In Greek mythology, the chimera was a beast of fire and fury; a terrifying creation part-lion, part-goat, part-serpent, and all destruction. It took demigod Bellerophon to slay the monster, driving a lead-tipped lance into its throat.
One wonders what Bellerophon might have made of the chimeras running around Steve Goldman’s labs.
The son of Poseidon would certainly be less threatened; they are, after all, just mice. But inside their tiny furred heads, their brains are significantly human — and it shows.
These human-mouse chimeras are smarter than their “pure” mouse counterparts, and excel on all the standard tests of brain function.
They’re not solving cryptic crosswords or doing Sudoku just yet.
But these chimeric creatures are nonetheless on a challenging frontline, of both stem cell medicine and research ethics.
Making mice brains more human
Professor Goldman and his colleagues are studying diseases of the brain and central nervous system, at the Centre for Translational Neuromedicine at the University of Copenhagen and the University of Rochester.
They’re interested in a class of cells called glia, which are found in the brain and central nervous system.
Glia are essential to the healthy functioning of the nervous system — although they’re not neurons — and are at the centre of diseases such as multiple sclerosis and Parkinson’s disease.
There’s also the suggestion that glia could be important in diseases such as schizophrenia and even autism.
Studying the underlying physiology of these diseases in humans can be difficult, because researchers can’t biopsy a living human brain to see how the cells are behaving and changing.
But mouse models of these diseases aren’t a perfect facsimile of what’s happening either.
This is where the chimeras come in
Professor Goldman’s lab takes skin cells from healthy children and children with schizophrenia, tweak those cells using stem cell technology so they become glial progenitor cells — cells that can turn into any form of glial cell — then implant those cells into the brains of mice.
Over time, the human glial progenitor cells take over the mouse brain. As the mouse’s own glial-derived cells reach the end of their life cycle, they are replaced by the ones produced by the human glial progenitor cells.
Eventually, the mice reach the point where the majority of their glial cells are human.
“It’s like using the mouse as a test tube within which to look at how human cells do in the brain in vivo,” Professor Goldman said.
“Except as far as the cells are concerned, they’re in a human, they don’t know that the host is a mouse.”
The healthy chimeric mice learned more rapidly than normal mice on every test of performance.
And, most importantly for the purposes of understanding disease, the mice that received the progenitor cells from the patients with schizophrenia also displayed abnormal behaviour patterns that, while not strictly like human schizophrenia, were nonetheless a fairly consistent deviation from “normal” mouse behaviour.
While these chimeras aren’t human, can we still call them mice?
Professor Goldman argues that they’re still very much mice, but ones whose natural cognitive capacities have been enhanced by the addition of human cells.
“What we’re really doing is maximising the potential of the mouse brain,” he said.
While the glial cells might be mostly human, the underlying brain architecture — the neurons — are still mouse.
“That output is still coming through the neuronal network, so as long as it’s a neuronal network that’s mouse, then it’s still a mouse.”
How to grow an organoid
Over the other side of North America, Fred Gage is also making chimeras. At the Salk Institute in California, Professor Gage had been growing human brains in a dish — so-called brain organoids — using human stem cells to study human brain development and neurological disease.
But when the organoids got to a certain size, the interiors would start to die because of a lack of blood supply.
So Professor Gage and colleagues hit on the idea of implanting these tiny human brain organoids into the brain of a living mouse, so the mouse’s neuronal blood vessels could infiltrate the human brain organoid and keep it supplied with oxygen.
The implanted organoids did more than that. They started extending neurons out into the mouse brain, and interacting with the mouse neurons.
The researchers looked for changes in behaviour, but unlike Professor Goldman’s work, they saw little difference between implanted and non-implanted mice.
If anything, the implanted mice performed less well on some tests, but this may have been because of the damage done in the process of implanting the organoid.
‘Special’ human DNA?
Chimeras are nothing new in medicine. Engraftment studies — implanting or generating human organs in animals — have been done for quite some time, University of Melbourne stem cell scientist Megan Munsie points out.
But it’s not something that has always sat easily with the community.
“I think this blurring between species is always something that makes people uncomfortable,” said Dr Munsie, who is also head of Education, Ethics, Law & Community Awareness at Stem Cells Australia.
Scientists in the US have created the first human-animal hybrid foetuses
She stresses that there is strict ethical oversight of chimeric research — as with all medical research — and there are also clearly established boundaries to prevent the creation of human-animal embryos.
“You take steps to ensure that either they cannot contribute to the formation of gametes [eggs or sperm], or if there is a chance, then there is no opportunity to breed.”
But even she was intrigued by the notion that mice implanted with brain organoids might behave differently, and what this could mean for their “identity”.
“At the moment, that should be the question that the ethics committees that oversee this work are asking and are thinking about, at that institutional level,” Dr Munsie said.
“The science is evolving all the time, we need to make sure discourse is also evolving.”
Chimeras, and the discomfort with them, highlight what Monash University bioethicist Robert Sparrow describes as a “hypocrisy” in the way we regulate the medical uses of animals.
“We still have this idea that just being human makes us special, just having human DNA makes us special,” Professor Sparrow said.
“And there’s a long history of argument in philosophy and bioethics, pioneered by Peter Singer, which says actually what matters is not what you’re made of, but what you can do or how conscious you are.”
These neurological chimeras in medical research put pressure on both those schools of thought.
Now that the mouse has human cells in it, people start to think it’s special, Professor Sparrow says.
But pigs can out-perform a mouse routinely and have a complex emotional life — yet huge numbers of pigs are used in medical research, without warranting any special treatment.
Our world is deeply organised around the distinction between human and non-human animals, Professor Sparrow said, so crossing those boundaries matters.
“You don’t do these experiments if you think that merely having DNA makes you special; you couldn’t do these experiments, except that you run a line that DNA doesn’t matter,” he said.
“But if DNA doesn’t matter, then we probably shouldn’t be doing … ordinary primate experiments; we should probably be vegetarians.”
However, from Dr Munsie’s perspective as a stem cell scientist, the benefits of this sort of research far outweigh the cost.
“The fundamental question has to be, what is the justification for this technique?” she said, pointing to research done with brain organoids that explored the devastating effects of Zika virus on foetal brain development.
“That is a huge contribution to knowledge, from this new technology, and to me that’s a justification for why we should grow brains in a dish.”