Chimeric Monkeys? Where Do We Go From Here?

What is a “chimeric monkey”? Why would anyone want to create them? And why should anyone care?

In ancient myth, a chimera was an animal with a human head and, say, the body of a horse or a lion. That’s not what’s going on here.

In biology today, a chimera is an animal that comes from two or more embryos. This happens naturally, when twins are conceived but the two fertilized eggs fuse into one embryo, eventually producing one individual.

In research, scientists create chimeras in order to study how cells function. Mice chimeras are now commonplace in stem cell labs around the world. Researchers add stem cells to an early-stage mouse embryo (a blastocyst). If the experiment goes well, the developing mouse will have cells from two sources: the “host” embryo and the implanted cells. The implanted cells often integrate into the body and brain of the mouse pup. By this test, researchers know that the implanted cells are truly stem cells—or, more precisely, that they are pluripotent, capable of becoming any type of cell in the mouse body.

Caption: Chimero, a chimeric Rhesus monkey produced by aggregating six Rhesus blastocysts. Photo credit: OHSU.

Researchers also implant human stem cells into mice. If they multiply and are fully integrated into the body, it’s pretty clear that they are pluripotent and capable of functioning within a living biological system and not just in a dish in a lab. In that case, the mouse is an “inter-species” chimera. Two embryos, of course, but from two different species, human and mouse.

For all the ways in which mice resemble human beings, there are big differences, some of which are particularly noticeable at the earliest stages of life. So when researchers at the Oregon National Primate Research Center at Oregon Health & Science University tried to put pluripotent monkey stem cells into monkey blastocysts, they failed. At the blastocyst stage, Rhesus monkeys don’t behave like mice.

The Oregon team, led by Shoukhrat Mitalipov, kept trying other approaches, finally discovering a completely different technique. Instead of using embryonic or pluripotent stem cells and adding them to a blastocyst, they backed things up, at least in terms of embryonic development. How far back? All the way to the four-cell stage. When a Rhesus monkey egg is fertilized (in this case, in a lab dish), it divides into two cells, then four. What happens if two cells in one blastocyst were combined with two cells from another blastocyst? Success—but still only partly so.

So they tried another approach, one that seems complex and counterintuitive. Researchers “aggregated” three blastocysts—and “they” began to function as one embryo. Four blastocysts—same result. Five, even six blastocysts. They did this 29 times and produced 29 viable chimeric embryos. Or to quote the original paper: “Remarkably, all 29 aggregates developed to blastocysts…”

Just what will this mean for the field of stem cell research? At the very least, this research points to the complexity of living biological systems. It’s nice to think that researchers can extract pluripotent stem cells, keep them multiplying indefinitely, direct them to develop just the right way, and implant them into the human body to regenerate tissues. If only it were that simple. As the field advances, it is clear that what was once called “pluripotency”—the ability to become any cell type—is anything but clear or simple to define.

All the more reason, I believe, why the field needs to move forward as a whole. It’s morally and scientifically simplistic to say that the field can advance without cells from embryos.

But does the Oregon work suggest a step too far? For many, it may be morally permissible to work with cells derived from blastocysts, perhaps donated from IVF clinics and due to be discarded anyhow. But what the Oregon work seems to signal is that when it comes to primates—including human beings—the cells in the living blastocyst are significantly different from the cells derived from the blastocyst. The cells in the living blastocyst, though dynamic and changing, can be regarded as totipotent, capable of becoming any cell type including the placenta and umbilical cord. Cells derived from the blastocyst—human “embryonic” stem cells or pluripotent cells—have lost part of this potential.

Does this mean that research, in order to go forward, needs access to cells as they exist in living blastocysts? That would be a step clearly beyond federal funding guidelines (the “Dickey-Wicker Amendment”). Even with private funding, it would likely exceed what most Americans can support. In some states and many countries, it would be plainly illegal.

And yet this is exactly what lead Oregon researcher Shoukhrat Mitalipov seems to have in mind. "We need to study not just cultured embryonic stem cells but also stem cells in embryos,” Mitalipov said in a release from the journal Cell. “It's too soon to close the chapter on these cells." Is that OK as long as he sticks to non-human primates?

