Learning to Create a Line of Big Brained Geniuses

The discovery of a master-gene for controlling human brain development may eventually open the door to the creation of a genetic line of big brained genius humans. UW-Madison scientists learned that the transcription factor Pax6 is something of a master-controller for the development of human brain cells.

The research, reported this week in Cell Stem Cell, provides "exciting new insights into the fundamental process of neural induction," said Kate Storey, a developmental biologist at the University of Dundee in the UK who was not involved in the research, in an email.

Pax6 is one in a family of paired box (Pax6) transcription factors that control embryonic development in a variety of cell lineages. The best-studied of the Pax factors, Pax6 is highly conserved and important to the development of eyes, pancreas, and cerebrum across many species. Now, Su-Chun Zhang and colleagues at the University of Wisconsin-Madison report that Pax6 is also the master regulator of early specification of the neuroectoderm, the outer layer of an embryo that develops into all neural tissues, in humans but not in mice.

...When Zhang's team silenced Pax6 in mouse ESCs, the cells still generated neural stem cells when other factors, such as Sox proteins, compensated. But when they did the same in human ESCs, no neural stem cells developed, either in a Petri dish or in vivo. "It's very different from what we see in animals," said Zhang. Though the protein has the exact same amino acid sequence in mice and humans, it seems to be playing a novel role in human brain development.

"The early expression of Pax6 in humans probably has something to do with our unique brain size and intelligence," said Zhang. "For better or for worse," he added with a laugh.

Zhang pursued the protein to determine how it works in human neural development. Through a series of additional experiments, the team found that Pax6 is responsible for suppressing stem cell genes, like Oct4 and Nanog, while simultaneously activating neural-specific genes. Because of these dual roles, Zhang said, it is appropriate to call Pax6 a "master switch," turning some genes on and others off. The factor is so powerful, said Zhang, that even when the researchers tried to block the development of neural cells through three different non-genetic methods, such as adding factors to guide ESCs toward a mesoderm fate, Pax6 won out. As long as the factor was being expressed, cells went on to become neurons. "It's a very powerful factor in humans," he said.

Since Pax6 so strongly drives hESCs to become neural stem cells, the team is now looking to see if Pax6 can also be used to maintain an adult population of those same cells. While ESCs and iPS can be maintained in a pluripotent state, it is currently very difficult to do the same in adult somatic stem cells -- over time they begin to differentiate and lose their potential. Zhang is also interested in seeing if Pax6 can reprogram other adult cells directly into neural stem cells, skipping the iPS cell state altogether. "Because of its powerful effect in multiple aspects, we are looking at many areas," said Zhang. _the-scientist(blog)

Neurology and anatomy professor Su-Chun Zhang said the discovery could lead to new treatment options for major brain-related diseases like Alzheimer’s and Parkinson’s. Zhang says it could also be possible for researchers to rejuvenate brain stem cells inside a patient’s body, instead of in a lab dish to repair damage from diseases. _WHBL

"In human brain development, this plays a really important role," says Xiaoqing Zhang. "In humans, the cortex is a major part of the brain. In the mouse, the cortex is a much smaller part of the brain."

Adds Su-Chun Zhang, "In a way, it makes sense that the human brain is regulated in a different way. The brain distinguishes the human as a unique species."

In practical terms, the new finding will help scientists refine and improve techniques for making specific types of neural cells. Such cells will be critical for future research, developing new models for disease, and may one day be used in clinical settings to repair the damaged cells that cause such conditions as Parkinson's disease and amyotrophic lateral sclerosis or Lou Gehrig's disease.

"This gives us a precise and efficient way to guide stem cells to specific types of neural cells," says Xiaoqing Zhang. "We can activate this factor and convert stem cells to a particular fate."

The discovery of the new role of Pax6, says Su-Chun Zhang, is the first time researchers have discovered a single genetic factor in human cells that is responsible for shepherding blank slate stem cells to become a particular tissue stem cell type. "Until now, for any organ or tissues, we didn't know any determinant factors. This is the first," he says.

There are certainly other genes at play in the cells of the developing brain, says Su-Chun Zhang: "You may need additional genes, but they're in a supporting role. Pax6 is the key." _Eurekalert

Of course there are many other factors present in the developing brain which influence the fate of neuronal stem cells. But we need an entry point into the multi-dimensional interplay of the thousands of factors influencing the gene expression of the brain. The UW-Madison study raises more questions than it answers, but then most truly good science will do that.

When intervening in the development of the human brain, it is more likely that one will do harm rather than doing good. The brain is an organ of chaos, after all. Although we crave to understand our brains as a whole, we tend to comprehend them only by bits and pieces. We will need new ways of seeing and comprehending, before we will be in a position to effectively make ourselves more intelligent -- in a harmonious and fulfilling manner.

We will have to perform a large number of experiments in systems and synthetic biology. We may have to resort to feeding artificial components into the machinery of life. We are unlikely to stumble across a "magic mushroom" that transforms our mundane thought processes into those of a super-genius of great wisdom and knowledge.

Champions of machine super-intelligence have thrown down the gauntlet, and have declared the obsolescence of the human body and brain. They have done so somewhat prematurely, it would seem to me, but their chain of logic is fairly clear.

We have seen that the natural trend for human intelligence is downward. If nothing is done to reverse the trend, the global average human IQ will drop from near 90 points currently to the mid to low 80's by mid-century. The dysgenic trend is occurring due to differential birth rates, which are somewhat to very high in low IQ populations and quite low in most high IQ populations.

What can be done? Think about it.