Researchers make functional tissue like a brain

Researchers have made a functional brain-like tissue that could have huge implications for studying neural diseases.

Researchers who created functional 3-D brain-like tissue say it could help scientists find new treatments for brain injuries and diseases and improve knowledge about normal brain function.

The tissue, which can be kept alive in the laboratory for more than two months, is structurally similar to tissue in a rat's brain. It's also functionally like brain tissue.

In early experiments with the tissue, researchers used it to study chemical and electrical changes that occur immediately after brain injury and the changes that occur in response to a drug.

The tissue was developed at Tuft University's Tissue Engineering Resource Center, which is funded by the U.S. National Institute of Biomedical Imaging and Bioengineering (NIBIB). The research is described in an article published online Aug. 11 in the Proceedings of the National Academy of Sciences.

"This work is an exceptional feat," Rosemarie Hunziker, program director of Tissue Engineering at NIBIB, said in an agency news release. "It combines a deep understand of brain physiology with a large and growing suite of bioengineering tools to create an environment that is both necessary and sufficient to mimic brain function."

This tissue offers advantages over using live animals to study brain injury, according to project leader David Kaplan, a professor of engineering at Tufts and director of the Tissue Engineering Resource Center.

In live animals, researchers can't start assessing the effects of a brain injury immediately after it occurs. That's because the animal's brain has to be dissected and prepared for experiments.

With the new 3-D brain-like tissue, "you can essentially track the tissue response to traumatic brain injury in real time," Kaplan said. "Most importantly, you can also start to track repair and what happens over longer periods of time."

The longevity of the tissue also makes it valuable for studying brain diseases and disorders.

"The fact that we can maintain this tissue for months in the lab means we can start to look at neurological diseases in ways that you can't otherwise because you need long timeframes to study some of the key brain diseases," Kaplan said.

He and his colleagues are now trying to find ways to make the tissue model even more brain-like.

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Study shows more signs that autism begins during pregnancy

A study shows that due to the nature of brain development during pregnancy and autism, it is very likely that autism development begins while a mother is pregnant.

Children with autism show key "patches of disorganization" in the outer layers of the brain, according to a new study said to offer more evidence that the developmental disorder begins in the womb.

Experts have long believed autism involves disruptions in typical brain development, going back to pregnancy. The new study, reported online March 27 in the New England Journal of Medicine, offers more direct evidence of such early origins.

For the study, researchers examined samples of brain tissue from 22 children after death -- 11 with autism and 11 without. They were able to spot tiny patches of disrupted development dotting the outer layers of the brain in the children with autism.

Differences like that would take shape during prenatal development, said Ed Lein, a researcher at Seattle's Allen Institute for Brain Science, who worked on the study.

"This is pretty direct evidence of a prenatal origin," Lein said.

An autism researcher who reviewed the study agreed. "The foundation for this would likely be prenatal," said Dr. Walter Kaufmann, a neurologist at Boston Children's Hospital. "How early in the prenatal period? That's hard to say."

An even bigger question is, What causes the early disruptions in brain development? Lein and Kaufmann said it's impossible to pin down.

"We still need to try to understand that," Lein said.

In general, however, experts believe autism arises from genetic susceptibility and yet unknown environmental factors. "Ultimately, it's an interplay between genes and environment," Kaufmann said.

In the United States, an estimated one in 88 children has an autism spectrum disorder, which affects the ability to communicate and interact with others. Some kids are profoundly affected, speaking very little or not at all and focusing obsessively on just a few interests. Others have milder problems communicating and reading social cues, such as other people's gestures and facial expressions.

Researchers have managed to find a few hundred genes that are linked to autism risk. And although there is no definite environmental culprit, studies have tied certain factors during pregnancy to an increased risk, including exposure to high levels of air pollution, low intake of the B vitamin folate and viral infections.

For the new study, Lein and his colleagues examined small samples of the neocortex -- the outer surface of the brain. During fetal development, the neocortex forms six layers, each with its own specialized brain cells. As those cells develop, they take on a "genetic signature" that can be visualized in tissue samples, using sophisticated techniques.

Overall, the study found, brain tissue from children with autism showed tiny patches where certain genetic signatures were absent from brain cells.

What's more, those patches were concentrated in areas associated with higher order brain functions, such as understanding language and social cues.

"That makes sense," Kaufmann said. "Those are the areas where you would expect to find abnormalities."

The phenomenon, he said, was seen in 10 of the 11 autistic children, even though the severity of their symptoms varied. Some, for example, had been diagnosed with intellectual disability, while others had not.

Lein said the fact that the brain tissue showed small patches of disruption, rather than pervasive abnormalities, is "potentially good news." It suggests that much of the neocortex is actually typical in children with autism, he said.

That might help explain why autistic toddlers who get early behavioral therapy often show significant improvements, Lein said. It's possible the brain is able to "rewire," to an extent, to get around some of the trouble spots seen in this study.

In general, experts say the earlier such therapy starts, the better. The problem is, most children are not diagnosed with autism until after they reach age 4, according to the U.S. Centers for Disease Control and Prevention.

