The monkeys in Douglas Munoz’s Kingston lab look like other monkeys.
They socialize and move around and eat and drink in the same way. They don’t fall over or stagger around. In fact, the only thing separating the macaques from their unaltered lab mates is the elevated level of a specific human protein implanted inside their brains — proteins that accumulate in the brains of humans with Alzheimer’s disease.
The monkeys have been injected with beta-amyloid, a molecule that, in high-enough amounts, is toxic to human brain tissue.
Munoz and collaborators are studying the earliest changes in those monkey cerebrums. Normally it takes several decades for Alzheimer’s to unfold in human brains. The researchers don’t have that kind of time. The injections speed things up.
If left alone, eventually the monkeys will start to show signs of Alzheimer’s. They make more mistakes on memory tasks and their reaction time slows.
Alzheimer’s research relies heavily on rodents. Munoz is trying to develop a monkey model of Alzheimer’s, because one of the biggest reasons for the staggering string of flops in the search for an effective treatment for the brain-ravaging disease is the species gap. The rat brain is a long way away from the human brain. Not so much a monkey’s.
Munoz, Canada Research Chair in neuroscience at Queen’s University, has reported his work using brain molecules. Others are implanting monkeys with fragments of human brain tissue extracted from people who died with Alzheimer’s.
Now, however, some are going further, and proposing the creation of human-monkey chimeras — part-human beings with entire portions of the brain, like, say, the hippocampus, entirely human derived.
For Munoz, the idea of biologically humanizing large portions of a monkey’s brain is seriously unnerving. “To be honest, it just really ethically scares me,” he said. He believes in animal research as a fundamental way of understanding how the brain works. However, “For us to start to manipulate life functions in this kind of way without fully knowing how to turn it off, or stop it if something goes awry really scares me.”
However, in a new book on the science and ethics of chimeras, Yale University researchers say it’s time to explore, cautiously, the creation of human-monkey chimeras.
“The search for a better animal model to stimulate human disease has been a ‘holy grail’ of biomedical research for decades,” they wrote in Chimera Research: Ethics and Protocols.
“Realizing the promise of human-monkey chimera research in an ethically and scientifically appropriate manner will require a co-ordinated approach.”
For me, crossing into the central nervous system, with any species, is probably crossing the line
To some, that may seem all fine and good. However, some scientists aren’t waiting for the ethics to be worked out.
In April, Chinese researchers announced they had inserted a human brain gene into monkey embryos, a gene critical for human brain development.The experiment provoked revulsion, and fascination. Ethicists and philosophers condemned it as hugely morally risky, while the scientists behind the work are said to be keen on implanting even more human genes into monkey embryos, including one presumed to play a role in human intelligence.
Chimeras were once only monsters out of Greek mythology. Today, stem-cell technologies and gene-editing tools like CRISPR may make the generation of these once fantastical creatures possible.
In fact, scientists are already using “xenotransplantation” techniques to create human-pig chimeras, in the hope of one day generating human organs for transplant.
The approach involves using pluripotent human stem cells, cells that have the ability to morph into virtually any type of cell in the body. If the technical hurdles can be overcome, the idea is to block or delete genes critical for the development of a given organ (a pancreas, say) in a fertilized pig egg, and then inject human stem cells into the embryo, to fill the empty gap or niche, and grow the missing pancreas.
The strategy has already been used to grow a rat pancreas in a mouse, and vice versa. Two years ago, Salk Institute scientists reported they had succeeded in creating the first human-pig chimera embryos. None were allowed to grow beyond four weeks, and half were abnormally and weirdly small. But, in others, the human stem cells survived and turned into progenitors for different organs and tissues.
In theory, one could generate a human hippocampus in a monkey in much the same way, by injecting stem cells into a monkey embryo that has been “hippocampus disabled,” said Alejandro De Los Angeles, a visiting researcher in the department of psychiatry at Yale University School of Medicine.
“Such an experiment could prove useful for modelling neurological conditions with human-specific biological features,” he and his co-authors write in Chimera Research.
It’s called “neural blastocyst complementation.”
“Why do it,” De Los Angeles asked in an interview, before the question could be posed. “Why would you want to do this? Why make human-monkey chimeras?”
For one thing, Alzheimer’s and other neurological diseases are particularly horrific. More than 419,000 Canadians aged 65 and older are diagnosed with dementia, two-thirds of them women. It is the only major cause of death in Western countries without an effective treatment, despite billions spent trying to find one.
