This blog has been dormant for four years, and I don’t know if this will be a single post or actually represents a first step in attempting to re-establish a writing practice beyond papers and reviews and grant applications again. Time is an issue – not least because ideally I would like to research the topics I write about more than I have done this time. On the other hand, I’m hopeful that I’m on my way to recover some of my time and also inspiration, and arguably I also have more experience to fall back on wi
Two headlines in this week’s mail alert from Nature have inspired the heading. Both have to do with animal embryos developing with human cells incorporated into their bodies. Japanese researchers have been successful in achieving this by injecting the cells directly into the amniotic fluid of pregnant mice, whereas a Chinese team reports growing hearts containing human cells in pig embryos. The Japanese project seems to be more of a technology breakthrough – if that term is even justified for what is perhaps better described as a successful attempt to do something the researchers themselves didn’t really expect to work:
The team used reprogrammed stem cells to grow human organoids of the gut, liver and brain in a dish. Shen says the researchers then injected the organoids into the amniotic fluid of female mice carrying early-stage embryos. “We didn’t even break the embryonic wall” to introduce the cells to the embryos, says Shen. The female mice carried the embryos to term.
“It’s a crazy experiment; I didn’t expect anything,” says Shen.
Within days of being injected into the mouse amniotic fluid, the human cells begin to infiltrate the growing embryos and multiply, but only in the organ they belonged to: gut organoids in the intestines; liver organoids in the liver; and cerebral organoids in the cortex region of the brain. One month after the mouse pups were born, the researchers found that roughly 10% of them contained human cells in their intestines — making up about 1% of intestinal cells
Of course, we should keep in mind that none of the studies have yet been peer reviewed and published. We don’t know the quality of the studies or whether the results can be replicated. But making animals that produce human cells has been a big goal for many researchers for decades, and I don’t see any reason why technology would not continue to develop in that direction. This is not to say that I don’t think this is an unquestionable given, but so far this research is ethically and legally possible in enough countries where there are also resources to develop it. And the technology hurdles are probably gradually being overcome – although as we will see below not everyone is convinced that this is happening any time soon.
Which, then, are the consequences seen from the perspective of my own area of research, animal ethics and the 3Rs of animal research?
In terms of the general ethics of how humans treat other animals, this represents another way in which humans use animals for their own benefit. Whether or not we agree with this widespread human attitude (and there’s a lot to be said about the ethical aspects of it!), for the animals the practice described here is not radically different from other ways they are handled in research and technology. Non-human animals are unlikely to suffer from the concept of being used; what matters is probably what they experience as a consequence of what is done to them – largely what we cover in considerations of the 3rd R of Refinement. Since the studies haven’t been published, how exactly the animals were handled is not known outside the research team itself, but the most affected animals are probably the females carrying the embryos, and that as a consequence of the procedures done to them rather than related to the nature of the embryos.
The 2nd R – Reduction (of animal number) is where this kind of research really has consequences. On the one hand, given that the aim is to have liveborn animals with human tissue (for research or for transplantation), the use of animals is required (in other words, no possibility for Replacement, the first of the 3Rs). On the other hand, this is the kind of research that when successful may lead to an increasing use of animals. The possibility to do research on animals that have organs based on human cells is attractive for biomedical research as a way to overcome the biological differences between species, which then may increase the demand for research animals. In a paper entitled The 3Rs Alone Will Not Reduce Total Animal Experimentation Numbers: A Fundamental Misunderstanding in Need of Correction, philosopher Nico Müller at the University of Basel develops this argument:
The basic problem is that innovation occurs not just in NAMs, but also in animal methods. The assumption that NAMs innovation will in time lead to lower total distress discounts innovation at the other end of the spectrum, that of new distress-inducing animal methods. But of course, innovation in this area is constantly blooming, as every new animal experiment is also a methodological innovation. What is more, these innovations may often conform better to established paradigms and face fewer obstacles than innovative NAMs (Lohse 2021). A stark example of a breakthrough innovation in animal experimentation can be seen in the advent of genetically modified research animals, which led to a significant increase in total animal experimentation numbers worldwide (Ormandy, Schuppli, and Weary 2009). Actual conditions aside, in principle, for every distress-inducing technique replaced, reduced, or refined, two new ones can be invented, such that total distress increases despite the steady progress of the 3Rs. On the whole, the 3Rs can diminish total distress only under conditions that, by coincidence or by design, hinder the innovation and proliferation of new distress-inducing methods. But the 3Rs cannot ensure that such conditions obtain.
https://www.theguardian.com/science/2021/may/15/mixed-messages-is-research-into-human-animal-hybrids-ethical-chimera
Regarding the challenge to how we think about ourselves, I was about to say that this is a question that goes outside my own area of research. But that isn’t entirely true, in that we did discuss the question of species barriers in a series of interviews done by then PhD student Pedro Ramos and published two years ago in New Genetics and Society. We interviewed scientists working with gene editing, and their view of the issue is very similar to that of the scientists that spoke to The Guardian around the same time about chimeras:
Nakauchi, now at Stanford University in California, says that the ethics of such experiments are most fraught if they generate “ambiguous animals, such as a pig with a human face or human brain”. That might be impossible even in principle, given the evolutionary distance between pigs and humans – but for monkeys it’s less clear. So we should avoid making human-animal chimeras with a large human component, he says – and perhaps use genetically modified human stem cells that can’t make brain cells. Wu agrees, but stresses that they never intended to implant any of their chimeric embryos for further growth anyway – the aim is not to grow human organs in monkeys. He doesn’t think that should be contemplated if we don’t know where the human cells might end up. “What matters to me is where the human cells go and how many there are,” says biologist Marta Shahbazi, who works on embryo development at the University of Cambridge. “If we confine them exclusively to an organ of interest, like a pancreas, that’s OK: a mouse with a pancreas made of human cells is in no meaningful sense ‘human’. But for a mouse with human stem cells spread throughout all the tissues, the answer is not so clear. And for a monkey, things get even more blurry.”
What these scientists are speaking about is what philosopher Bernard Rollin describes as telos. As long as the pigness of the pig is not overrun by human characteristics that we prefer confined to the humanness of the human, things are fine. Of course, where to draw that line is not an easy task. Other scientists, however, have a different perspective altogether on whether this is something we need to discuss at all.
Alfonso Martinez Arias, a developmental biologist at Pompeu Fabra University in Barcelona thinks the claims of Izpisua Belmonte and colleagues are completely overblown anyway. He thinks all they have really shown is that when some human cells are added to monkey embryos, they become moribund. “If you add some extraneous cells that make it more difficult for the embryo to survive, what have you learned from what is a rather sick biological entity?” he asks.
“Human-monkey chimeras are not coming soon, and may never come,” he says. “In any case, we don’t need them – not to answer biological questions, nor to solve problems associated with organ donors.”