Tuesday, June 18, 2013

Can Human Brain Tissue Make Mice Smarter? Emory Neuroethics Journal Club Review

What makes humans smart?  This was the primary question posed in the final Journal Club of the Spring 2013 semester.  Led by Riley Zeller-Townson, the club discussed Han et al. (2013), a paper that discusses the enhancement of learning in mice after grafting human glial progenitor cells into their brains. Riley began by explaining the paper and the work leading up to it. Most of the roles of glial cells involve supporting and protecting neurons, such as synaptic plasticity, myelination, and maintaining the blood-brain barrier (Barres, 2003). This study focuses on one subtype of glia, called astrocytes, cells that provide nutrients to neurons (Tsacopoulos et al, 1996).

Neurons (shown on left) possess both axons and dendrites and are shaped differently than glial cells (Source).  The glial cell shown on the right is an astrocyte, which is more “star” shaped due to its many branched processes (Han et al 2013).
While people generally think of neurons as being the important type of brain cells, research is beginning to show that the merits of glial cells were previously underestimated. Interestingly, post-mortem analysis of Albert Einstein’s brain showed that he had more glia than the average person (Diamond et al, 1985).  Along the same vein, previous studies have shown that primate glia are larger, more complex, and faster than those of mice (Colombo, 1996; Oberheim et al., 2009). Therefore, is it possible that glial cells are the root of intelligence?
Han et al. tested this hypothesis by grafting human astroglia progenitors into neonatal immune-deficient mice.  Because the mice retained their own astroglia as well, the mice were chimeric, or having both mouse and human glia.  The human glial cells were fluorescently labeled before implantation so that they could be identified after each mouse was sacrificed, which occurred anywhere from 0.5-20 months of age.  The successfully grafted glial cells were found to have distributed across the forebrain, including the hippocampus and cortex.  Additionally, human glia were found in the amygdala, thalamus, and neostriatum in mice ages 12-20 months.

Next, the authors did a battery of tests that revealed that the cells were not only present, but also functional.  The authors found that not only were the human astrocyte progenitor cells present in the mouse brain, but they actually differentiated into humanoid protoplasmic astrocytes that formed synapses with mouse astrocytes.  In the chimeric mouse brain, the human astrocytes produced Ca2+ signals that were three times faster than Ca2+ signals produced by mouse astrocytes (this had previously been demonstrated in human tissue, but held true for chimeric mouse tissue). Next, the authors compared hippocampal dentate synaptic activity in chimeric mice to unengrafted and allografted mice and found that tissues with engrafted human glia showed a greater level of excitatory synaptic transmission. This finding goes hand in hand with the next subsequent finding that Long Term Potentiation (LTP), an experimental measure correlated with memory formation, increased in chimeric mice. The authors speculate that this increase was due to insertion of GluR1, a specific type of excitatory receptor often associated with memory and learning, into mice neurons by human glia, which lowered the threshold for LTP induction.

Because LTP was increased in chimeric mice, one would assume that these mice, not just their cells, would also showed quicker learning behaviors than the control mice. As expected, mice engrafted with human glia performed better in all four behavioral tasks compared to unengrafted and allografted mice, showing that the improvement was due to the human glia, not the act of engrafting cells into the mice.

Overall, the results of the paper suggest that astrocytes play a role in learning, and that more complex astrocytes might increase learning by lowering the threshold at which LTP occurs. Furthermore, the paper implies that human astrocytes, and possibly other subtypes of untested human glial cells, play a role in the high level of cognition observed in humans (and possibly in mice).

The Rats of NIMH (Source)
After introducing the paper and its findings, the subject turned to the ethical considerations associated with the study.  Riley introduced another paper (Greely et al 2007) as a response to Han et al.  In his paper, Greely discusses the possible ethical issues that would arise by performing this type of study.  Greely lists several possible ethical issues, including the risk of conferring humanity upon the mice, the potential for pain and suffering, public reaction, and respect for human tissues.

In response to Greely’s first concern, journal club attendee and bioethics professor Dr. Jonathan Crane pointed out that “conferring humanity” upon the mice was the wrong term, as “humanity” simply means the traits that make us human.   Dr. Crane pointed out that humans do not really have any unique capabilities that other animals do not have, we just have them in a different degree.  He points out the Greely is most likely concerned about the risk of conferring “personhood,” or making the mouse a autonomous individual to the same extent that an adult human is.

