Foetal alcohol syndrome is the leading preventable cause of developmental disorders in developed countries. And foetal alcohol spectrum disorder (FASD), a range of alcohol-related birth defects that includes foetal alcohol syndrome, is thought to affect as many as 1 in 100 children born in the United States.

Any amount of alcohol consumed by the mother during pregnancy poses a risk of FASD, a condition that can include the distinct pattern of facial features and growth retardation associated with foetal alcohol syndrome as well as intellectual disabilities, speech and language delays, and poor social skills. But drinking can have radically different outcomes for different women and their babies. While twin studies have suggested a genetic component to susceptibility to FASD, researchers have had little success identifying who is at greatest risk or what genes are at play.

Research from Harvard Medical School and Veterans Affairs Boston Healthcare System sheds new light on this question, identifying for the first time a signalling pathway that might determine genetic susceptibility for the development of FASD.

‘Our work points to candidate genes for FASD susceptibility and identifies a path for the rational development of drugs that prevent ethanol neurotoxicity,’ said Michael Charness, chief of staff at VA Boston Healthcare System and HMS professor of neurology. ‘And importantly, identifying those mothers whose foetuses are most at risk could help providers better target intensive efforts at reducing drinking during pregnancy.’

The discovery also solves a riddle that had intrigued Charness and other researchers for nearly two decades. In 1996, Charness and colleagues discovered that alcohol disrupted the work of a human protein critical to foetal neural development—a major clue to the biological processes of FASD. The protein, L1, projects through the surface of a cell to help it adhere to its neighbours. When Charness and his team introduced the protein to a culture of mouse fibroblasts cells, L1 increased cell adhesion. Tellingly, the effect was erased in the presence of ethanol (beverage alcohol).
Charness and his team went on to develop multiple cell lines from that first culture, and that’s where they encountered the riddle: In some of those lines, alcohol disrupted L1’s adhesive effect, while in others it did not.

‘How could it be possible that a cell that expresses L1 is completely sensitive to alcohol, and others that express it are completely insensitive?’ asked Charness, who is also faculty associate dean for veterans hospital programs at HMS and assistant dean at Boston University School of Medicine.

Clearly, something else was affecting the protein’s sensitivity to alcohol — but what? Studies of twins provided one clue: Identical twins are more likely than fraternal twins to have the same diagnosis, positive or negative, for FASD. ‘That concordance suggests that there are modifying genes, susceptibility genes, that predispose to this condition,’ Charness said.

In the current study, Charness’ team and collaborators at the University of North Carolina School of Medicine in Chapel Hill conducted cell culture experiments to identify specific molecular events that contribute to the alcohol sensitivity of L1 adhesion molecules. They focused on what was happening to the L1 molecule inside a cell that could affect an event outside the cell such as disruption by alcohol.

‘We found that phosphorylation events that begin inside the cell can render the external portion of the L1 adhesion molecule more vulnerable to inhibition by alcohol,’ said Xiaowei Dou, HMS instructor in neurology in the Charness Lab and first author on the new study. ‘Phosphorylation was controlled by the enzyme ERK2, and occurred at a specific location on the internal portion of the L1molecule.’

Phosphorylation plays a significant role in a wide range of cellular processes. By adding a phosphate group to a protein or other molecule, phosphorylation turns many protein enzymes on and off, and thereby alters their function and activity.

The researchers also found that variations in ERK2 activity correlated with differences in L1 sensitivity to alcohol that they observed across cell lines and among different strains of mice. ‘Dou showed that he could take these cells that had been insensitive to alcohol for 13-14 years, and make them sensitive by ramping up the activity of this kinase’ Charness said.

These variations suggest that genes for ERK2 and the signalling molecules that regulate ERK2 activity might influence genetic susceptibility to FASD. Moreover, their identification of a specific locus that regulates the alcohol sensitivity of L1 might facilitate the rational design of drugs that block alcohol neurotoxicity.

‘The only thing this modification blocked was alcohol’s ability to inhibit L1,’ Charness said. ‘If you’re looking for a drug, ideally you’re looking for it to block the effects of the toxin without interfering with the target molecule of the toxin.’

The findings will also help guide an international consortium in its search for genes linked to families with fetal alcohol spectrum disorders. Harvard Medical School

An international team of scientists led by the University of Leicester has found new evidence that links faster ‘biological’ ageing to the risk of developing several age-related diseases – including heart disease, multiple sclerosis and various cancers.
The study involved scientists in 14 centres across 8 countries, working as part of the ENGAGE Consortium.
The project studied a feature of chromosomes called telomeres. Telomeres sit on the end of our chromosomes – the strands of DNA stored in the nucleus of cells. The telomeres shorten each time a cell divides to make new cells, until they reach a critical short length and the cells enter an inactive state and then die. Therefore telomeres shorten as an individual gets older. But, individuals are born with different telomere lengths and the rate at which they subsequently shorten can also vary. The speed with which telomeres wear down is a measure of ‘biological ageing’.

