Researchers funded by the National Institutes of Health Genotype-Tissue Expression (GTEx) project, including scientists from the Broad Institute of MIT and Harvard, have created a new and much-anticipated data resource to help establish how differences in an individual’s genomic make-up can affect gene activity and contribute to disease. The new resource will enable scientists to examine the underlying genomics of many different human tissues and cells at the same time, and promises to open new avenues to the study and understanding of human biology.
GTEx investigators reported initial findings from a two-year pilot study in several papers. These efforts provide new insights into how genomic variants – inherited spelling differences in the DNA code – control how, when, and how much genes are turned on and off in different tissues, and can predispose people to diseases such as cancer, heart disease, and diabetes.

“GTEx was designed to sample as many tissues as possible from a large number of individuals in order to understand the causal effects of genes and variants, and which tissues contribute to predisposition to disease,” said Emmanouil Dermitzakis, Ph.D., professor of genetics at the University of Geneva Faculty of Medicine, Switzerland, and a corresponding author. “The number of tissues examined in GTEx provides an unprecedented depth of genomic variation. It gives us unique insights into how people differ in gene expression in tissues and organs.”

NIH launched the GTEx Project in 2010 to create a data resource and tissue bank for scientists to study how genomic variants may affect gene activity and disease susceptibility. Investigators are collecting more than 30 tissue types from autopsy and organ donations in addition to tissue transplant programs. The DNA and RNA from those samples are then analysed using cutting-edge genomic methods. The project will eventually include tissue samples from about 900 deceased donors.

“GTEx will be a great resource for understanding human biological function, and will have many practical applications in areas such as drug development,” said NHGRI Program Director Simona Volpi, Pharm.D., Ph.D. “Scientists studying asthma or kidney cancer, for example, will be interested in understanding how specific variants influence the biological function of the lung, kidney, and other organs.” Broad Institute

Sleep seems simple enough, a state of rest and restoration that almost every vertebrate creature must enter regularly in order to survive. But the brain responds differently to stimuli when asleep than when awake, and it is not clear what brain changes happen during sleep. “It is the same brain, same neurons and similar requirements for oxygen and so on, so what is the difference between these two states?” asks Rodolfo Llinás, a professor of Neuroscience at New York University School of Medicine and a Whitman Center Investigator at the Marine Biological Laboratory (MBL) in Woods Hole. In a recent paper, Choi, Yu, Lee, and Llinás announced that a specific calcium channel plays a crucial role in healthy sleep, a key step toward understanding both normal and abnormal waking brain functions.

To tackle the broad question of sleep, Llinás and his colleagues focused on one crucial part of the puzzle in mice. Calcium channels, selective gates in neuron walls, are integral in neuron firing, ensuring that all parts of the brain keep talking to one other. But during sleep, calcium channel activity is increased, keeping a slow rhythm that is different from patterns found during wakefulness. Based on this clue, the scientists removed one type of calcium channel, Cav3.1, and looked at how the absence of that channel’s activity affected mouse brain function.

This calcium channel turns out to be a key player in normal sleep. The mice without working Cav3.1 calcium channels took longer to fall asleep than normal mice, and stayed asleep for much shorter periods. “They basically took cat naps,” says Llinás. Their brain activity was also abnormal, more like normal wakefulness than sleep. Most importantly, these mice never reached deep, slow-wave sleep. “This means that we have discovered that Cav3.1 is the channel that ultimately supports deep sleep,” Llinás says.

Because these mice completely lack the ability to sleep deeply, they eventually express a syndrome similar to psychiatric disorders in humans. Llinás believes that studying how the brain functions during unconsciousness is key to understanding normal consciousness, as well as abnormal brain activity. This paper begins to uncover one of the key mechanisms of normal sleep, as well as the role for one important calcium channel in overall brain function. The Marine Biological Laboratory

A blood test undertaken between 10 to 14 weeks of pregnancy may be more effective in diagnosing Down syndrome and two other less common chromosomal abnormalities than standard non-invasive screening techniques, according to a multicentre study led by a UC San Francisco researcher.

