Scientists bioengineer artificial functional 3D brain tissue
Bioengineers have created three-dimensional brain-like tissue that functions like and has structural features similar to tissue in the rat brain and that can be kept alive in the lab for more than two months.
As a first demonstration of its potential, researchers used the brain-like tissue to study chemical and electrical changes that occur immediately following traumatic brain injury and, in a separate experiment, changes that occur in response to a drug. The tissue could provide a superior model for studying normal brain function as well as injury and disease, and could assist in the development of new treatments for brain dysfunction.
The brain-like tissue was developed at the Tissue Engineering Resource Center at Tufts University, Boston, which is funded by the US National Institute of Biomedical Imaging and Bioengineering (NIBIB) to establish innovative biomaterials and tissue engineering models. David Kaplan, Ph.D., Stern Family Professor of Engineering at Tufts University is director of the centre and led the research efforts to develop the tissue.
Currently, scientists grow neurons in petri dishes to study their behaviour in a controllable environment. Yet neurons grown in two dimensions are unable to replicate the complex structural organization of brain tissue, which consists of segregated regions of grey and white matter.
In the brain, grey matter is comprised primarily of neuron cell bodies, while white matter is made up of bundles of axons, which are the projections neurons send out to connect with one another. Because brain injuries and diseases often affect these areas differently, models are needed that exhibit grey and white matter compartmentalization.
Recently, tissue engineers have attempted to grow neurons in 3D gel environments, where they can freely establish connections in all directions.
Yet these gel-based tissue models don’t live long and fail to yield robust, tissue-level function. This is because the extracellular environment is a complex matrix in which local signals establish different neighbourhoods that encourage distinct cell growth and/or development and function.
Simply providing the space for neurons to grow in three dimensions is not sufficient. In the August 11, 2014 early online edition of the journal Proceedings of the National Academy of Sciences, a group of bioengineers report that they have successfully created functional 3D brain-like tissue that exhibits grey-white matter compartmentalization and can survive in the lab for more than two months.
“This work is an exceptional feat,” said Rosemarie Hunziker, Ph.D., program director of Tissue Engineering at NIBIB. “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.” The key to generating the brain-like tissue was the creation of a novel composite structure that consisted of two biomaterials with different physical properties: a spongy scaffold made out of silk protein and a softer, collagen-based gel.
The scaffold served as a structure onto which neurons could anchor themselves, and the gel encouraged axons to grow through it.
The researchers found that the neurons in the 3D brain-like tissues had higher expression of genes involved in neuron growth and function. In addition, the neurons grown in the 3D brain-like tissue maintained stable metabolic activity for up to five weeks, while the health of neurons grown in the gel-only environment began to deteriorate within 24 hours.
In regard to function, neurons in the 3D brain-like tissue exhibited electrical activity and responsiveness that mimic signals seen in the intact brain, including a typical electrophysiological response pattern to a neurotoxin. Because the 3D brain-like tissue displays physical properties similar to rodent brain tissue, the researchers sought to determine whether they could use it to study traumatic brain injury.
To simulate a traumatic brain injury, a weight was dropped onto the brainlike tissue from varying heights. The researchers then recorded changes in the neurons’ electrical and chemical activity, which proved similar to what is ordinarily observed in animal studies of traumatic brain injury.
Kaplan says the ability to study traumatic injury in a tissue model offers advantages over animal studies, in which measurements are delayed while the brain is being dissected and prepared for experiments.
“With the system we have, you can essentially track the tissue response to traumatic brain injury in real time,” said Kaplan. “Most importantly, you can also start to track repair and what happens over longer periods of time.”
Genetic risk for autism outweighs other risk factors, study finds
Most of the genetic risk for autism comes from versions of genes that are common in the population rather than from rare variants or spontaneous glitches, researchers funded by the US National Institutes of Health have found.
Heritability also outweighed other risk factors in this largest study of its kind to date. About 52% of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6% of the total risk.
“Genetic variation likely accounts for roughly 60% of the liability for autism, with common variants comprising the bulk of its genetic architecture,” explained Joseph Buxbaum , Ph.D., of the Icahn School of Medicine at Mount Sinai (ISMMS), New York City. “Although each exerts just a tiny effect individually, these common variations in the genetic code add up to substantial impact, taken together.” Buxbaum, and colleagues of the Population- Based Autism Genetics and Environment Study (PAGES) Consortium, report on their findings in a unique Swedish sample in the journal Nature Genetics, July 20, 2014.
l Reference: Gaughler T, et al. Most genetic risk for autism resides with common variation. Nature Genetics, July 20, 2014.
