Mention the word Epidemiology and instantly my mind conjures up the Centre for Disease Control (CDC) in America being swarmed by zombies or men in bright orange astronaut-type suits in The Crazies. While it’s true that it includes studying highly infectious diseases and how they spread (zombies and end of world scenarios aside!), it can be applied to any disease.
Having spent much of my time in the last year working on the data that was collected from our recent epidemiology study, I was keen to shout about the fact that the data is now ready for researchers to use. The analysis of this data will add great value to samples that we already have in our DNA Bank.
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.
By 2011 the UK motor neurone disease (MND) DNA Bank had collected over 3,000 samples from people living with MND in the UK, their family members and healthy controls.
Several years since the first sample was taken, the MND Association can now proudly announce that the UK MND DNA Bank is ‘open for business’ to the worldwide MND research community.
The sun is leaving us, the nights are beginning to draw in and Christmas treats such as mince pies are beginning to fill the shops. MND researchers around the world, however, have been given an early Christmas present – the opening of the UK MND DNA Bank!
At present, the cause of MND is thought to be a combination of subtle genetics, lifestyle and environmental factors. We know a small number of these genetic factors, but not all of them, thus the Association created the UK MND DNA Bank. Back in 2003, co-ordinated by the three MND care centres (King’s College London, Sheffield and Birmingham) a multicentre collaboration across the UK invited people living with MND to participate in a project, which hopes to answer the question: What causes MND?
Dr Johnathan Cooper-Knock from the Sheffield Institute for Translational Neuroscience (SITraN) has been awarded with the fifth Medical Research Council (MRC)/MND Association Lady Edith Wolfson Clinical Research Fellowship.
Through his three-year fellowship, Dr Cooper-Knock will use the MND Association’s DNA bank to study how recently discovered mistakes (known as mutations) in a gene called C9ORF72 can cause the disease.
Dr Johnathan Cooper Knock explains, “I believe that the genetics of MND are a key to understanding both the cause of the disease and how to treat it. The discovery of mutations in C9ORF72 are a great opportunity to get a hold on mechanisms of disease which has so far been elusive. I am excited by the opportunity my fellowship will give me to pursue this important discovery.
“By the end of my fellowship I aim to have contributed significantly to the understanding of disease mechanisms related to C9ORF72 dysfunction in MND. As a result I hope to have identified a number of therapeutic targets for development into new treatments by myself and others.”
C9ORF72: the facts so far
We know that a repeated six-letter code within a gene called C9ORF72 can cause MND and a related condition called fronto-temporal dementia (FTD) for approximately 40% of cases with a positive family history of MND and/or FTD.
Most genetic mistakes found in MND to date have been swaps of genetic letters, which can change the meaning of that part of the gene. The C9ORF72 genetic mistake on the other hand, is a repeat expansion. This means that six letters within the genetic code (CCCCGG) are repeated hundreds of times for people with C9ORF72 MND. In healthy individuals, this repeat is found about 30 times. We already know that the exact size of the repeat varies substantially between people with this genetic mistake. How this repeat causes MND and how the size of the repeat may affect disease progression is currently unknown but this is something that Dr Cooper-Knock wants to find out.
We also don’t know what role C9ORF72 normally has in the body. Even its name, which stands for ‘chromosome 9 open reading frame 72’ refers to where it is in the genetic code and not what it does. This isn’t unusual as it’s currently estimated that we have over 20,000 genes, and understandably, researchers haven’t yet found out what every one of these does – including C9ORF72.
So far, 96 journal articles have been published about C9ORF72 (by searching on Pubmed for C9ORF72). The oldest of these was published in 2011, and describes the original MND/FTD C9ORF72 finding. All subsequent articles on C9ORF72 have been of a direct consequence from this pivotal genetic discovery in the past year.
These 96 studies were focused on finding out how many people have the C9ORF72 genetic repeat and finding out what this mistake ‘looks like’ both clinically in terms of progression rates, age of onset and symptoms; and in terms of post-mortem findings to compare with other forms of MND. Coincidently, the most recent post-mortem and clinical C9ORF72 finding was authored by Dr Cooper-Knock (when searching for C9ORF72 and post mortem on PubMed).
It’s reassuring to know that researchers aren’t resting on their laurels with this genetic finding. There’s a huge international research effort in place to push forward our understanding of C9ORF72, with a number of our own newly funded projects, starting later this year, dedicated to creating new laboratory models of this genetic mistake to better understand how it can cause the disease.
How do we currently think C9ORF72 causes MND?
Due to the sheer size of the repeat expansion in C9ORF72, it’s thought that it causes MND by disruption of the editing process of genetic information.