Today, the best monkey model of Alzheimer’s disease is just an old, aging primate. But whether monkeys or other nonhuman primates even get Alzheimer’s is controversial. As well, while aging primates, like humans, undergo cognitive decline, their hippocampus, the region associated with memory, is largely spared.
“You could imagine if you had a disease model that more closely recapitulated human disease, that would be helpful for the community,” De Los Angeles said. Chimeras could be used to study the disease and screen promising therapies. “Probably the closest thing to a human brain would be to have a human-monkey chimeric brain,” he said.
I think that is a place we should not be goinggr
But when does a chimeric brain becomes less monkey, and more human?
“It’s a very ethically sensitive topic,” De Los Angeles admitted. It’s one of the reasons why he and his co-authors don’t propose doing human-ape chimeras, only human-monkey, because we’re more distantly related. Human-monkey beings, he said, “may not develop the level of human consciousness that people are afraid of.”
It also depends on the “contribution” levels, he said, meaning, what proportion of donor cells come from species A — the human. One per cent might be enough where it’s still beneficial, he said, but where the risk of the chimera being “too human” isn’t too high.
He and his co-authors do worry about the enhanced capacity for suffering. As well, “Whether chimerism in portions of the monkey brain would affect cognition or emotion is unknown,” they wrote. (The monkeys created with human brain genes in China are exhibiting eerie changes that suggest they might be smarter.)
“The issue is complicated by the fact that no human-monkey chimera can have any chance at life at all,” they wrote, “except as a research subject; it may be that, if the chimera has a life that is not too burdensome, there may be fewer objections to its having been created in a lab.”
The authors are recommending a step-by-step approach. For example, before making human-monkey chimeras, it might be prudent to make monkey-ape chimeras, they said. All human-monkey chimera research should be independently monitored, to make sure it complies with animal welfare standards. And, should any “abnormal” behaviours in the chimeras be discovered, “researchers and oversight committees should try to assess any changes in moral status,” others argue in a separate chapter on chimeras and the “moral staircase.”
The U.S. restricts federal funding for certain types of stem cell-based interspecies chimeras, but, through private and nonfederal funding, the research is happening.
As Dalhousie University bioethicist Francois Baylis has pointed out, only one type of part-human chimera research is criminally outlawed in Canada under the Assisted Human Reproduction Act — the kind that involves putting nonhuman stem cells into human embryos. Directionality,” she wrote in Impact Ethics, matters.
De Los Angeles, co-editor of the new resource guide on chimeras, said patient need is driving this. “We need guidance on whether there are compelling ethical reasons not to conduct this research,” he said, “especially reasons that are sufficient to outweigh its humanitarian aims.”
But others said not enough is known about how cells and genes function. What kind of things would we need to turn on and off so that researchers could selectively have a piece of human hippocampus, but the rest of it is monkey?
And, even if the human complement is kept to one per cent of cells, one per cent of what? One per cent of all cells throughout the body? Okay then, sure. It’s going to look like a monkey, and act like a monkey.
“But if all of those one per cent of cells are in the brain, then at least in that organ there is a much bigger percentage,” Munoz said.
Certainly, any science that raises the risk of the humanization of a monkey brain provokes a visceral horror. It’s one thing to “humanize” an animal for, say, a pancreas, it’s another thing when you are talking about the brain, said Dr. Judy Illes, professor of neurology and Canada Research Chair in neuroethics at the University of B.C.
And, if human-monkey chimeras are enough to serve as ideal models of Alzheimer’s, or psychiatric illnesses like bipolar, are they human enough to deserve the same moral status?
Why would you want to do this? Why make human-monkey chimeras?
“For me, crossing into the central nervous system, with any species, is probably crossing the line,” Illes said.
“The brain gives us cognition, gives us reflection, gives us insight, and gives us language. And I think that is a place we should not be going.”
The scientific logic is also fractured, she argued. “Why humanize a monkey, if that’s what we need to do? If that’s justified scientifically, then we just need to be doing the experiment on humans. We don’t need to do it on a humanized monkey.”
We need to slow down and think through the ethical ramifications, added philosopher Letitia Meynell, of Dalhousie University.
Yes, it’s “really cool science,” she said. “But it’s highly speculative it would ever work out.”
What’s more, monkeys and other nonhuman primates are cognitively and emotionally complex, social animals, Meynell said. Left in their natural habitat, they form large families, large social groups.
“We have to ask, what is it about humans that make it wrong to do certain kinds of things to us? And, once we have identified what that feature is in us, we can look at other animals and say, ‘well, do they have that feature too?’
“My worry is, are they already sufficiently like us in the relevant ways that maybe we shouldn’t be doing these things to them?”