What a Smart Mouse Can Tell Us about Evolution

Just a few years ago, we thought that brains were all about neurons.  Sure, we also have glial cells, but the job of the lowly glia is to take care of the neurons, which do all the serious cognitive work. 

But why are the glia of humans and other primates so large and varied in their shape and structure?  Why are they so different from the simpler, smaller glia found in mice and other rodents?  Could the difference play a role in the evolution of human intelligence?

One way to compare a mouse and a human is to create a mouse that is part human.  That’s exactly what researchers at the University of Rochester did.  They implanted human cells into mouse brains.  More precisely, they implanted human glial progenitor cells into newborn mouse pups. 

What they got were chimeras, mice with human cells integrated into their brains.  When the researchers examined the brains of these chimeric mice, they found that the human cells proliferated and were widely present throughout the brain. Although interacting with mouse brain cells, the human cells remained distinctly human in their unusually large size and varied structures.

Photo credit:  A 23 week human culture astrocyte stained for GFAP.   From Wikimedia Commons.  Date: 24 February 2012.  Author: Bruno Pascal. 

Most surprising is that the chimeric mice were  smarter than unaltered mice born in the same litters.  Human glia in a mouse brain seems to make a smarter mouse.  

Why?  The answer probably involves one type of glial cell called astrocytes. Compared to other species, human brains have many more astrocytes.  Ours are larger and more varied in their structure, capable of connecting many neurons and coordinating the activity that occurs at many synapses. 

Based on this study, published in the March 7, 2013 issue of Cell Stem Cell, we now know that human astrocytes boost intelligence in chimeric mice as measured by standard testing procedures.  

This is pretty good evidence to suggest that the evolution of the larger, more complex glial cells was a critical aspect of the evolution of higher intelligence.  At least that is the conclusion drawn by one of the senior authors of the paper, Steven Goldman. “In a fundamental sense are we different from lower species,” he said, according to a press release from the University of Rochester. “Our advanced cognitive processing capabilities exist not only because of the size and complexity of our neural networks, but also because of the increase in functional capabilities and coordination afforded by human glia.”

What makes this study intriguing is that it uses stem cell technology to study brain function and to learn something important about evolution.  By implanting stem cells in create chimeric mice, researchers learn that glia play a critically important role in intelligence and that evolved changes in glial cells are a key part of the story of the rise of intelligence. 

Concerning the role of glial cells in the complex brain, Maiken Nedergaard, another senior author, had this to say:  “I have always found the concept that the human brain is more capable because we have more complex neural networks to be a little too simple, because if you put the entire neural network and all of its activity together all you just end up with a super computer.”

“But human cognition is far more than just processing data, it is also comprised of the coordination of emotion with memory that informs our higher abilities to abstract and learn,” Nedergaard added.

And concerning what chimeric mice have to teach us about evolution, Steven Goldman made this comment: “This study indicates that glia are not only essential to neural transmission, but also suggest that the development of human cognition may reflect the evolution of human-specific glial form and function.”

Or to quote the original paper: “These observations strongly support the notion that the evolution of human neural processing, and hence the species-specific aspects of human cognition, in part may reflect the course of astrocytic evolution.”

The paper does not address the interesting ethical questions raised by making smarter mice.  Over the past decade, ethicists have debated the moral legitimacy of chimeric animals.  One point of concern has been the creation of nonhuman animals with human brain cells.  To defend this practice, it is often said that a mouse brain with human cells is still a mouse brain.  It still has the structure or architecture of a mouse brain.  It may have human cells, but in no way is it a human brain or even a half mouse/half human brain.

This study suggests we should take a closer look at that line of thinking.  Maybe it is true that adding human neurons to a mouse brain does not change the mouse brain structure.  But this study implies that adding human astrocytes to a mouse brain may begin some small but significant change in structure and function. 

The study is clear about the fact these chimeric mice are more intelligent than the unmodified mice.  Their brains are quite literally faster. 

Once again, Goldman: “The bottom line is that these mice demonstrated an increase in plasticity and learning within their existing neural networks, essentially changing their functional capabilities.”

These animals have been cognitively “elevated,” to use a word sometimes found in the debate.  Probably no one will object to the idea of a slightly smarter mouse.  Researchers take special care to make sure these mice do not breed and produce pups of their own.  But even if they did, the added intelligence would not pass to future generations.  They would produce normal lab mice. 

Even so, this study—combining stem cells technology, neuroscience, and evolution in one elegant package—raises intriguing moral questions.  Are we smart enough to know how far we should go in creating smarter mice?  