Kaufmann said researchers are working on finding objective "biomarkers," such as proteins in the blood, that could be used to detect autism earlier. But any such tests are a long way off, he said.

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How sleep can help protect your brain

A study shows that sleep deprivation can result in a loss of brain tissue due to certain molecules found in the brain after losing sleep.

A new study from Uppsala University, Sweden, shows that one night of sleep deprivation increases morning blood concentrations of NSE and S-100B in healthy young men. These molecules are typically found in the brain. Thus, their rise in blood after sleep loss may indicate that a lack of snoozing might be conducive to a loss of brain tissue. The findings are published in the journalSleep.

Fifteen normal-weight men participated in the study. In one condition they were sleep-deprived for one night, while in the other condition they slept for approximately 8 hours.

"We observed that a night of total sleep loss was followed by increased blood concentrations of NSE and S-100B. These brain molecules typically rise in blood under conditions of brain damage. Thus, our results indicate that a lack of sleep may promote neurodegenerative processes," says sleep researcher Christian Benedict at the Department of Neuroscience, Uppsala University, who lead the study.

"In conclusion, the findings of our trial indicate that a good night's sleep may be critical for maintaining brain health," says Christian Benedict.

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Scientists grow mini human brains

Scientists found a way to grow mini three-dimensional human brains in a lab. This will help in the discovery of brain development and how different disorders may develop.

Complex human brain tissue has been successfully developed in a three-dimensional culture system established in an Austrian laboratory. The method described in the current issue of Natureallows pluripotent stem cells to develop into cerebral organoids -- or "mini brains" -- that consist of several discrete brain regions.

Instead of using so-called patterning growth factors to achieve this, scientists at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences (OeAW) fine-tuned growth conditions and provided a conducive environment. As a result, intrinsic cues from the stem cells guided the development towards different interdependent brain tissues. Using the "mini brains," the scientists were also able to model the development of a human neuronal disorder and identify its origin -- opening up routes to long hoped-for model systems of the human brain.

The development of the human brain remains one of the greatest mysteries in biology. Derived from a simple tissue, it develops into the most complex natural structure known to man. Studies of the human brain's development and associated human disorders are extremely difficult, as no scientist has thus far successfully established a three-dimensional culture model of the developing brain as a whole. Now, a research group lead by Dr. Jürgen Knoblich at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) has just changed that.

Brain Size Matters

Starting with established human embryonic stem cell lines and induced pluripotent stem (iPS) cells, the group identified growth conditions that aided the differentiation of the stem cells into several brain tissues. While using media for neuronal induction and differentiation, the group was able to avoid the use of patterning growth factor conditions, which are usually applied in order to generate specific cell identities from stem cells. Dr. Knoblich explains the new method: "We modified an established approach to generate so-called neuroectoderm, a cell layer from which the nervous system derives. Fragments of this tissue were then maintained in a 3D-culture and embedded in droplets of a specific gel that provided a scaffold for complex tissue growth. In order to enhance nutrient absorption, we later transferred the gel droplets to a spinning bioreactor. Within three to four weeks defined brain regions were formed."

After only 15 -- 20 days, so-called "cerebral organoids" formed which consisted of continuous tissue (neuroepithelia) surrounding a fluid-filled cavity that was reminiscent of a cerebral ventricle. After 20 -- 30 days, defined brain regions, including a cerebral cortex, retina, meninges as well as choroid plexus, developed. After two months, the mini brains reached a maximum size, but they could survive indefinitely (currently up to 10 months) in the spinning bioreactor. Further growth, however, was not achieved, most likely due to the lack of a circulation system and hence a lack of nutrients and oxygen at the core of the mini brains.

Microcephaly in Mini Brains

The new method also offers great potential for establishing model systems for human brain disorders. Such models are urgently needed, as the commonly used animal models are of considerably lower complexity, and often do not adequately recapitulate the human disease.

Knoblich's group has now demonstrated that the mini brains offer great potential as a human model system by analysing the onset of microcephaly, a human genetic disorder in which brain size is significantly reduced. By generating iPS cells from skin tissue of a microcephaly patient, the scientists were able to grow mini brains affected by this disorder. As expected, the patient derived organoids grew to a lesser size.

Further analysis led to a surprising finding: while the neuroepithilial tissue was smaller than in mini brains unaffected by the disorder, increased neuronal outgrowth could be observed. This lead to the hypothesis that, during brain development of patients with microcephaly, the neural differentiation happens prematurely at the expense of stem and progenitor cells which would otherwise contribute to a more pronounced growth in brain size. Further experiments also revealed that a change in the direction in which the stem cells divide might be causal for the disorder.

"In addition to the potential for new insights into the development of human brain disorders, mini brains will also be of great interest to the pharmaceutical and chemical industry," explains Dr. Madeline A. Lancaster, team member and first author of the publication. "They allow for the testing of therapies against brain defects and other neuronal disorders. Furthermore, they will enable the analysis of the effects that specific chemicals have on brain development."

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