Professor Nilesh Samani, British Heart Foundation Professor of Cardiology at the University of Leicester and Director of the National Institute for Health Research (NIHR) Leicester Cardiovascular Biomedical Research Unit, who led the project said: ‘Although heart disease and cancers are more common as one gets older, not everyone gets them – and some people get them at an earlier age. It has been suspected that the occurrence of these diseases may in part be related to some people ‘biologically’ ageing more quickly than others.’

The research team measured telomere lengths in over 48,000 individuals and looked at their DNA and identified seven genetic variants that were associated with telomere length. They then asked the question whether these genetic variants also affected risk of various diseases. As DNA cannot be changed by lifestyle or environmental factors, an association of these genetic variants which affect telomere length with a disease also would suggest a causal link between telomere length and that disease.

The scientists found that the variants were indeed linked to risk of several types of cancers including colorectal cancer as well as diseases like multiple sclerosis and celiac disease. Most interestingly, the authors found that in aggregate the seven variants also associated with risk of coronary artery disease which can lead to heart attacks.

Professor Samani added: ‘These are really exciting findings. We had previous evidence that shorter telomere lengths are associated with increased risk of coronary artery disease but were not sure whether this association was causal or not. This research strongly suggests that biological ageing plays an important role in causing coronary artery disease, the commonest cause of death in the world. This provides a novel way of looking at the disease and at least partly explains why some patients develop it early and others don’t develop it at all even if they carry other risk factors.’

Dr Veryan Codd, Senior Research Associate at the University of Leicester who co-ordinated the study and carried out the majority of the telomere length measurements said: ‘The findings open of the possibility that manipulating telomere length could have health benefits. While there is a long way to go before any clinical application, there are data in experimental models where lengthening telomere length has been shown to retard and in some situations reverse age-related changes in several organs.’ University of Leicester

A gene linked to autism spectrum disorders that was manipulated in two lines of transgenic mice produced mature adults with irreversible deficits affecting either learning or social interaction.
The findings have implications for potential gene therapies but they also suggest that there may be narrow windows of opportunity to be effective, says principal investigator Philip Washbourne, a professor of biology and member of the University of Oregon’s Institute of Neuroscience.
The research, reported by an 11-member team from three universities, targeted the impacts of alterations in the gene neuroligin 1 — one of many genes implicated in human autism spectrum disorders — to neuronal synapses in the altered mice during postnatal development and as they entered adulthood. One group over-expressed the normal gene, the other a mutated version.
Mice with higher-than-normal levels of the normal gene after a month had skewed synapses at maturity. Many were larger, appearing more mature, than normal. In these mice, Washbourne said, there were clear cognitive problems. ‘Behaviour was just not normal. They didn’t learn very well, and they were slower to learn, but their social behaviour was not impacted.’
Mice over-producing a mutated version of the gene reached adulthood with structurally immature synapses. ‘They were held back in development and behaviour — the way they behave in terms of learning and memory, in terms of social interaction,’ he said. ‘These were adult mice, three months old, but they behaved like normal mice at four weeks old. We saw arrested development. Learning is a little bit better, they are more flexible just like young mice, they learn faster, but their social interaction is off. To us, this looked more like Asperger’s syndrome.
‘So with the same gene, doing two different manipulations — over-expressing the normal form or over-expressing a mutated form — we’ve gone to two different ends of the autism spectrum,’ said Washbourne, whose lab focuses on basic synapse formation and what goes wrong in relationship to autism. Work has been done in both mice and zebra fish.
‘We made these mice so that we can turn the genes on and off as we want,’ Washbourne said. ‘Using an antibiotic, doxycycline, it turns off these altered genes that we inserted into their chromosomes. While on doxycycline, the mice are absolutely normal.’
However, if the inserted gene was turned off after the completion of development, mice still showed altered synapses and behaviour. This result suggests that any kind of gene therapy may have to be applied to individuals with autism early on.
Effects seen in the social behaviour of mice with the mutated gene, he said, are not unlike observations reported by parents of many autistic children. While normal mice prefer to engage with new mice entering their world rather than familiar others, or even a new inanimate object, these mice split their time equally. ‘It’s not a deficit in memory regarding which mouse is which, it’s more a weighting of their interaction. Does that mean they are autistic? I don’t know, but if you talk to parents of autistic children, one of the frustrating things they report is that their children treat complete strangers in exactly the same way that they treat them.’
While the findings provide new insights, Washbourne said, any translation into treatment could be decades away. ‘A problem with autism is there are many different genes potentially involved. It could be that some day, if you are diagnosed with autism, a mouth swab might allow for the identification of the exact gene that is mutated and allow for targeted therapy,’ he said. ‘Genome sequencing already has turned up subtle mutations in lots of genes. Autism might be like cancer, with hundreds of potential combinations of faulty genes.’ University of Oregon

