The UK MND DNA Bank 6 months on…

It’s been six months since the UK MND DNA Bank (DNA Bank) opened its doors to researchers around the world, so what has been happening to all those samples? Dr Lucy Smith, Research Information Administrator at the MND Association, explains:

The DNA Bank is the first UK biobank dedicated to MND and has 3000 samples under its roof. Over an 8 year period, blood samples were collected from people living with MND and their family members, together with unrelated controls. The DNA was extracted, and the entire collection is now stored and managed in partnership with BioBanking Solutions (BBS) at the University of Manchester. Important clinical information, such as gender and the age of onset of the people who gave the sample is also stored within the collection.

Alongside DNA, the DNA Bank also stores some cells lines at the European Collection of Cell Cultures (ECACC), Public Health England. The cell lines were made as a guarantee that the DNA supply wouldn’t run out, however the cell lines have become hugely important over recent years and are now a valuable resource themselves.

So, how have the samples been used?

All the samples withdrawn from the bank so far have been used in projects which fit under the large umbrella that is genetic research. Many of the projects are trying to identifying genetic variations associated with MND, both those that are disease causing and those that might make individuals more likely to develop the disease.

When sample collection started for the DNA Bank only a small number of MND cases were accounted for genetically, and mostly through mutations in the SOD 1 gene. A decade on and the list of genes causing MND grows longer every day. Indeed in March this year an international team, including two of our own funded researchers from University College London, newly identified Matrin 3 as an MND causing gene. These are exciting times indeed, however with the arrival of new technology allowing sequencing of entire ‘chunks’ of DNA, many of these so called ‘gene hunting projects’ now require large numbers of high quality DNA samples for screening. Luckily, this is where the DNA Bank can help.

Back in 2010, the first large scale gene screening project was published using samples withdrawn from the DNA Bank. In this Genome Wide Association Study (GWAS), 663 DNA Bank samples were analysed together with samples taken from all over the world. Genome wide association is a complex technique used to look for common genetic changes within two different populations –controls vs disease. Common changes in one group can lead to the discovery of new genes and from this GWAS researchers identified a genetic change within chromosome 9 responsible for both sporadic and inherited MND, and frontotemporal dementia. The results were published in The Lancet and the mutation, an expansion in c9orf72, is now one of the most widely studied mutations in the field accounting for over 40% of inherited MND cases and a quarter of inherited FTD cases. It was a hugely important finding.

But, what happened at the end of the project?

Once the GWAS finished it wasn’t the end for the samples. As part of the deal in using samples from the DNA bank, researchers are asked to publish their results in an open access journal. This means that their findings will be seen by as many people as possible free of charge. Researchers are also asked to share large datasets, such as those from screening projects, in centralised databases, eg ALSOD (Amyotrophic Lateral Sclerosis Online Database), which are accessible to other researchers.

As more information is gained about the specific samples used in a project, they become more and more popular, and are used again and again by other researchers. Once the GWAS results were published, three different research projects made their sample selection based upon findings from this screen. In turn, researchers in the future will make their sample selection in the same way, data will be re-used and research information shared. In this way, samples from the DNA Bank are continually contributing to an increasing number of research projects and widening our knowledge all the time about how genetic changes can cause MND.

It’s not all DNA, DNA, DNA…

Today many of the researchers requesting samples from the DNA Bank have moved away from classic gene hunting projects and are turning their attention to what happens next in the cell. By growing cell lines from the DNA Bank, researchers can take out other genetic material, such as RNA and protein and use it as the basis for their research. We now know that some of the genes that cause MND change the way that RNA and proteins do their jobs within the cell. By studying these building blocks, researchers can hopefully work out what is going wrong in the cell as a result of the genetic changes, and more importantly whether it can be fixed or changed so it is less damaging – see our blog from last year for a recap on how mistakes in DNA causes problems in the cell.

Researchers from SITraN in Sheffield are investigating how the C9Orf72 mutation causes disease in this way. The team, led by the MND Association/ Medical Research Council (MRC) Lady Edith Wolfson Clinical Research Fellow, Dr Johnathan Cooper Knock, have grown cells, obtained from the DNA Bank, taken from patients with familial MND who have the C9orf72 expansion. The team has looked carefully at which levels of RNA are higher or lower in those individuals with disease. This technique, called Gene Expression Profiling allows researchers to see which key genes are switched on – giving higher levels of RNA, or off – giving lower levels of RNA, directly as a result of the C9Orf72 mutation. The team are looking at which pathways are disrupted within the cell and the role these may play in the disease. By having a clearer picture of what is happening within the cell, researchers can use this knowledge to create new disease models that reflect more faithfully what is happening in people with MND and ultimately could identify new targets for therapy. It is clear that moving away from DNA is also important.

So to the future…

In the 6 months since its launch the UK MND DNA Bank has gone a long way to uphold the promise of the Association to support research that leads to a new understanding and treatments, and brings us closer to a cure for MND. DNA and cell line samples are being used in a huge variety of genetic research projects, the results from which are widely published in scientific journals. The technical advances that continually drive new research in the field means that, high quality samples such as those provided by the DNA Bank will be in constant demand.

The future is bright at the bank…