In the study, which followed pregnancy outcomes in close to 16,000 women, the cell-free DNA blood test resulted in correctly identifying all 38 foetuses with Down syndrome, a condition associated with cognitive impairments and an increased risk of several medical disorders. The diagnosis was confirmed by newborn exam, prenatal or postnatal genetic analysis.

The test focuses on the small percentage of foetal DNA found floating in a pregnant woman’s blood. DNA is amplified by PCR, and sequenced so that comparisons can be made between relative amounts of each chromosome’s DNA. A greater quantity of DNA is indicative of some chromosomal conditions, including Down syndrome, which is characterized by an extra copy of chromosome 21, one of the 23 pairs of chromosomes.

When the same women underwent standard screening, 30 of the 38 foetuses with Down syndrome were flagged, according to the study published on April 1, 2015, in the New England Journal of Medicine. The screening comprises a blood draw in which hormones and proteins associated with chromosomal defects are identified, together with an ultrasound of the nuchal fold fluid in the back of the neck, an excess of which is suggestive of Down syndrome.

The average age of the pregnant women was 30 and approximately one-quarter were over 35 – the age at which women have traditionally been considered high risk and offered prenatal invasive testing with procedures like amniocentesis.

A second compelling advantage of cell-free DNA analysis, reported by the researchers who were led by first author Mary Norton, MD, professor of clinical obstetrics and gynaecology at UCSF, was the relatively low incidence of Down syndrome misdiagnoses. While standard testing is acknowledged to result in a large number of false positives, these were significantly less likely with the cell-free DNA tool. There were nine false positives resulting from this method, vs. 854 with standard screening. University of Central Florida

What began as a chat between husband and wife has evolved into an intriguing scientific discovery. The results show a ‘highly significant’ correlation between periodic solar storms and incidences of rheumatoid arthritis (RA) and giant cell arteritis (GCA), two potentially debilitating autoimmune diseases. The findings by a rare collaboration of physicists and medical researchers suggest a relationship between the solar outbursts and the incidence of these diseases that could lead to preventive measures if a causal link can be established.

RA and GCA are autoimmune conditions in which the body mistakenly attacks its own organs and tissues. RA inflames and swells joints and can cause crippling damage if left untreated. In GCA, the autoimmune disease results in inflammation of the wall of arteries, leading to headaches, jaw pain, vision problems and even blindness in severe cases.

Inspiring this study were conversations between Simon Wing, a Johns Hopkins University physicist and first author of the paper, and his wife, Lisa Rider, deputy unit chief of the Environmental Autoimmunity Group at the National Institute of Environmental Health Sciences in the National Institutes of Health, and a coauthor. Rider spotted data from the Mayo Clinic in Rochester, Minnesota, showing that cases of RA and GCA followed close to 10-year cycles. ‘That got me curious,’ Wing recalled. ‘Only a few things in nature have a periodicity of about 10-11 years and the solar cycle is one of them.’

Wing teamed with physicist Jay Johnson of the U.S. Department of Energy’s Princeton Plasma Physics Laboratory, a long-time collaborator, to investigate further. When the physicists tracked the incidence of RA and GCA cases compiled by Mayo Clinic researchers, the results suggested ‘more than a coincidental connection,’ said Eric Matteson, chair of the division of rheumatology at the Mayo Clinic, and a coauthor. This work drew upon previous space physics research supported by the DOE Office of Science.

The findings found increased incidents of RA and GCA to be in periodic concert with the cycle of magnetic activity of the sun. During the solar cycle, dramatic changes that can affect space weather near Earth take place in the sun. At the solar maximum, for example, an increased number of outbursts called coronal mass ejections hurl millions of tons of magnetic and electrically charged plasma gas against the Earth’s magnetosphere, the magnetic field that surrounds the planet. This contact whips up geomagnetic disturbances that can disrupt cell phone service, damage satellites and knock out power grids. More importantly, during the declining phase of the solar maximum high-speed streams develop in the solar wind that is made up of plasma that flows from the sun. These streams continuously buffet Earth’s magnetosphere, producing enhanced geomagnetic activity at high Earth latitudes.