Researchers say BMI indicator may be missing 25% of kids with excess body fat
Physicians using body mass index (BMI) to diagnose children as obese may be missing 25% of kids who have excess body fat despite a normal BMI, which can be a serious concern for long-term health, according to a Mayo Clinic study published online in Pediatric Obesity.
The researchers found that BMI has high specificity in identifying pediatric obesity, meaning BMI accurately identifies children who are obese, but has a moderate sensitivity, meaning the BMI tool misses children who actually should be considered obese, according to the percent of fat in their bodies.
“If we are using BMI to find out which children are obese, it works if the BMI is high, but what about the children who have a normal BMI but do have excess fat? Those parents may get a false sense of reassurance that they do not need to focus on a better weight for their children,” says Francisco Lopez-Jimenez, M.D., senior study author and director of preventive cardiology at Mayo Clinic.
In the meta-analysis, the researchers used 37 eligible studies that evaluated 53,521 patients, ages 4 through 18. It is the first systematic review and metaanalysis to assess the diagnostic performance of BMI to identify excess body fat as compared with techniques considered reference standard to measure obesity. These other techniques include skin-fold thickness measurement and dual-energy X-ray absorptiometry, which can be used to measure body composition and fat content.
It is known that childhood obesity can lead to an increased risk of type 2 diabetes and cardiovascular disease, says Asma Javed, M.D., the study’s first author and a pediatric endocrinology fellow at Mayo Clinic Children’s Center. “Our research raises the concern that we very well may be missing a large group of children who potentially could be at risk for these diseases as they get older,” Dr. Javed says.
“We hope our results shine a light on this issue for physicians, parents, public health officials and policymakers.” While not part of this study, its results mirror what has been found in Dr. Lopez- Jimenez’s research of adults.
Over several years of research, he and investigators discovered what they call normal weight obesity (NWO), wherein adults have a normal BMI but a large percentage of body fat. NWO shares some of the risks of obesity, which can lead to pre-diabetes, metabolic syndrome and cardiovascular death.
“The lesson is that we need additional research in children to determine the potential impact of having high fat in the setting of normal BMI to recognize this issue and perhaps justify the use of body composition techniques to detect obesity at an early stage,” he says.
Study shows extreme obesity may shorten life expectancy up to 14 years
Adults with extreme obesity have increased risks of dying at a young age from cancer and many other causes including heart disease, stroke, diabetes, and kidney and liver diseases, according to results of an analysis of data pooled from 20 large studies of people from three countries. The study, led by researchers from the US National Cancer Institute (NCI), part of the US National Institutes of Health, found that people with class III (or extreme) obesity had a dramatic reduction in life expectancy compared with people of normal weight. The findings appeared July 8, 2014, in PLOS Medicine.
“While once a relatively uncommon condition, the prevalence of class III, or extreme, obesity is on the rise.
In the United States, for example, 6% of adults are now classified as extremely obese, which, for a person of average height, is more than 100 pounds over the recommended range for normal weight,” said Cari Kitahara, Ph.D., Division of Cancer Epidemiology and Genetics, NCI, and lead author of the study.
“Prior to our study, little had been known about the risk of premature death associated with extreme obesity.” In the study, researchers classified participants according to their body mass index (BMI), which is a measure of total body fat and is calculated by dividing a person’s weight in kilograms by their height in meters squared.
BMI classifications (kilogram/ meter-squared) are:
– Normal weight: 18.5-24.9
– Overweight: 25.0- 29.9
– Class I obesity: 30.0-34.9
– Class II obesity: 35.0-39.9
– Class III obesity: 40.0 or higher
The 20 studies that were analyzed included adults from the United States, Sweden and Australia.
These groups form a major part of the NCI Cohort Consortium, which is a large-scale partnership that identifies risk factors for cancer death. After excluding individuals who had ever smoked or had a history of certain diseases, the researchers evaluated the risk of premature death overall and the risk of premature death from specific causes in more than 9,500 individuals who were class III obese and 304,000 others who were classified as normal weight.
The researchers found that the risk of dying overall and from most major health causes rose continuously with increasing BMI within the class III obesity group. Statistical analyses of the pooled data indicated that the excess numbers of deaths in the class III obesity group were mostly due to heart disease, cancer and diabetes. Years of life lost ranged from 6.5 years for participants with a BMI of 40-44.9 to 13.7 years for a BMI of 55-59.9. To provide context, the researchers found that the number of years of life lost for class III obesity was equal or higher than that of current (versus never) cigarette smokers among normal-weight participants in the same study.