The study, entitled “Forebrain engraftment by human glialprogenitor cells enhances synaptic plasticity and learning in adult mice,” appears in the March 7, 2013 issue of Cell Stem Cell. 

   

 

Parthenogenesis and "Virgin Birth"? Rhetoric and Research

Despite roadblocks, the field of stem cell research remains profoundly attractive. The idea of being able to regenerate damaged or diseased cells in the human body is appealing to nearly everyone who cares about human health.

But technical problems remain. Much has been learned in the past decade, but the pathway to medical treatments still faces many challenging problems. One worry in particular is that implanted stem cells might develop into cancer. Others challenges including getting the cells to multiply, integrate with other cells, function as they should, and avoid being rejected as an infection.

A new solution may be on the horizon, one that addresses many of these problems—moral and technical—all at once. At least that’s the claim made by a team led by Wolfram Zimmerman and colleagues at Georg-August-Universität Göttingen in Germany. Working with laboratory mice, Zimmerman’s team used mouse eggs to create what are known as parthenotes. Without being fertilized, the mouse eggs were manipulated so that they began to develop as if they were fertilized, up to a point.

PHOTO: Mouse embryonic stem cells. This image is a work of a National Science Foundation employee, taken or made as part of that person's official duties. As a work of the U.S. federal government, the image is in the public domain. This image was copied from wikipedia:en.

Parthenogenesis exists in nature. It has been observed in some plants, fish, and reptiles. Over the past decade, researchers have learned how to induce parthenogenesis in mice, monkeys, and humans. In every case, however, the resulting parthenotes fail to develop normally, which means they could never be implanted to produce a child. But they do develop for a few days, long enough for the precursors of pluripotent stem cells to develop.

What is new in the research reported on February 22, 2013 is unexpected success in the use of these stem cells derived from mouse parthenotes. These cells—parthenogenetic stem cells or PSCs—were developed and eventually implanted into damaged mouse hearts. Quite simply, they worked in ways that seem to overcome most if not all of the technical hurdles.

The research appears in the Journal of Clinical Investigation, which carried a companion article claiming that the new research “may overcome all…formidable barriers” that currently stand in the way of stem cell medicine. The original article makes this claim: “One of our key observations involved the capacity of PSCs to exhibit essentially normal cardiogenesis in vitro and in vivo.” In other words, both in the dish and in the mouse, implanted cells fully integrate into the beating heart.

Both the research article and the companion piece make another claim: PSCs are ethically acceptable. That’s because parthenotes are not embryos. Taking cells from parthenotes avoids all the moral concerns that surround the use of cells derived from embryos. Here is the claim: Research using human PSCs, derived from human parthenotes, involves “no destruction of viable embryos,” according to the research article. The companion piece simply notes that compared to embryonic stem cells, PSCs “do not have the same ethical implications.”

If only it were that simple. But plain the fact is that some who object to the use of human embryos in research are already on record as objecting to the use of human parthenotes.

Their logic is fairly straightforward. If human embryos are off limits and if parthenotes cannot be clearly and definitely distinguished from embryos, then human parthenotes are equally off limits to research.
They are not claiming that parthenotes are little people, nor are they being silly or obstructionist. They are only claiming that we do not have enough scientific clarity and certitude to proceed with moral confidence in the work of creating and destroying parthenotes, regardless of the benefit.

Just to be clear, I personally disagree with this objection. But researchers and regulators should be aware that some, at least, will balk at this new line of research, technically attractive as it may be.

For example, in a statement given to the UK Parliament, the Church of Scotland made this comment:

“We reject the suggestion made by various researchers that hybrid embryos, parthenotes and embryos that have been modified to make then non-viable would be an ethical solution to deriving stem cells from embryos. Whatever the status of such creations, it is would be at least as unethical to use methods that would create an ‘embryo’ so deformed that it could not be viable and which therefore inherently denies its potential to develop.” 

Politically more important is the response that will come from Catholics. Some Catholic scholars have defended the moral legitimacy of research using human parthenotes. There is simply no way, they argue, to equate the parthenote with the embryo. The parthenote is not a product of conception. In more popular rhetoric: If “life begins at conception,” then the parthenote is not “life.” Nor can it develop normally. It meets none standard definitions of an embryo.

Others are not so certain. They translate scientific and theological uncertainty into a moral prohibition. Creating and destroying a parthenotes requires that we know for sure that they are not embryos. Such certainty is lacking, at least for now. In the face of uncertainty, they argue, we must not proceed.