Of course, if personhood were conferred upon a species that we cannot communicate with, would we even be able to recognize it?  It seems a big issue with this type of study is not only the possibly innately unethical problem of creating an unnatural sentient being, but also the issue of creating a (more?) autonomous being, not realizing it as such, and continuing to treat it like a typical lab animal.

Greely’s second concern, the potential for pain and suffering in the chimeric mouse, was also addressed.  While Greely’s paper noted the possibility of increased pain in the mouse due to having human neurons, the group discussed the mouse’s possibly increased emotional pain as well.  It was addressed that a mouse with human “intelligence” might also gain a human-like propensity for depression or realizing the futility of life as an experimental animal.   The authors seem to have guarded against this in the Han et al. study by noting that the chimeric mice were just as social as normal mice.  However, if these types of studies continue and mice intelligence is further increased, depression and suffering in the chimeric mouse will be a concern. The experimenters compared the reaction times and pain thresholds of chimeric mice to normal mice and found them to be the same.  These findings, coupled with the observation that the chimeric mice are just as social as normal mice are checks the experimenters used to show that the mice were not suffering mentally or physically.  These checks should also be present in future studies with chimeric species.  However, the downside is that these tests cannot gauge suffering until it has already happened.

Greely’s concern about public reactions was also discussed.  When discussing public reactions, it was addressed that different groups would be opposed to this study for different reasons.  Some groups would be opposed because of the belief that implanting human brain cells into a disvalues human intelligence.   Emory medical ethicist Dr. John Banja noted that some would question whether or not it is ethical to create hybrid species in the first place.  Dr. Crane pointed out that the study is also an affront to the mouse, as it is attempting to improve an animal that is perfect to begin with.

Riley’s main concern was that progression of this experiment will continue to create new species that we know nothing about.  Without knowing which mouse traits and which human traits a hybrid will have, it is impossible to care for it in the correct way from the beginning.  Riley pointed out that sometimes it takes thousands of years to create a cultural consensus on what is ethical regarding a certain issue, so if a new species pops up overnight society may not treat the animals respectfully.  Furthermore, these animals could completely change biological science: furthering this study could lead to a greater understanding of the mechanisms for learning, memory, and eventually even consciousness in humans.  An alternative to this however would be is a unique and species is created that is later discovered to have human-like consciousness and increased suffering.  The scientific community would stall as it would have to deal with public dissent amidst trying to find a more ethical method of testing the same hypotheses.

While future advancements along this line of work could have the potential to help us understand exactly what intelligence is, how it works, and why some people have more of it than others, these types of experiments could also have the ability to create a brand new species that society is not ready to care for or treat with respect.  Furthermore, it may not be possible to determine when the ethical boundary has been overstepped until it has already happened. Therefore, in continuations of this study, it is important to use chimeric animals with discretion and continue testing for possible suffering.

If you missed out on this journal club meeting you can watch a video of it and previous meetings here.

References

Alexander V. Gourine, V. K. (2010). Astrocytes Control Breathing Through pH-Dependent Release of ATP. Science, 571-575.

Barres, B. A. (2003). What is a Glial Cell? Glia, 4-5.

Colombo, J. (1996). Interlaminar astroglial processes in the cerebral cortex of adult monkeys but not of adult rats. Cells Tissues Organ, 57-62.

Henry T. Greely, M. K. (2007). Thinking About the Human Neuron Mouse. The American Journal of Bioethics, 27-40.

Magistretti, M. T. (1996). Metabolic Coupling between Glia and Neurons . Journal of Neuroscience, 877-885.

Marian C. Diamond, A. B. (1985). On the brain of a scientist: Albert Einstein. Experimental Neurology, 198–204.

Oberheim, N. W. (2006). Astrocytic complexity distinguishes the human brain. Trend in Neuroscience, 547-553.

Xiaoning Han, M. C. (2013). Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice. Cell, 342-353.


Want to cite this post?

Young, E. (2013). Can Human Brain Tissue Make Mice Smarter? Emory Neuroethics Journal Club Review. The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2013/06/can-human-brain-tissue-make-mice.html.

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