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.

Eating, Aging, and the Brain

Two recent studies shed new light on the relationship between food and the brain.

The first study involves mice on a calorie-restricted diet. Restricting calories to about 70% of normal intake kept the mice—and their rodent brains—young when compared to control mice who could eat whenever they wanted. And while there’s no proof yet that this works with human beings, there is a lot of interest by researchers in finding out what is going on in the relationship between aging and eating.

The latest research is reported in the December 19 of PNAS. Researchers at the Catholic University of Sacred Heart in Rome report their finding that a naturally-occurring protein, CREB1, plays a key role in mediating between caloric restriction and the delay of aging. Caloric restriction seems to trigger CREB1, which in turn activates many other genes involved in longevity and brain function.

What is new in this research is the relationship between caloric restriction and CREB1 activity. Discovering how these molecules interact opens the possibility that the activity of CREB1 can be increased without having to keep to a fairly austere diet.

According to Giovambattista Pani, one of the lead researchers, “Our hope is to find a way to activate CREB1, for example through new drugs, so to keep the brain young without the need of a strict diet.”

“This discovery has important implications to develop future therapies to keep our brain young and prevent brain degeneration and the aging process. In addition, our study shed light on the correlation among metabolic diseases as diabetes and obesity and the decline in cognitive activities,” according to Dr. Pani.

The second study is published in the December 28 issue of Neurology and does involve human beings. Just in time for New Year’s resolutions, researchers at Oregon State University report on the brains and the diets of 104 seniors with an average age of 87. The result is pretty sobering. Those who ate fast foods and snack loaded with trans-fats scored much worse on cognitive tests than those who ate diets rich in the healthy oils commonly found in fish or consumed high levels of vitamins B, C, D, and E.

How much worse? The fast-food seniors scored 17% lower on thinking and memory tests and had a shocking 37% lower active brain size based on an MRI. And that’s after other factors such as age or education level are removed. Diet alone, it appears, makes a significant difference. Eating the right food seems to help slow down the age-related shrinkage of the brain.

Someday there might be a pill that makes us and our brains resist aging. For now, it’s what we eat that counts. These results need to be confirmed, but obviously it is very exciting to think that people could potentially stop their brains from shrinking and keep them sharp by adjusting their diet," according to Gene Bowman of the Oregon Health & Science University in Portland and author of the study.

This would not have surprised Saint Athanasius, bishop of Alexandria in the mid-4th century. Like many of his age, Athanasius was fascinated by the story of Saint Anthony of Egypt, one of the earliest Christian ascetics. Athanasius wrote a spiritual biography of Anthony, interpreting his life and turning him into the prototype of Christian monks.

Anthony gave away the family fortune and lived in isolation in the Egyptian desert, eating almost nothing. The result? He lived to 105 and was known for his wisdom to the very end.

Todd Daly has written about Athanasius and Anthony, including an essay in my recent book, Transhumanism and Transcendence. Daly makes it clear that Anthony’s purpose was not longevity or a youthful brain. This is no science experiment, and if Anthony is the first monk, he’s not the first transhumanist. But according to Athanasius (and to Daly), Anthony is conducting a spiritual experiment. His question is whether it is possible to regain some small portion of the original human condition…humanity as God intended, in other words, rather than the fallen humanity we experience. By denying his body, he sought to expand his soul. Without realizing it, he kept his brain from shrinking.

The amazing thing is that by asking a seemingly arcane theological question—and by sticking with it for decades—Anthony anticipates today’s research.

The PNAS article was published on December 19. The Oregon study was published online on December 28 by the journal Neurology.

Enhancing the Brain: A New Approach?

A molecule that protects you against viruses may also be slowing down your brain. That’s the startling finding just reported by researchers at the Baylor College of Medicine.

In the December 9 issue of Cell, a research team led by Mauro Costa-Mattioli report on how a key component of the immune system may also play a central role in the brain’s ability to form memories.

The molecule in question is the enzyme “protein kinase RNA-activated” or PKR for short. PKR is well-known to biomedical researchers. It is found in nearly all vertebrates and helps fight viral infections.

What was unknown is how PKR plays a pivotal role in regulating how the brain forms memories. Using mice, Costa-Mattioli’s team found that PKR actually slows down the brain’s ability to form memories. By blocking the production of PKR in mice, Costa-Mattioli’s team was able to produce mice with enhanced memory.

“The molecule PKR (the double-stranded RNA-activated protein kinase) was originally described as a sensor of viral infections, but its function in the brain was totally unknown," said Costa-Mattioli in a press release issued by Baylor Medical College.

The researchers used two methods to block PKR. They produced mice that were genetically modified so they couldn’t produce PKR. But they also used a drug that inhibits the production of PKR. In both cases, memory capacity was enhanced.

How does PKR act in the brain? Apparently by interacting with another key molecule, interferon-γ or IFN-γ, which is also best known for its role in the immune system. Researchers believe that in the brain, PKR and IFN-γ interact, keeping each other in balance. Suppressing PKR seems to increase the role of IFN-γ and the activity of the brain, particularly the neurons that are creating long-term memories.

“These data are totally unexpected, and show that two molecules classically known to play a role in viral infection and the immune response regulate the kind of brain activity that leads to the formation of long-term memory in the adult brain,” said Costa-Mattioli.

What is perhaps most startling about the report is that a drug that inhibits PKR enhances memory in mice. “It is indeed quite amazing that we can also enhance both memory and brain activity with a drug that specifically targets PKR,” according to Costa-Mattioli.

