It is striking just how little we know about human development, especially given we are now decades into the modern era of biology. How is it possible that we understand exquisitely well how worms, fruit flies, and rodents develop, but our own species’ development remains a black box?



Paul Knoepfler (@pknoepfler) is a stem cell biologist at UC Davis and writes about science at The Niche. His most recent book is GMO Sapiens: The Life-Changing Science of Designer Babies.

One big reason is that for a long time, the politics of doing science on human embryos and fetuses have been radioactive. The recent smear campaign against Planned Parenthood’s fetal tissue practices is just the latest example of how these ongoing attacks have had a chilling effect on laws that might advance human developmental biology research. But things are beginning to thaw. On August 4, the National Institutes of Health (NIH) announced that it is poised to reverse a previous policy barring funding from a potentially lucrative area of research involving human chimeras.

Human chimeras are mixtures of human cells with rodent, pig, or other animal embryos. It is important to note that this research does not directly use human embryos or fetuses, instead relying on pluripotent stem cells, which can be taken from a person’s skin and genetically engineered to be pluripotent—meaning they can develop into nearly any cell type. Human chimeras have great potential to enhance our understanding of human development. Among other things, this kind of work could lead to discoveries about human brain development, a fascinating, but scientifically very challenging area of study. Human chimera work could also shed new light on serious human developmental problems, and even be used to manufacture donor organs—if chimeric embryos are allowed to develop into fetuses.

As a stem cell and developmental biologist, I find the prospect of chimera research exciting and generally support this work, as long as it is conducted under appropriate oversight and training. But there are tough bioethical questions here, too.

For instance, how long should human chimeras be permitted to develop in a research laboratory? There is no universal, concrete answer, but this question must be discussed and clear guidelines established depending on the number of human cells used.

How do we handle human cells being present in a developing chimeric brain? How many human cells would be too many, risking creating a brain that has substantial human attributes? There is a Catch-22 situation here. The closer you get to the valuable range for neuroscience research (at least a few percent human neurons, for instance, in the chimeric brain), the thornier the ethics get.

To illustrate the complexity, we can look at the example of a recent study in which scientists created chimeric mice with a type of human brain cell called glia; these cells were present in a high abundance in the mouse brains. While glia are not believed to directly contribute to human thought, as neurons do, these chimeric mice were much smarter than normal mice. For instance, the chimeras were about twice as good at navigating mazes as regular mice and exhibited other signs of exceptional memory. This intriguing finding also points to the complexities of possible human chimera outcomes. There’s no clear dividing line on the question of “overly” human chimeric brains because we lack an understanding of at what point “humanization” of an animal brain could lead to more human-like thought or consciousness. We don’t even know when this happens in the normal developing human brain.

What if a research team, only after studying a chimeric brain, realized that despite careful planning they had created a chimera that had an unexpectedly high number—say, 50 percent—of human neurons? Is it then retroactively unethical to have made and used that chimera in research? Did that chimera potentially fall into some uncomfortable gray zone between an animal and human research subject? What if researchers developed an organ transplant chimera that was all pig except for one human kidney, but it also accidentally had human sperm or eggs? Is that ethically okay, as long as it isn’t allowed to breed? When it comes to human chimeras, we need to anticipate and discuss such theoretical outcomes, no matter how remote, before scientists start the NIH-funded chimera research in earnest.

Other tough questions are popping up as well in related areas of cutting-edge research using human pluripotent stem cells. For example, researchers are now able to grow miniature versions of human brains and other organs from pluripotent stem cells in a dish in the lab. This powerful research on so-called human “organoids” has tremendous potential for biological research and organ transplants. But along with that potential come profoundly challenging questions. What if human mini-brains in a dish could “think” or be conscious at a certain level? Some scientists believe that could never happen. I am not so sure that “never” is a safe response. These are not just philosophical musings. While my own laboratory does not do chimera research, right now there are human mini-brains in development.

At the level of practical medicine, there’s a desperate need for kidneys, livers, and other organs for those people on the (all too often fatal) transplant waiting list. The actual first organ transplant from a chimera could be a decade or more away. But, scientists like me have real hope that this could happen, and we have to start down that research path to have a chance of realizing its potential.

Overall, human pluripotent stem cell and chimera research can be both ethical and uniquely catalyze new discoveries that have strong impact on knowledge and health. However, we must accept the reality that this innovative work will yield chimeric outcomes of biomedical advances mixed with difficult questions. If we tackle, rather than avoid, these questions, not only can these efforts provide a foundation for more ethically rigorous research, but also produce revolutionary insights into what it means to be human.

Excerpt from:  

Human Chimera Research’s Huge (and Thorny) Potential