The research, which tracked correlations of the diseases with both geomagnetic activity and extreme ultraviolet (EUV) solar radiation, focused on cases recorded in Olmsted County, Minnesota, the home of the Mayo Clinic, over more than five decades. The physicists compared the data with indices of EUV radiation for the years 1950 through 2007 and indices of geomagnetic activity from 1966 through 2007. Included were all 207 cases of GCA and all 1,179 cases of RA occurring in Olmsted County during the periods and collected in a long-term study led by Sherine Gabriel, then of the Mayo Clinic and now dean of the Rutgers Robert Wood Johnson Medical School.

Correlations proved to be strongest between the diseases and geomagnetic activity. GCA incidence — defined as the number of new cases per capita per year in the county — regularly peaked within one year of the most intense geomagnetic activity, while RA incidence fell to a minimum within one year of the least intense activity. Correlations with the EUV indices were seen to be less robust and showed a significantly longer response time.

The findings were consistent with previous studies of the geographic distribution of RA cases in the United States. Such research found a greater incidence of the disease in sections of the country that are more likely to be affected by geomagnetic activity. For example, the heaviest incidence lay along geographic latitudes on the East Coast that were below those on the West Coast. This asymmetry may reflect the fact that high geomagnetic latitudes — areas most subject to geomagnetic activity — swing lower on the East Coast than on the opposite side of the country. While Washington, D.C., lies just 1 degree farther north than San Francisco geographically, for example, the U.S. capital is 7 degrees farther north in terms of geomagnetic latitude.

Although the authors make no claim to a causal explanation for their findings, they identify five characteristics of the disease occurrence that are not obviously explained by any of the currently leading hypotheses. These include the east-west asymmetries of the RA and GCA outbreaks and the periodicities of the incidences in concert with the solar cycle. Among the possible causal pathways the authors consider are reduced production of the hormone melatonin, an anti-inflammatory mediator with immune-enhancing effects, and increased formation of free radicals in susceptible individuals. A study of 142 electrical power workers found that excretion of melatonin — a proxy used to estimate production of the hormone — was reduced by 21 percent on days with increased geomagnetic activity.

Confirming a causal link between outbreaks of RA and GCA and geomagnetic activity would be an important step towards developing strategies for mitigating the impact of the activity on susceptible individuals. These strategies could include relocating to lower latitudes and developing methods to counteract direct causal agents that may be controlled by geomagnetic activity. For now, say the authors, their findings warrant further investigations covering longer time periods, additional locations and other autoimmune diseases. Princeton Plasma Physics Laboratory

Despite modern chemoradiation therapy it is still very difficult to give reliable prognoses for malignant gliomas. Surgical removal of the glioma is still the preferred method of treatment. Doctors at Universitätsklinikum Erlangen’s Department of Neurosurgery have now developed a new procedure for analysing radiological imaging scans which makes it possible to predict the course of a disease relatively precisely.

The Friedlein Grading A/B (FGA/B) classification system – named after the physician Katharina Friedlein – is a quick and precise way of determining whether surgical removal is the best possible treatment method for a given tumour. Essentially, the Erlangen-based doctors classify tumours according to their position in the brain in the context of a routine magnetic resonance imaging (MRI) scan. Tumours that are not located in functional brain regions or that are located at a certain distance from such regions are classified as FGA, while tumours that are close to or inside a functional brain region are classified as FGB.

With the FGA/B method it possible to plan the consequences of tumour surgery, which is crucial for the success of the treatment, in a precise, low-risk and quantitative manner. This makes the Friedlein Grading system the first classification system which can be easily applied in clinical practice. ‘There have already been several attempts in medicine to develop such a classification system. However, most approaches were too complicated and were based on academic values only, which made it difficult to use them in clinical practice,’ says PD Dr. Nicolai Savaskan from FAU’s Chair of Neurosurgery. ‘The FGA/B method can be applied on the basis of a standard MRI scan which glioma patients have to undergo anyway and is highly reliable despite being so simple. We hope that our colleagues in neurosurgery departments in smaller hospitals will also be able to use it successfully in everyday clinical practice.’ Universitätsklinikum Erlangen