Tiny biomolecular chambers called nanopores that can be selectively heated may help doctors diagnose disease more effectively if recent research by a team at the National Institute of Standards and Technology (NIST), Wheaton College, and Virginia Commonwealth University (VCU) proves effective. Though the findings may be years away from application in the clinic, they may one day improve doctors’ ability to search the bloodstream quickly for indicators of disease—a longstanding goal of medical research.
The team has pioneered work on the use of nanopores—tiny chambers that mimic the ion channels in the membranes of cells—for the detection and identification of a wide range of molecules, including DNA. Ion channels are the gateways by which the cell admits and expels materials like proteins, ions and nucleic acids. The typical ion channel is so small that only one molecule can fit inside at a time.
Previously, team members inserted a nanopore into an artificial cell membrane, which they placed between two electrodes. With this set-up, they could drive individual molecules into the nanopore and trap them there for a few milliseconds, enough to explore some of their physical characteristics.
‘A single molecule creates a marked change in current that flows through the pore, which allows us to measure the molecule’s mass and electrical charge with high accuracy,’ says Joseph Reiner, a physicist at VCU who previously worked at NIST. ‘This enables discrimination between different molecules at high resolution. But for real-world medical work, doctors and clinicians will need even more advanced measurement capability.’
A goal of the team’s work is to differentiate among not just several types of molecules, but among the many thousands of different proteins and other biomarkers in our bloodstream. For example, changes in protein levels can indicate the onset of disease, but with so many similar molecules in the mix, it is important not to mistake one for another. So the team expanded their measurement capability by attaching gold nanoparticles to engineered nanopores, ‘which provides another means to discriminate between various molecular species via temperature control,’ Reiner says.
The team attached gold nanoparticles to the nanopore via tethers made from complementary DNA strands. Gold’s ability to absorb light and quickly convert its energy to heat that conducts into the adjacent solution allows the team to alter the temperature of the nanopore with a laser at will, dynamically changing the way individual molecules interact with it.
‘Historically, sudden temperature changes were used to determine the rates of chemical reactions that were previously inaccessible to measurement,’ says NIST biophysicist John Kasianowicz. ‘The ability to rapidly change temperatures in volumes commensurate with the size of single molecules will permit the separation of subtly different species. This will not only aid the detection and identification of biomarkers, it will also help develop a deeper understanding of thermodynamic and kinetic processes in single molecules.’ EurekAlert

Using the Department of Defense Serum Repository (DoDSR), University of Cincinnati researchers have identified a number of biomarkers for inflammatory bowel disease (IBD), which could help with earlier diagnosis and intervention in those who have not yet shown symptoms.
The DoDSR is a biological repository operated by the U.S. Department of Defense and contains over 50 million human serum specimens, collected primarily from applicants to and members of the U.S. uniformed services.
‘With collaborators from Walter Reed, we were able to identify all of the active duty service men and women who developed IBD and then used the repository to go back and look at various biomarkers to see what each person had in common,’ says Yacyshyn, a professor of medicine at the UC College of Medicine and UC Health gastroenterologist.
IBD is a group of inflammatory conditions of the colon and small intestine. The main types of IBD are Crohn’s disease and ulcerative colitis; inflammatory bowel diseases are considered autoimmune diseases in which the body’s own immune system attacks elements of the digestive system.
In this study, researchers used the repository to identify 50 cases of Crohn’s disease and 50 cases of ulcerative colitis. They analysed proteins from three samples per case—two taken before and one after diagnosis—using a statistical analysis format.
Certain proteins were found in elevated levels in samples from patients who developed IBD.
‘The selection of proteins we chose to analyse was based on a prior study conducted at UC,’ Yacyshyn says. ‘Although the presence of proteins in those who develop Crohn’s disease varies from those present in ulcerative colitis patients, we were able to show that there were elevated levels of certain proteins in patients who developed IBD.’
‘Future large validation studies are needed to confirm the presence of biomarkers to guide in diagnosis, prevention and management of these patients,’ he adds. UC Academic Health News