If a drug enhances memory capacity in mice, could it work in humans? That’s a big jump, one that will take much more research before anything is even tested in human beings. But researchers suggest that this is possible and worth exploring. Costa-Mattioli said, "More investigation is undoubtedly necessary to translate these findings to effective therapies but we would be delighted if our scientific studies were to contribute in some way to this ultimate goal."

“Our identity and uniqueness is made up of our memories," Costa-Mattioli said. "This molecule could hold the key to how we can keep our memories longer, but also how we create new ones.”

Will this provide a new strategy in dealing with diseases that rob us of our old memories and of our capacity to create new ones? Given the stakes, research will explore these possibilities.

If the research is applicable to human beings (and why not?) and if it provides a new path to preventing or delaying dementia, it will also open new ways to think about the enhancement of human cognition. The mice in the study were not suffering from any memory loss, but the speed at which they were able to learn a new task was enhanced nearly four-fold.

Given the wide-spread interest in cognitive enhancement, especially on university campuses and among transhumanists, we should expect to hear more about how inhibiting PKR just may make you smarter.

The article, "Suppression of PKR Promotes Network Excitability and Enhanced Cognition by Interferon-γ-Mediated Disinhibition,” appears in the December 9 issue of Cell.

Evolutionary Fast-Track for Human Brains

More than 35 years ago, Allan Wilson and Mary-Claire King made an astonishing proposal. Maybe what separates humans and chimps is not just our genes. Maybe it’s also how our genes are expressed or regulated.

Research published in today’s issue of PLoS Biology builds on decades of intervening advances in evolution and genetics and take the question much further. The difference between humans and nonhuman primates in cognitive ability is explained in large part by differences in gene expression, especially during the critical periods when young brains are being formed.

Humans share many of their genes with other species, especially chimps. In fact, we share so many genes that it is hard to explain how we can be so different in terms of cognitive ability. If genes make all the difference, how can they explain the differences between chimp and human brains? And how can a mere six million years of human-chimp divergence give us enough time to accumulate enough genetic change?

The answer seems to lie in the relatively rapid evolution of differences in gene expression. In other words, while the genes themselves evolved slowly, the regulation of their expression evolved more rapidly. It’s not just the genes but their expression that’s important. It’s not just the evolution of genes but the evolution of gene expression that drives the rapid divergence between human and chimp brains.

This is especially true in the genes that control the development of the prefrontal cortex of the brain. In other words, there has been relatively rapid evolution in the genetic mechanisms that regulate genes directly responsible for the early-childhood neural development of the critically-important prefrontal cortex, which is involved in abstract thinking, planning, social intelligence, and working memory.

According to the article, “humans display a 3-5 times faster evolutionary rate in divergence in developmental patterns, compared to chimpanzees.” Most important, however, is the way this research identifies specific regulators that have evolved rapidly since human-chimp divergence. These regulators are “micro-RNAs,” some of which are specifically identified in the article, with the claim that “changes in the expression of a few key regulators may have been a major driving force behind rapid evolution of the human brain.”

According to the study’s senior author, Philipp Khaitovich, this finding suggests that "identifying the exact genetic changes that made us think and act like humans might be easier than we previously imagined." Kkaitovich was quoted in a press release issued by the journal, PLoS Biology.

The article is entitled "Micro-RNA-Driven Developmental Remodeling in the Brain Distinguishes Humans from Other Primates" and appears in the December 6 issue of PLoS Biology, where it is freely available to the public.

Evolution and the Human Brain

How did the human brain become so complex so quickly? Did old genes learn new tricks? Or did new genes appear, bringing new functions?

A paper appearing today in PLoS Biology suggests that new genes play a bigger role than previously thought in explaining the complex functions of the human brain. Researchers at the University of Chicago Department of Ecology and Evolution reached this conclusion by comparing the age of genes with transcription data from humans and mice. Where are new genes most often expressed? In humans, it’s in the brain. Even more interestingly, it’s in the developing brain of the fetus and the infant.

One of the researchers, Yong E. Zhang, was motivated to ask these questions because he accompanied his pregnant wife to prenatal ultrasound appointment, according to a press release issued by the University of Chicago Medical Center. According to Zhang, “Newer genes are found in newer parts of the human brain.” The press release also quotes co-author Patrick Long: “What’s really surprising is that the evolutionary newest genes on the block act early….The primate-specific genes act before birth, even when a human embryo doesn’t look very different from a mouse embryo. But the actual differences are laid out early,” Long explained.

In the language of the PLoS Biology paper, the authors “observed an unexpected accelerated origination of new genes which are upregulated in the early developmental stages (fetal and infant) of human brains relative to mouse.” In other words, compared to all the genes in the human genome, younger genes are significantly more involved in those parts of the brain that make us distinctly human. More than that, these genes play a greater than expected role in prenatal and infant development, the very period in which the brains of humans develop so rapidly compared to the brains of other species.

How did these new genes arise? By all the various means by which new genes arise—by various processes of duplication and by de novo origination. Rather remarkably, the authors make this observation: “…young genes created by all major gene origination mechanisms tend to be upregulated in [the] fetal brain. Such generality suggests that a systematic force instead of a mutational bias associate with a specific origination mechanism contributed to the excess of young genes in the fetal brain.”

What “systematic force”? Clearly, the authors are not speculating about anything more than a statistical correlation. But their work will give rise to new questions for research. What role do these young genes actually play in the developing brain? What role did natural selection play in the evolution of these genes? Does this surprising correlation shed any light at all on our rapid rise as a species and the stunning complexity of the human brain?

The paper, "Accelerated Recruitment of New Brain Development Genes into the Human Genome," is published in the October 18 issue of PLoS Biology [10.1371/journal.pbio.1001179].