I’ll explain: In real life terms, our DNA can be thought of as being held within a library, which is the control centre of the cell (the nucleus). Each book (gene) is stored on a particular shelf (chromosome). Gene ‘books’ aren’t allowed to be taken out of the nucleus, but they can be photocopied. These copies (RNA) are edited and transported out of the nucleus to be used as instructions to create proteins that perform specific roles in and sometimes out of the cell.
Unlike real life books, genes are fraught with errors, variations and nonsense from one person to the next. It looks messy, but it’s normal. Genetic editors are needed to edit and chop the RNA into a readable format so that it can be understood by the parts of the cell that use RNA as instructions.
As normal, healthy copies of C9ORF72 hold approximately 30 repeats to be chopped out as RNA, the effect of having much larger repeats may be having a knock-on effect on the efficiency of the editing process. This could then lead to a much higher risk of developing MND.
Finding out exactly how C9ORF72 can cause MND, and whether this theory is right, will provide us with a deeper insight into MND and potentially provide therapeutic targets that can be further investigated.
Dr Cooper-Knock’s fellowship
Dr Cooper-Knock will be using a cutting-edge genetic technique called ‘gene expression profiling’ to study the various levels of RNA in samples provided by people with the C9ORF72 genetic mistake. From this, he’ll find out which genes are switched on and off because of the C9ORF72 repeat expansion.
He will also study whether the size of the C9ORF72 repeat expansion has an effect on symptoms or progression rates to identify factors that may modify disease progression and may therefore be targets for future therapies.
Technology specialised for identifying misassembled RNA will also be applied to skin cells donated by people with the C9ORF72 repeat expansion who have MND/FTD and healthy controls. This will help to elucidate what the C9ORF72 protein does.
As well as skin cells from people with MND/FTD, this study will use post-mortem brain and spinal cord tissue from people with the C9ORF72 repeat expansion and healthy controls within the Sheffield tissue bank; as well as cells from the blood of C9ORF72 patients and healthy controls obtained from the MND Association’s DNA Bank.
Talking about the importance of people with MND having provided these numerous samples Dr Cooper-Knock said “Without the participation of patients and their families MND research will get nowhere; and equally with their participation, doors are opened towards new and exciting treatments. At this time, with discoveries like the mutations in C9ORF72 to build from, we can do even more with the participation of those who have been affected by this disease, who like us are passionate to see it cured.”
Our DNA bank contains over 3,400 samples from people with MND and their families. By using these samples scientists in this country have already made significant discoveries into the causes of MND. To advance research into MND we now want to make the DNA bank available to researchers across the world. To do this, we’re asking people to donate funds to the BBC Radio 4 charity appeal for our DNA bank. All money raised through the appeal will go towards maintaining the samples and making them accessible to worldwide researchers. It will take a global research effort to beat MND, and the DNA bank is a very important tool in the fight against the disease.
Samples from the DNA bank will help scientists identify genes that cause familial (inherited) MND or those that influence susceptibility to sporadic MND. This will offer crucial insight into the causes of MND. Understanding the causes of MND will lead to the development of new treatments.
To listen to the broadcast narrated by Joss Ackland, listen in on Sunday 8 January at 7:55am or 9:26pm to BBC Radio 4. This will also be repeated on Thursday 12 January at 3:27pm, or you can listen again after the broadcast.
More information: DNA bank samples are currently being used in a number of studies investigating the causes of familial and sporadic MND. For more information, please see the DNA bank pages of our website.
We’ve been extremely excited about this research finding for a while now and have closely followed the progress of Prof Ammar Al-Chalabi’s publication as it was accepted into the prestigious journal Lancet Neurology. At times this was a rollercoaster journey – one that we were carefully watching from the sidelines with baited breath.
The reason why we’re more excited than normal is that this is also the first time that results from DNA samples from our very own DNA bank have been published. The DNA bank has been collecting blood samples from people living with MND, family members and controls in the UK for over seven years and it now collectively holds nearly 3,000 samples.
Over 600 of the samples donated by people living with sporadic MND were used in this ‘whole genome wide association study’ (which uses state of the art technology to scan the genetic code for spelling variations as compared to healthy controls) to find a region of DNA (that contains three genes) within chromosome 9 that is associated with sporadic MND, a condition called ‘fronto-temporal dementia’ (FTD) that affects behaviour, emotional response and language skills, as well as a rare inherited form of MND called MND-FTD.
This means that people who have already donated a blood sample to our DNA bank have played a vital role in this research finding. As all of the samples are anonymised, it is not possible to find out which samples have been used in this research project.
So, this is not only another ‘hop’ forward onto the next stepping stone on our journey to understand more about the underlying causes of MND, but it’s also an exciting step forward in the development of the DNA bank. We hope this is the first of many!
At present, only the researchers who have helped us to set up the DNA bank can apply to use the samples in their studies but at some point in the near future we will open the bank to other researchers so that they can apply to use them in their studies.