How Scientists Grew Human / Monkey Chimeras to 20 Days Gestation
There is an ethical limit somewhere. We need to figure out where the line is ASAP.
It’s a tale as old as civilization, and probably older. The human-animal chimera. From the minotaur of King Minos, to the Fly of Jeff Goldblum, we are simultaneously fascinated and horrified at the possibility of bridging the gap between humankind and wild beasts.
To be fair, science fiction has outpaced science fact in this regard. But human-animal chimeras have been created. Though, never, until now, in as advanced a state as is reported in this paper appearing in Cell — which has pushed our ethical envelope further than ever before and will force us all to grapple with some really fundamental questions — like what it means to be human.
The headlines write themselves, of course. “Human-monkey chimera created” is, well, now technically not hyperbole. But let’s be really clear about how this set of experiments worked, and how they were different from what went on before.
Chimeras — single life-forms with cells bearing different genotypes — are everywhere. You need look no further that your local florist to find chimeric roses, for example.
And human chimeras — individuals with at least some cells having a different genotype (probably an absorbed twin) were documented as early as 1953.
But interspecies chimeras, in the animal kingdom at least, are a bit of a hurdle. Species that are relatively closely related can chimerize more easily — one of the first successes was a sheep-goat chimera documented in Nature in 1984.
What about Mules? And Ligers? Bred for their skills and magic? No — they are hybrids not chimeras — they have a single genotype, albeit contributed by parents of two different species, as opposed to multiple genotypes in one organism.
Rat-Mouse chimeras work out pretty well — the two rodents diverged evolutionarily only about 18 million years ago. Here’s a rat-mouse chimera with its pups for example.
That organism is about mouse-sized, but has rat cells throughout. There are rat neurons in its brain, talking to all the mouse neurons. It’s actually sort of mind-blowing. Rat cells end up in the mouse gallbladder, acting just like gallbladder cells. But rats don’t have gallbladders. The mouse microenvironment was essentially able to turn on some latent gallbladder cell making machinery in rat DNA. Mind blown.
To make a chimera, you take some developing cells from one animal, and stick in some developing cells from another animal. Yes, it is more complicated than this, but that’s the gist.
The trick is figuring out what cells you want to inject. And this has not just scientific, but ethical implications. For example, in 2003 human skin cells were inserted into a rabbit ova which went on to develop for a few days before being destroyed.
Skin cells are one thing — but pluripotent stem cells — those bundles of pure possibility that can morph into any cell in the body, from white blood cell to neuron, from cardiac myocyte, to proximal tubule cell — those raise thorny questions.
But, until now, we haven’t had to face them head on. Because human pluripotent stem cells don’t integrate well with developing cells from other species. Prior studies trying to integrate human pluripotent stem cells into mouse or pig embryos were not terribly successful — the human cells sort of died off as the embryo grew.
But mice are not men. And though all animals are equal, some are more equal than others.
Enter the Crab-Eating Macaque (Macaca Fascicularis). This old-world monkey is closer to us on the tree of life — our common ancestor lived about 25 million years ago.
Researchers, led by Tao Tan from China, thought a Monkey-Human chimera might be more stable.
The team took monkey embryos at 6 days after fertilization, and injected them with 25 human pluripotent stem cells.
Then, using a novel technique, they allowed the embryos to develop, ex vivo, for up to 20 days. That’s pretty long as these experiments go. The human cells carried a fluorescent label, so they could track their descendants over time.
The big news comes from this figure.
Up to day 20, you have persistence of human cells in the developing embryo, particularly in the epiblast which will give rise to the major cell lineages. About 8% of the embryonic cells were human. Just to drive home the point, 92% were monkey. This is several orders of magnitude more retention than prior experiments using other mammals.
The authors go on to show how these cells behave and interact — the paper is definitely worth a read, but the implications are pretty startling. This could be the start of an entirely new field of medical research. The main limitation of animal research has always been that the cells we are studying in the animals aren’t human. Now, we can see how a drug affects a living, functioning, real human hepatocyte — not in cell culture, but in a working liver — without exposing a living, functioning, real human to the risk.
But it also means we’ve reached a point where we need to ask hard questions. The researchers didn’t allow these embryos to develop fully, but what if they did?
If 1% of cells in that baby monkey were human, is the monkey human? What about 10%? 50%? Where do you draw the line?
What if instead of pluripotent cells we use cells that can only develop into one organ? Would you treat a monkey with human cardiac myocytes different than one with human hepatocytes? What about human neurons? Does the host matter? Would you feel differently if this experiment was done in Chimpanzees?
Currently, the NIH moratorium on funding human-animal chimera research stands, but they have announced an intention to lift it — although perhaps excluding cell lines that could produce human neurons.
The American public, according to one survey, broadly supports this research.
Barring substantial opposition, human-monkey chimeras may soon be coming to a lab near you. No, it probably won’t be the Rats of NIMH. But it is a Brave New World.
A version of this commentary first appeared on medscape.com