The researchers noted, the results highlight the need to develop more effective interventions to combat the growing public health problem of extreme obesity.
“Given our findings, it appears that class III obesity is increasing and may soon emerge as a major cause of early death in this and other countries worldwide,” said Patricia Hartge, Sc.D., Division of Cancer Epidemiology and Genetics, and senior author of the study.
New combination drug therapy shown to cure chronic hepatitis C
A multicenter team of researchers report that in a phase III clinical trial, a combination drug therapy cures chronic hepatitis C in the majority of patients co-infected with both HIV and hepatitis C.
“In many settings, hepatitis C is now a leading cause of death among HIV coinfected patients,” says Mark Sulkowski, M.D., medical director of the Johns Hopkins Infectious Disease Center for Viral Hepatitis and professor of medicine at the Johns Hopkins University School of Medicine. Approximately one-third of HIV patients in the United States have hepatitis C, with an estimated 7 million co-infected patients worldwide.
Because of poor tolerability to the previous standard of treatments for hepatitis C, including injections of interferon-alpha and medications that can have interactions with anti-retroviral medications used to treat HIV, this population of co-infection patients has been considered difficult to treat. Data from this phase III clinical trial were incorporated into the FDA’s approval of the new drug, sofosbuvir, December 2013, so treatment with this alloral regimen – sofosbuvir and ribavirin – is considered on-label.
The trial, paid for by the developers of sofosbuvir, Gilead Sciences, is published in the July 23 issue of The Journal of the American Medical Association. Researchers and doctors enrolled study participants from the United States and Puerto Rico through 34 academic, private practice and community health centres.
In addition, says Sulkowski: “Doctors and patients alike recognize the idea that it would be difficult, if not impossible, to randomize clinical trial participants to an injectable treatment (interferon) that’s linked to many side effects versus an oral treatment (sofosbuvir plus ribavirin).” For these reasons, the clinical trial, named PHOTON-1, was open-label, nonrandomized and uncontrolled.
“The PHOTON-1 study represents the first clinical trial to demonstrate that we can cure hepatitis C in patients with HIV co-infection without the use of interferon,” says Sulkowski. “As such, it represents a transformative step in our approach to this therapeutic area.”
New hope for diabetes cure
Work by scientists at the Universities of Manchester and Auckland suggest that both major forms of diabetes, type-1 and type-2, are the result of the same mechanism.
The findings, published 20 August in the FASEB Journal, provide compelling evidence that juvenile-onset or type-1 diabetes and type-2 diabetes are both caused by the formation of toxic clumps of a hormone called amylin.
The results, based on 20 years’ work in New Zealand, suggest that type-1 and type-2 diabetes could both be slowed down and potentially reversed by medicines that stop amylin forming these toxic clumps.
Professor Garth Cooper, of The University of Manchester and with his University of Auckland-based research team, led the study.
According to the American Heart Association, the prevalence of diabetes for all age groups worldwide was estimated to be 2.8% in 2000 and is projected to be 4.4% in 2030. The total number of people with diabetes is projected to rise from 171 million in 2000 to 366 million in 2030. Similar figures have been produced by other groups such as the International Diabetes Federation.
As well as producing insulin, cells in the pancreas also produce another hormone called amylin. Insulin and amylin normally work together to regulate the body’s response to food intake. If they are no longer produced, then levels of sugar in the blood rise resulting in diabetes and causing damage to organs such as the heart, kidneys, eyes and nerves if blood sugar levels aren’t properly controlled.
However, some of the amylin that is produced can get deposited around cells in the pancreas as toxic clumps, which then, in turn, destroy those cells that produce insulin and amylin. The consequence of this cell death is diabetes.
Research published previously by Professor Cooper suggested that this is the causative mechanism in type-2 diabetes. This new research provides strong evidence that type-1 diabetes results from the same mechanism.
The difference is that the disease starts at an earlier age and progresses more rapidly in type-1 compared to type-2 diabetes because there is more rapid deposition of toxic amylin clumps in the pancreas. Professor Cooper’s group expects to have potential medicines ready to go into clinical trials in the next two years and it is anticipated that these will be tested in both type-1 and type-2 diabetic patients. These clinical trials are being planned with research groups in England and Scotland.
“The pathogenic mechanism of diabetes varies with the degree of overexpression and oligomerization of human amylin in the pancreatic islet beta cells” FASEB J - Journal of the Federation of American Societies for Experimental Biology (www.fasebj.org), 20 August 2014.
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