On the Catholic website www.ewtn.com, E. Christian Brugger addresses the question: Is the parthenotes enough like and embryo to be considered an embryo? His answer:

“The question presently is unsettled.” He adds this: “Although the empirical question of the status of a human parthenote is unsettled, the underlying moral principle is straightforward. Unless we have moral certainty that a dividing parthenogenetically activated human oocyte is not an embryo, we have an obligation to avoid research with human parthenotes.”

And at the end he concludes:

“Having said this, the present evidence on whether parthenotes are ever embryos seems to me inconclusive. Given the evidence to date, at least with which I am familiar, I do not think it can be established with moral certitude that parthenotes are never human embryos.”

Personally, I want to see this research go forward, and so I have some suggestions for researchers and reporterss in this field.

First, help religious scholars build the case scientifically, showing in clear terms to the wider public why parthenotes are not functionally like embryos and why a morally robust boundary separates the two. Science itself cannot create that boundary, but it can provide evidence supporting moral and philosophical arguments in favour of such a boundary.

Second, stop using provocative phrases like “virgin birth.” Regrettably, the companion piece in the Journal of Clinical Investigation is published with this title: “Virgin birth: engineered heart muscles from parthenogenetic stem cells.”

Sure, “parthenos” is Greek for virgin, so the etymology supports the use of the term “virgin birth.” But for billions of Christians around this world, this term has a very special religious meaning, one that many associate with the most tender core of their faith.

For scientists to claim they are simulating the “virgin birth” is offensive to anyone who takes the religious meaning of the phrase seriously. It is needlessly provocative, almost the worst thing that could be said if religious support for research is desired.

What’s more, associating parthenogenesis with the “virgin birth” has the bizarre effect of equating the parthenote with the embryo. Christians who hold to the “virgin birth” will claim that in one profoundly non-trivial example (Jesus), what scientists now claim they are creating turned out to be a fully viable embryo. And then they say, “But don’t worry; it’s not a human being”?

The original article, entitled "Parthenogenetic stem cells for tissue engineered heart repair," is published in the February 22, 2013 issue of the Journal of Clinical Investigation, together with the companion piece.

A New Source for New Neurons

The day when stem cell research will give us treatments for common brain disorders such as Parkinson’s or Alzheimer’s just got a little closer. So, by the way, did the day when this research will be used to enhance the capacities of the normal or healthy human brain. The latest advance comes from an international team based mostly in Germany, which has figured out a way to generate new neurons from cells that already exist in the human brain.

The human brain naturally contains specialized cells called pericytes. Usually they are located at the edge of the capillaries that carry blood to the brain. They play a vital role in maintaining the blood-brain barrier.

Neurons. Photo from National Institutes of Health.

Now, thanks to the discovery reported in the October 5 issue of Cell Stem Cell, pericytes might be about to learn a new trick: forming new neurons. Using stem cell reprogramming techniques, researchers learned that two factors—Sox2 and Mash1—would induce pericytes to change their developmental state and begin to function as newly-formed neurons.

According to the article, “these induced neuronal cells acquire the ability of repetitive action potential firing and serve as synaptic targets for other neurons, indicating their capability of integrating into neuronal networks.” In other words, they do what neurons normally do. They process signals from one end of the cell to another. They form synaptic connections with other neurons. And they integrate into larger networks.

Will this become a new strategy for treating diseases or injuries to brain cells? That is the hope, but difficult challenges remain. How can living pericytes in a functioning human brain be targeted and induced to become neurons? If they generate new neurons, will they function properly? Will they integrate themselves into a functioning brain, preferably taking up the cognitive processes that are lost because of disease or injury?

The authors conclude that “much needs to be learned” but that “our data provide strong support for the notion that neuronal reprogramming of cells of pericytic origin within the damaged brain may become a viable approach to replace degenerated neurons.”

According to Benedikt Berninger of the Johannes Gutenberg University in Mainz, a leader in the research team, “The ultimate goal we have in mind is that this may one day enable us to induce such conversion within the brain itself and thus provide a novel strategy for repairing the injured or diseased brain."

That may be the goal, but it's hard to imagine this research will be limited to therapy. In fact it may turn out to be easier to use it to enhance the cognitive capacity of normal or healthy aging brains than it is to treat disease. Anything that stimulates the growth of new neurons is likely to be very appealing to aging adults.

If human stem cell research is to reach its full promise, many more advances like this will have to occur. With each advance, however, comes growing confidence that the promise of the field may be highly challenging, but it is not hype.

The article entitled “Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells” is published in the October 4, 2012 issue of Cell Stem Cell.