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For the first time, scientists have reproduced tumour chromosomal translocations within cells associated with two types of cancer – a development that could lead to new therapeutic interventions.

Researchers at the Spanish National Cancer Research Centre (CNIO) and the Spanish National Cardiovascular Research Centre (CNIC) made the breakthrough. The chromosomal modifications they produced are genetically identical to those observed in leukaemia and other types of human cancer.

Modifications that lead to tumour development occur due to multiple changes in cell physiology and specifically in the cell genome. 

Exchanges of large DNA fragments occur between different chromosomes in leukaemia and other sarcomas. These are known as chromosomal translocations and are necessary for the generation and the progression of a number of neoplastic processes.

The team used RNA-Guided Endonuclease (RGEN) technology or CRISPR/Cas9 genome engineering technology in order to produce these translocations, reproducing them in human stem cells derived from blood and mesenchymal tissue that are identical to those observed in patients with acute myeloid leukaemia or Ewing's sarcoma.

"With this breakthrough it is possible to generate cell models with the same alterations as observed in tumour cells from patients, which will allow us to study their role in tumour development," says CNIO researcher Sandra Rodriguez-Perales. 

"In this way, it will be possible to experimentally recapitulate the necessary subsequent steps for normal cells to transform into cancer cells."

The RGEN tool was developed in 2013 for gene manipulation in eukaryotic cells, including human ones.

It is based on the design of a small RNA (RNAsg) that is complementary and specific to a 20 nucleotide DNA region.

RNAsg binds to the DNA double helix and acts as a signal for the Cas9 enzyme to make a cut on the edge of the marked DNA. This allows researchers to make cuts on the DNA double helix wherever it is necessary to do so.

Transferring the RGEN components into primary human cells enabled regions of the exchanged chromosomes in some tumours to be marked, thus generating cuts in those chromosomes.

The team claims that better understanding the process of chromosomal translocation will lead to the development of therapeutic interventions.

Researchers have obtained an unprecedented view of a type of brain cell receptor that is implicated in a range of neurological disorders, including  Alzheimer's disease, Parkinson's disease, depression, schizophrenia, autism, and ischemic injuries associated with stroke.

The team of scientists from Cold Spring Harbor Laboratory say the atomic-level picture of  the intact NMDA (N-methyl, D-aspartate) could prove useful in the development of therapeutic compounds. Their work is published in the journal Science.

NMDA receptors play an essential role in communication between different neurons, integrating both chemical and electrical signals. Such communication forms the basis of memory, learning, and thought, and critically mediates brain development. Increased and decreased NDMA activity is associated with a range of neurological disorders.

A technique known as X-ray crystallography was used to determine the structure of the intact receptor. Numerous interactions between the sub-units of the receptor were identified and the researchers gained new insights into how the complex is regulated.

Protein purification methods were used to isolate the intact receptor, the structure of which was found to resemble a hot air balloon. The 'basket' of the balloon is the transmembrane domain, which forms an ion channel that allows electrical signals to propagate through the neuron

Ion channels act as a gate in a neuronal membrane. When they are closed, ions – electrically charged atoms – are unable to pass through and gather outside cells. When they open, ions travel in and out of cells, generating an electric current that travels through the neuron.

Currents cannot jump between neurons and rely on neurotransmitters, which are triggered by the electrical pulse, to travel the distance between neurons and bind to receptors, such as the NMDA receptor, on the surface of neighboring cells.

Neurotransmitters unlock the ion channels within the receptor and propel the electrical signal across another neuron and, ultimately, across the brain.

The 'balloon' section of NDMA is found outside the cell and binds to neurotransmitters. The structure of the multi-subunit receptor complex helps to explain some of the existing data about how NMDA receptors function.

The team were able to see how one domain on the exterior side of the receptor – the amino terminal domain – directly regulates the ion channel within the membrane and why this is specifically important for the activity of the NMDA receptor.

Scientists at the Columbia University Medical Center have shed new light on the genetic factors behind an individual's risk of developing schizophrenia.

According to the research, which is published in the latest edition of Neuron, the overall number and nature of mutations – rather than the presence of one single mutation – influence an individual's risk of developing the disease, as well as its severity.

The team sequenced the "exome"- the region of the human genome that codes for proteins – of 231 schizophrenia patients and their unaffected parents. They were able to use the data to demonstrate that collective damage across several genes gives rise to schizophrenia.

