Building a Blueprint for the Human Brain

How does a brain blossom from a small cluster of cells into nature’s most powerful supercomputer? The answer has long puzzled scientists, but with new advances in stem cell biology, researchers are quickly mapping the complex suite of connections that together make up the brain.

UCLA scientists have developed a new system that can map the development of brain cells.

UCLA scientists have developed a new system that can map the development of brain cells.

One of the latest breakthroughs comes from Dr. Daniel Geschwind and his team at the University of California, Los Angeles (UCLA), who have found a way to track precisely how early-stage brain cells are formed. These findings, published recently in the journal Neuron, shed important light on what had long been considered one of biology’s black boxes—how a brain becomes a brain.

Along with co-lead authors and UCLA postdoctoral fellows Drs. Luis de la Torre-Ubieta and Jason Stein, Geschwind developed a new system that measures key data points along the lifetime of a cell, as it matures from an embryonic stem cell into a functioning brain cell, or neuron. These new data points, such as when certain genes are switched on and off, then allow the team to map how the developing human fetus constructs a functioning brain.

Geschwind is particularly excited about how this new information can help inform how complex neurological conditions—such as autism—can develop. As he stated in a news release:

“These new techniques offer extraordinary promise in the study of autism, because we now have an unbiased and genome-wide view of how genes are used in the development of the disease, like a fingerprint. Our goal is to develop new treatments for autism, and this discovery can provide the basis for improved high-efficiency screening methods and open up an enormous new realm of therapeutic possibilities that didn’t exist before.”

This research, which was funded in part by a training grant from CIRM, stands to improve the way that scientists model disease in a dish—one of the most useful applications of stem cell biology. To that end, the research team has developed a program called CoNTEXT that can identify the maturity levels of cells in a dish. They’ve made this program freely available to researchers, in the hopes that others can benefit. Said de la Torre-Ubieta:

“Our hope is that the scientific community will be able to use this particular program to create the best protocols and refine their methods.”

Want to learn more about how stem cell scientists study disease in a dish? Check out our pilot episode of “Stem Cells in your Face.”

Genetic Analysis of 115 Year-Old Offers New Hints to the Limits of Human Longevity

New genetic analysis of a 115 year-old ‘supercentenerian’ reveals surprising clues as to what really helps people lead a long, healthy life free of disease—and what may be the underlying culprit that eventually helps contribute to their death.
Mutations, or ‘errors’ in a person’s genetic code have been linked to many devastating diseases, including blood cancers such as acute myeloid leukemia. But scientists had yet to examine the blood cells of healthy individuals to see whether they too, harbored similar mutations.
So, an international team of researchers collected a blood sample from a woman who, at the time of her death in 2005, was the oldest person in the world at 115 years old. And their results, published this week in Genome Research were shocking.
Using advanced whole-genome analysis, the team counted upwards of 400 mutations in the DNA extracted from the woman’s white blood cells—a number far higher than expected, thus revealing that the sheer amount of mutations accumulated is not the sole indicator of disease. But the more interesting finding came when the team examined another type of cell in the sample, the hematopoietic stem cell, or HSC.
HSCs are the ‘precursors’ to both white and red blood cells. They are stored in the bone marrow and continually replenish a person’s blood supply over time. It is this replenishing—the constant generation of new cells—that can cause genetic mutations in the cells’ DNA to develop over time. In this case, they found that even the blood cells of a healthy, supercentenerian were full of mutations. But the real bombshell was when the team examined the woman’s HSCs. As the study’s lead author Henne Holstage explained in a recent news release:

“To our great surprise we found that, at the time of her death, the…blood was derived from only two active hematopoietic stem cells—which were related to each other.”

Why were only these two cells helping to replenish the blood supply? Holstage and his team have a hypothesis, based on the lengths of the telomere. The telomere is a stretch of DNA at each end of each of our 23 pairs of chromosomes. Its job is to protect the chromosome—and the DNA that comprises it—from degrading over time. The telomeres of the supercentenerian’s blood cells were remarkably short, and were thus not as adept at protecting the cells’ DNA.

“Because these blood cells had extremely short telomeres, we speculated that most [of the other] hematopoietic stem cells may have died from ‘stem cell exhaustion,’ reaching the upper limit of stem cell division.”

In future studies, Holstage and his team will further delve into this concept of ‘stem cell exhaustion.’ Even so, these early findings point to new understanding of how stem cells are a vital component to maintaining health—even at a very advanced age.
They also highlight the growing relationship between the two fields of genetics and stem cell biology, a relationship that CIRM recently agreed to foster with our new Genomics Initiative.
Anne Holden