Human/monkey chimeric embryos: context and questions

'What is the moral status of these novel creatures?' Scientists raise ethical concerns after lab creates a human-monkey HYBRID for cancer research' – Headline from the Daily Mail

On 15 April 2021, the journal Cell published a paper reporting the creation of part monkey, part human embryos (see BioNews 1091). The international team of researchers had injected human stem cells into 'blastocysts' (embryos about six days after fertilisation) of cynomolgus monkeys (aka 'crab-eating macaques'). Each blastocyst received 25 human cells, produced from a human donor's skin cells. Monkey blastocysts, like human blastocysts, normally must be transferred into a uterus by the sixth or seventh day to survive. These instead were treated with new methods allowing them to live in the lab for about 20 days. By the fourth day after the injection (tenth after fertilisation), about 100 embryos were still developing; that plummeted to three by day 19 and zero by day 20. Embryos that had continued to develop contained non-trivial amounts of human cells, on average three to four percent.

I was disappointed in the British tabloids. I expected headlines along the lines of 'I, For One, Welcome Our New Humkey Overlords'. (The Daily Mail did, at least, confuse chimeras with hybrids, as can be seen above.) But the experiment did attract substantial attention.

In the same issue of Cell, my colleague Professor Nita Farahany and I published a commentary on this experiment in which we laid out what the ethical issues with this experiment were – and were not. We were given 1000 words and took 1100, but much remains to be said. Here I was given 800 words, expanded on appeal to 1100, which I will use to note three crucial contextual aspects of this experiment and then the five ethical questions.

First, no humkeys were created or sought to be created. The embryos were never moved into a uterus and had no chance of developing; all died by the 20th day after fertilisation. This was purely in vitro experimentation with tiny balls of cells.

Second, unlike almost all work with chimeras, this research injected cells into blastocysts – not just any cells but pluripotent ones, able to form many cell types. If you put human neurons into a rat's brain, they should stay neurons and stay in the brain, where they will be vastly outnumbered by rat neurons. With pluripotent cells in an otherwise normal blastocyst, the human cells could become any cell type, in any proportion. They might make up ten percent of one kidney, 50 percent of another, 25 percent of the cerebrum, 60 percent of the cerebellum, or all of the cells in one testis or ovary.

Third, monkeys are not rodents. They are millions of years closer to humans in evolutionary time; they are also vastly closer in their behaviours and perceptions to humans.

This experiment raises five ethical issues: its justification, animal welfare, human subjects, species mixing, and public engagement.

First, did the research goals justify this use of female monkeys, monkey embryos, and human pluripotent cells? The lead researcher for the paper in question, Professor Juan Carlos Ispuiza Belmonte, is eager to grow human organs in pigs to use as transplants in dying people. He does not want to grow human organs for transplant in monkeys. His earlier work had shown that pig embryos take up only a trivial number of human cells, and in this research he sought to find out whether the more closely related monkey embryos would take up more cells. He hoped to use success to figure out how to make pig embryos more receptive to human stem cells. In addition, this research might provide more information about how human cells develop in embryos beyond the current 14-day limit on keeping human embryos alive in a laboratory.

The goals seem worthwhile and at least marginally plausible. The researchers showed that monkey embryos take up more human cells (although still not many), and next they have to figure out whether that will help with pig embryos. This research is one step; it's like driving from Mexico to Oregon on Interstate 5 in my home state of California; they just passed La Jolla, at mile 26, but have 770 miles to go, with ever present risks of permanent blockages. Justifying the research on the grounds that it will provide insight into embryonic development has also taken a small step, although its value depends on how relevant the behavior of human cells in an ex vivo monkey embryo is to human cells in an in vivo human embryo.

Non-human animals were used in this research and animal welfare must be considered. Here it's not the welfare of the doomed and brainless embryos but of the female monkeys whose eggs were harvested to make the embryos. Animal research committees approved this work so presumably it was appropriate, but the questions must always be asked.

Humans were also used in this experiment; at least, a stem cell line derived from one human. Human research panels approved this research. Presumably, it met their standards for informed consent. But what standards? One hot issue in bioethics is whether particularly controversial research involving human tissue should require that the person whose human tissue is used specifically consented to such contentious research. Was there specific consent here? We don't know.

Some people believe any mixing of tissues from two species is wrong – against the wills of God or nature. Given the scope of this kind of chimeric mixing in nature (some women who have been pregnant carry some cells of their former fetuses in their bodies forever), in medicine (think of the many pig heart valves keeping people alive), and in research, it is hard to make an intellectually strong case that this kind of mixing is improper. Still, the argument has great visceral appeal.

Finally, this research was a surprise. A Spanish newspaper had leaked a story about it in July 2019 but the researchers didn't comment on the paper or confirm publicly what they were doing. Science makes a bad mistake when it springs disconcerting surprises on the public. The researchers have a strong case that their research is not just appropriate but is a moral response to the vast number of people who die every year waiting for organ transplants. They should have made that case, publicly before the decision was made to proceed with the research. Instead, they kept the research secret.

That is what I think about this experiment. But this research opens a door for further experiments, where the embryos are transferred into monkey uteruses for possible pregnancies or even, perhaps, for live births. What ethical, legal, social, and political issues would those experiments raise? This research is an alarm, warning us that it is now time to think about those next steps.