Mitalipov is clearly right: "We cannot model everything in the mouse." Rodents and primates are different in unexpected ways at the earliest stages. Stem cells inserted in mouse blastocysts form chimeras, but not in primate blastocysts.

Quoting Mitalipov once again: "The possibilities for science are enormous." All the more reason to think this through. As complex as the science might be, the moral and religious implications are even more complex.

I for one need time to think this through. I hope to be back here before long with some more thoughts. For now, let me recommend a statement that I helped prepare a few years ago on the question of chimeras.

The paper, "Generation of Chimeric Rhesus Monkeys," was released on January 5 and will appear in the January 20, 2012 issue of the journal, Cell.

Are You as Empathetic as a Rat?

Empathy is the capacity to share the emotional state of another. Politicians claim to have it when they say “I feel your pain.”

Even if they do not always show it, human beings are clearly capable of empathy. Other primates such as chimps have been observed acting in a way that is best explained by empathy. Rather than acting for their own benefit, they sometimes act because they share the feeling or distress of another chimp. Such behavior is said to be “empathy-driven.”

Once it was thought that only human beings could feel empathy. Now researchers are finding that empathy-driven behavior is more widespread than previously imagined. Not just other primates but even rodents, it seems, are biologically capable of empathy. For all the differences between the human and the rat brain, we share fundamental circuits that make it possible to feel the emotions of another, particularly when the other is in pain or distress.

In a simple experiment reported in the December 9 issue of the journal Science, researchers provide solid evidence that the much-maligned rat is capable of acting in a way that is most easily explained by empathy.

"This is the first evidence of helping behavior triggered by empathy in rats," said Jean Decety, a member of the research team at the University of Chicago. "There are a lot of ideas in the literature showing that empathy is not unique to humans, and it has been well demonstrated in apes, but in rodents it was not very clear. We put together in one series of experiments evidence of helping behavior based on empathy in rodents, and that's really the first time it's been seen," Decety said in a release issued by the University.

In order to act in a way that is empathy-driven, an animal must be capable of “emotional contagion.” To test whether rats have this capacity, an experiment was designed Chicago psychology graduate student Inbal Ben-Ami Bartal. Two rats were placed in an enclosure, one of them roaming freely while the other was locked inside a tube. The free rat, in time, could discover how to open the lock, but there was no reward for doing so.

The experiment was designed observe whether rats show they are capable of emotional contagion. Was the free rat biologically capable of emotional concern or what the paper defines as “an other-oriented emotional response elicited by and congruent with the perceived welfare of an individual in distress”?

PHOTO: ©Science/AAAS.

The free rats not only learned to open the container but did so repeatedly when it held another rat, something they did not do if it was empty or if it contained a stuffed animal.

Even more striking was their behavior when chocolate chips were involved. In one variation on the experiment, two enclosures were used, one with an enclosed rat and the other with five pieces of chocolate. The free rat has a choice: free the cagemate or eat the chocolate first. In the absence of empathy, the free rat will make the selfish choice. But at least half the time, the rat freed its cagemate first. According to the report, “these results show that the value of freeing a trapped cagemate is on par with that of accessing chocolate chips.”

"On its face, this is more than empathy, this is pro-social behavior," said Jeffrey Mogil of McGill University, who was not involved in the study. "It's more than has been shown before by a long shot.”

Without claiming to know what rats think, the authors conclude their report with their opinion that “the free rat was not simply empathetically sensitive to another rat’s distress but acted intentionally to liberate a trapped” member of their own species.

If rats are indeed capable of empathetic feelings, then it becomes clear that the biological substrate for shared emotion is deep in our evolutionary past and deep in the earlier parts of our brains. Far from being uniquely human, empathy seems to be widely shared. What is uniquely human, perhaps, is the way we override it with self-interest.

As I prepared this post, I was interrupted several times by others who were speaking of the history of racism in America and particularly the history of slavery. When I saw the pictures of rats in their enclosure, my mind went to chains and slave ships. If empathy is so deep in our mammalian evolution, so deeply rooted in our brains, what extraordinary rationalizations do we conjure up to negate it?

The paper, "Empathy and Pro-Social Behavior in Rats," is published Dec. 9 by the journal Science. http://www.sciencemag.org/content/334/6061/1427.abstract