Previous research into the disorder has sought to identify individual genes that might act as triggers, but the availability of high throughput DNA sequencing technology has contributed towards a more holistic approach to schizophrenia.

Sequencing data was used to look for genetic differences and identify new loss-of-function mutations in cases of schizophrenia that had not been inherited from the patients' parents. Such mutations are less common, but they have a more severe effect on ordinary gene function.

An excess of loss-of-function mutations was found in a variety of genes across different chromosomes. 

The team also studied what types of mutations are commonly passed on to schizophrenia patients from their parents and found that many of these are "loss of function" types. These were found to occur more frequently in genes with a low tolerance for genetic variation. 

Deeper examinations of the sequencing data were conducted in order to determine the biological functions of the disrupted genes involved in schizophrenia. Two damaging mutations were observed in a gene known as SETD1A, suggesting it contributes significantly to the disease.

SETD1A is involved in a process called chromatin modification – a crucial cellular activity that packages DNA into a smaller volume so it can fit into cells and that regulates how genes are expressed.

The result fits with a body of evidence that damage to chromatin regulatory genes is a common feature of various psychiatric and neurodevelopmental disorders.

An international team of scientists has made significant progress in understanding how enzymes 'edit' genes, which could enable genetic diseases to be corrected.

Researchers at the Universities of Bristol, Munster and the Lithuanian Institute of Biotechnology have studied the process through which enzymes known as CRISPR bind and alter the structure of DNA.

These enzymes were first identified in the 1980s as an immune defence used by bacteria against invading viruses. More recently, it has been shown that one type of CRISPR – Cas9 – can be used to edit the human genome.

CRISPR enzymes have been tailored to target a single pair of letters within the three billion base pairs that make up the DNA molecule. This has been likened to correcting one misspelt word in an encyclopedia of 23 volumes.

In order to accomplish this, the enzymes use a molecule of RNA, which is similar in structure to DNA. The enzymes are required to pull the DNA strands apart and insert the RNA to form a sequence-specific structure known as an R-loop.

Modified microscopes were used to test the R-loop model. DNA models were stretched in a magnetic field and by changing the altering force on the DNA, researchers were able to directly monitor R-loop formation events by individual CRISPR enzymes.

As a result of this technique, the scientists were able to uncover previously hidden steps in the process and to investigate the influence of the sequence of DNA bases.

Professor Mark Szczelkun, from Bristol University's School of Biochemistry, said it is particularly challenging to ensure only one specific area in a genome is targeted when using the genome-editing tools.

"Our single molecule assays have led to a greater understanding of the influence of DNA sequence on R-loop formation," he added.

"In the future this will help in the rational re-engineering of CRISPR enzymes to increase their accuracy and minimise off-target effects. This will be vital if we are to ultimately apply these tools to correct genetic diseases in patients."

Scientists have discovered a molecule that slows the degradation of insulin in animals and has the potential to be used as a new treatment for diabetes.

The compound works by inhibiting insulin-degrading enzyme (IDE). Inhibiting IDE in mice elevates insulin levels and promotes insulin signaling in vivo. Researchers at Harvard University say this could be used to maintain higher insulin levels, improve glucose tolerance and therefore to treat diabetes.

Until now, scientists have been unable to regulate the degeneration of insulin and have relied on other methods to treat the disease, such as injecting insulin into diabetic patients.

DNA-templated synthesis, a method for creating new molecules that self-assemble according to an attached DNA sequence, was used to identify the molecule that inhibits IDE.

This system works by combining DNA "templates" – short segments of DNA – with the chemical building blocks of molecules, each of which has its own piece of DNA. When the segments are brought together, the building blocks combine and react, forming more complex molecules.

Sequencing the their DNA strands enables the identification of the resulting molecules.

Researchers incubated the DNA-linked compounds with IDE, hoping that some might bind to the enzyme.

Professor of Chemistry and Chemical Biology David Liu said they hypothesised IDE's activity could be modulated by molecules that were retained by IDE.

"In this case, right out of the library, we found quite a potent and selective inhibitor. Perhaps most important, this molecular had a good half-life in animals, so it could be used to answer the 60-year-old question of what happens when you slow down the natural degradation of insulin in the body," he added.

Experiments with mice showed the compound was able to regulate blood sugar levels. It was found that IDE degrades two other important glucose-regulating peptide hormones – glucagon and amylin – as well as insulin.

Professor Liu said it may be some time before the compound becomes available in pharmacies, as a number of tests and developments need to be made. However, he added that the experimental tools have been put in place for new therapies to be created.