For the first time, researchers have used cells from one species to restore the sense of smell in another.
In an article published April 25 in Cell, researchers from Columbia University described how they used neural stem cells from rats to restore olfactory neural circuits in mice. While the procedure didn’t work in all of the animal models, a subset of them were able to sniff out cookies hidden in their cages.
“This is the first time, to my knowledge, that the sensory system from one species could actually inform the behavior of another,” Kristin Baldwin, Ph.D., the paper’s lead author, told Fierce Biotech Research in an interview. “That tells you that it’s possible….[then the question becomes] how does it work and why does it work?”
Cross-species chimeras, including human-animal chimeras, have long been part of scientific research. “Humanized” mice—mice implanted with human cells, genes or tissues—are routinely used to study cancer and drug toxicity. Pig hearts have been transplanted into humans, as have their kidneys.
Such work in the brain, however, is only just catching up. The past few years have seen the first human-rat brain hybrids, including some that respond to visual stimuli. That’s not to say that same-species neural transplants haven’t already been tried, including in humans: A company called BlueRock Therapeutics is running a phase 1 clinical trial on a therapy that involves surgically transplanting dopamine neurons into patients with Parkinson’s disease.
The Baldwin lab’s approach to neural transplant involves a technique called blastocyst complementation, where pluripotent stem cells are transferred into a very early-stage embryo called a blastocyst. This is similar to how interspecies hybrid mice are made, but with a key difference: The animals on the receiving end have been rendered unable to perform certain functions—say, make a certain organ or cell type—that the transplant may be able to restore. And, in this particular instance, the transplanted cells are coming from a different species entirely.
While BlueRock Therapeutics’ idea of transplanting dopamine neurons in adults may be effective, mouse studies have shown that there are limits to how much function transplants at later stages can rebuild, Baldwin explained. The cells need to grow alongside other parts of the brain to form the prerequisite networks.
“We wanted to find out, if you start earlier, are there pathways of plasticity or ways that you can get the brain to be more welcoming, more permissive, more flexible in terms of incorporating other kinds of cells and using them functionally?” she said. “We’re sort of probing what’s possible and trying to find a way to understand when this kind of replacement works and doesn’t work.”
Give a (hybrid) mouse a cookie
Baldwin’s lab used two different types of mouse models for the research, one with its smell neurons completely removed—a so-called “killing” model—and another where they were simply “silenced,” or still intact but unable to communicate with each other. They used the same techniques to insert rat stem cells with green fluorescent markers into mouse blastocysts, then examined their form and function when the mice reached adulthood.
The team was surprised by the results. They had expected that the mice with the “silenced” smell neurons would be more amenable to replacement by the rat cells, Baldwin recalled. But that wasn’t the case. Despite the fact that the neural circuits looked “beautiful” compared to the ones in the mice that originally didn’t have olfactory cells at all—and appeared to be functional—the mice couldn’t find a hidden cookie in their cage.
“That was upsetting because we really wanted to rescue this,” Baldwin said. But when they ran the same type of experiment on the mouse models that originally had no olfactory neurons, they found that the rat cells had indeed restored their sense of smell: The mice were able to find the hidden cookies.
“It turned out that those animals actually could be rescued by the rat cells,” she said. “That was great because we had one model where it worked and another model where it didn’t. That’s saying that it can’t work in every case, but there are ways to understand the difference between rescuing a behavior and not. So it was a surprisingly good result.”
Why might the experiment have worked in the mice without any cells at all? While the team isn’t sure, one simple explanation might be that there was competition between the mouse cells and the rat cells, Baldwin said.
“When there are no mouse cells with no competition, perhaps the rat signal finds it easier to get through,” she explained. “But we don’t know, and we’re quite interested to find out.”
The researchers noticed that in the mice without any olfactory neurons, the rat stem cells formed their own processing centers rather than integrating into the ones in the mouse brain. The fact that these animals passed the cookie sniff test raises the intriguing possibility that they might be able to respond to odors detectable by rats, but not by mice.
“The number of animals needed kept us from really testing that, but it gave us an idea that you might be able to expand the sensory capacity of an individual animal or species at some point,” Baldwin said. “We know we can do that because some humans have more odor receptors than others and different ones. We’d love to delve further into that.”
Baldwin’s team also hopes to study more customizable circuit replacements that could be integrated into better models for studying human neurological disease and, ultimately, lend themselves to hybrid brains with more distant species, like non-human primates. They’re also curious about whether the brain is plastic enough to accommodate characteristics from both closely related and very different types of animals.
“The two main areas we’d like to go towards are more specificity and how much flexibility is in the brain to interpret signals from disparate species,” Baldwin said. “I mean, if you could put bat cells in and get sonar in a mouse, that would be fantastic.”
For human health, the main goal is not to use the techniques employed in the study to actually restore functionality, but rather to come up with human models that can help test potential treatments. Cross-species brain models could be used to study drugs on highly specific hybrid circuits implicated in diseases that would otherwise raise ethical issues, Baldwin said.
“At least with these models, we can try to do a lot of different experiments at a lower cost than a clinical trial,” she explained. “This is a type of model that hasn’t been available before.”