neurodevelopmental disorders
Study Shows Genes Unique to Humans Tied to Bigger Brains
Posted on by Dr. Francis Collins
Caption: Cortical organoid, showing radial glial stem cells (green) and cortical neurons (red).
Credit: Sofie Salama, University of California, Santa Cruz
In seeking the biological answer to the question of what it means to be human, the brain’s cerebral cortex is a good place to start. This densely folded, outer layer of grey matter, which is vastly larger in Homo sapiens than in other primates, plays an essential role in human consciousness, language, and reasoning.
Now, an NIH-funded team has pinpointed a key set of genes—found only in humans—that may help explain why our species possesses such a large cerebral cortex. Experimental evidence shows these genes prolong the development of stem cells that generate neurons in the cerebral cortex, which in turn enables the human brain to produce more mature cortical neurons and, thus, build a bigger cerebral cortex than our fellow primates.
That sounds like a great advantage for humans! But there’s a downside. Researchers found the same genomic changes that facilitated the expansion of the human cortex may also render our species more susceptible to certain rare neurodevelopmental disorders.
If I Only Had a Brain? Tissue Chips Predict Neurotoxicity
Posted on by Dr. Francis Collins
Caption: 3D neural tissue chips contain neurons (green), glial cells (red), and nuclei (blue). To take this confocal micrograph, developing neural tissue was removed from a chip and placed on a glass-bottom Petri dish.
Credit: Michael Schwartz, Dept. of Bioengineering, University of Wisconsin-Madison
A lot of time, money, and effort are devoted to developing new drugs. Yet only one of every 10 drug candidates entering human clinical trials successfully goes on to receive approval from the Food and Drug Administration (FDA) [1]. Many would-be drugs fall by the wayside because they prove toxic to the brain, liver, kidneys, or other organs—toxicity that, unfortunately, isn’t always detected in preclinical studies using mice, rats, or other animal models. That explains why scientists are working so hard to devise technologies that can do a better job of predicting early on which chemical compounds will be safe in humans.
As an important step in this direction, NIH-funded researchers at the Morgridge Institute for Research and University of Wisconsin-Madison have produced neural tissue chips with many features of a developing human brain. Each cultured 3D “organoid”—which sits comfortably in the bottom of a pea-sized well on a standard laboratory plate—comes complete with its very own neurons, support cells, blood vessels, and immune cells! As described in Proceedings of the National Academy of Sciences [2], this new tool is poised to predict earlier, faster, and less expensively which new or untested compounds—be they drug candidates or even ingredients in cosmetics and pesticides—might harm the brain, particularly at the earliest stages of development.
Genome Sequencing: Exploring the Diagnostic Promise
Posted on by Dr. Francis Collins
Caption: Whole genome sequencing revealed that sisters Addison and Trinity Hanners, ages 7 and 10, shown here with their mother Hanna, have a rare syndrome caused by a mutation in the MAGEL2 gene.
Credit: Courtesy of the Hanners family
At the time that we completed a draft of the 3 billion letters of the human genome about a decade ago, it would have cost about $100 million to sequence a second human genome. Today, thanks to advances in DNA sequencing technology, it will soon be possible to sequence your genome or mine for $1,000 or less. All of this progress has made genome sequencing a far more realistic clinical option to consider for people, especially children, who suffer from baffling disorders that can’t be precisely diagnosed by other medical tests.
While researchers are still in the process of evaluating genome sequencing for routine clinical use, and data analysis continues to be a major challenge, one area of considerable promise centers on neurodevelopmental disorders. Such disorders—which affect about 3 percent of children—range from relatively common conditions like autism spectrum disorder to very rare conditions that impair the development of the brain or central nervous system. In the latest study, an NIH-funded research team reports that sequencing either a patient’s whole genome or whole exome (the 1.5 percent of the genome that encodes proteins) appears to be an effective—as well as a cost-effective—strategy for diagnosing neurodevelopmental disorders that have eluded diagnosis through standard means.
A Blueprint for Brain Development
Posted on by Dr. Francis Collins
Caption: An image generated by whole-brain diffusion tensor tractography, one of a variety of innovative techniques used to create the 3-D gene expression atlas of the developing human brain.
Credit: Allen Institute for Brain Science and Bruce Fischl, Massachusetts General Hospital
There is mounting evidence that predisposition to autism, schizophrenia, and many other devastating brain disorders may begin in the womb when genes are turned on or off at the wrong time during early brain development. But because our current maps of the developing brain are not nearly as detailed or dynamic as we would like, it has been a major challenge to identify and understand the precise roles of these genes.
So, I’m pleased to report that NIH-funded researchers at the Allen Institute for Brain Science in Seattle have produced a comprehensive 3-D map that reveals the activity of some 20,000 genes in 300 brain regions during mid-prenatal development [1]. While this is just the first installment of what will be an atlas of gene activity covering the entire course of human brain development, this rich trove of data is already transforming the way we think about neurodevelopmental disorders.
