s lots of fascinating biology to be learnt from this [rat–mouse] chimaera,” says Jian Feng, a physiologist at the University of Buffalo in New York. He’s not surprised that the rat cells followed the pace of the mouse’s developmental ‘clock’. In 2020, his group published a paper about a mouse embryo that it had engineered to contain up to 4% human cells5. The embryo began developing human red blood cells 17 days into gestation — much earlier than these cells develop in human embryos — suggesting that human cells, too, could follow the molecular directions of their host.

Wu says that his laboratory now plans to use the technology developed for these studies to make chimaeras by transplanting cells from wild rodent species into lab mice. It’s difficult to study wild rodents, because they are hard to maintain and breed in captivity, he says. But making stem cells from their tissue samples and inserting them into mouse blastocysts might allow researchers to study how these other species’ brains develop and function.

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Computers

GameScent Wants You to Smell the Gunfire While You Play Video Games

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Burnt rubber and gunfire are not the most pleasing of smells, but for action games, they might be the most common. At least, that’s true for GameScent, a new device that aims to make gaming more immersive by adding smell to the equation.

GameScent, which dropped late last month to a bit of fanfare and some snickering, uses an adapter and an app on your phone to capture audio while you play. It then feeds those audio cues into the company’s “innovative AI,” which then triggers certain smells.

It’s a hexagonal device, compatible with most consoles, PCs, and virtual reality setups, built to hold six different aromas at a time. At launch, those smells are called gunfire, explosion, forest, storm, racing cars, and clean air—perhaps the most important, as it’s intended to neutralize whatever odors may linger.

“We feel like we are adding the missing link, if you will, to gaming, which is the use of olfaction,” says GameScent president Casey Bunce. Future scents the company intends to release include ocean, sports arena, and—perhaps troublingly—blood.

Bunce says that the device’s launch scents—which I’d argue are not the most aromatically pleasing lineup—were largely decided based on requests from gamers. They wanted smells to go along with action or horror games, thus all the explosions and gore.

GameScent atomizer without the lid

Courtesy of GameScent

Those smells can be strong. During a demo of the GameScent at this week’s Game Developers Conference, the device, paired up with Far Cry 6, dutifully pumped out the smell of carnage and burning rubber. It’s set to a two-minute timer, meaning it won’t create a complete haze over your room every time you get into a gunfight—but it’s still better to place the unit far from your gaming perch, rather than sit near it. While its tamer options like forest are nice in a Febreeze sort of way, anyone sensitive to smell, like myself, might get a headache after a few whiffs of car stink.

GameScent’s creators say they hope to release an additional 30-40 scents in the coming year, making it easier for players to customize what they’d like their experience to smell like.

The company’s products are largely made of essential oils, which you can easily pick up at the store. When I asked what’s to stop me from dumping in, for example, my own lavender oils, a rep for GameScent told me “honestly, it would probably work. Look, you might end up clogging the thing and then you just take it out and flush it out with water.” To keep essential oil enthusiasts from using their own smells, the company plans to work with its community through an “insider’s club,” which will take feedback into account.

That being said, GameScent doesn’t plan to supply every user’s demand. “We get a lot of like—you know, X-rated requests,” Bunce says. “Very strange requests.”

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