At a new Lundbeck Foundation research centre, under the direction of DNA detective Professor Eske Willerslev, scientists are rolling up their sleeves to make a start. The centre will map the DNA – the genetic material – of thousands of long-dead human beings in order to acquire knowledge about brain disorders. CADASIL – a hereditary brain disease showcased by the Brain Prize 2019 – is one of the trails they will follow.
Although research is being conducted into neurological disorders such as Alzheimer’s and Parkinson’s and psychiatric disorders such as schizophrenia and ADHD all over the world, in many ways, these and other brain disorders remain a scientific enigma:
Where do they come from, for instance? And why have brain disorders become ‘trapped’ in our human DNA when they obviously cause great suffering and make life incredibly difficult for lots of people?
These are some of the questions a new Danish research centre will now attempt to answer.
The new Lundbeck Foundation GeoGenetics Centre is a collaborative effort between the University of Copenhagen (UCPH) and the Lundbeck Foundation, which granted funding of DKK 60 million for the project.
The official opening is on 4 April. The centre is headed by Professor Eske Willerslev, an internationally renowned expert in analysis of ancient DNA (geogenetics), at both UCPH and the University of Cambridge in the UK.
Professors Thomas Werge and Rasmus Nielsen are also members of the centre’s management team.
Thomas Werge works at UCPH and the Mental Health Services, Capital Region of Denmark, and he is an expert in the genetics underlying psychiatric and neurological disorders.
Rasmus Nielsen is an expert in biostatistics and a professor at both UCPH and the University of California, Berkeley, USA.
Right back to the Stone Age
In order to delve into the genetic history of brain disorders, Eske Willerslev, Thomas Werge and Rasmus Nielsen will work with colleagues from the UK and the USA to perform complete DNA mapping – sequencing – of a total of 5,000 human beings who lived between 10,000 years ago and 1850 AD. This means that the oldest samples originate from as far back as the Palaeolithic Age.
The genetic material comes from bones and teeth – typically, material stored in archaeological collections in museums – and the DNA stems from both Europe and western Asia.
Originally, the idea was to generate 1,000 complete genomes of ancient human beings – the entire genetic fingerprints of 1,000 people long dead.
Now that the Lundbeck Foundation GeoGenetics Centre has begun collaborating with Illumina, an American producer of DNA sequencing equipment, this figure has risen almost explosively to 5,000. Illumina’s equipment is able to supply heaps of additional engine power.
According to Professor Willerslev, this research library of ancient DNA would have been the largest in the world even if they had stuck to the 1,000 genomes of ancient humans originally planned:
‘But this library will be five times bigger, and that’s a huge deal for our research. By delving into the material that will be sequenced, we can compare the genetics of brain disorders today – so, the specific DNA patterns typically found in disorders such as Alzheimer’s and ADHD – with the corresponding areas in the genomes of people who may have lived 10,000 years ago. So, we can try to trace a specific disorder back in time and see whether we can detect it in historical periods when there was a particularly high rate of infection from pathogenic bacteria or during periods when there was significant impact on the environment. And this also applies to any other kind of disorder that has nothing to do with brain disease.’
CADASIL needs to be investigated
One of the brain disorders Eske Willerslev, Thomas Werge and Rasmus Nielsen will be studying while their extensive library of ancient DNA profiles is growing is CADASIL.
This is a rare, hereditary disease which, today, is untreatable. There are estimated to be between 120 and 300 sufferers in Denmark.
CADASIL causes strokes in the small blood vessels in the brain, and in most cases it leads to considerable cognitive impairment, for instance dementia. It can also result in severe disability and premature death.
On 9 May, a team of French researchers will be awarded the Brain Prize 2019 at a ceremony in Copenhagen for their decades of research into this disease.
The Brain Prize, which the Lundbeck Foundation has awarded since 2011, is the world’s largest brain research prize. It is accompanied by a monetary award of 1 million euros – approximately 7.5 million Danish kroner – and the four recipient researchers, Marie-Germaine Bousser, Hugues Chabriat, Elisabeth Tournier-Lasserve and Anne Joutel share the amount – and the honour – equally.
They are receiving the prize for describing CADASIL and for proving that the disorder is due to mutations of a specific gene, the NOTCH3 gene, on chromosome 19. And Eske Willerslev points out that, in principle, once we have identified the location of these mutations in the genome, it will be easy to look for CADASIL in the ancient DNA profiles.
Anne Joutel finds the idea of acquiring information about CADASIL from thousand-year-old genetic material highly fascinating:
‘We four were the first to describe this disease around 30 years ago. But we’ve no idea how far back we can trace it – and it would be extremely interesting to gain more knowledge.’
However, even if Eske Willerslev and his colleagues do manage to detect this rare mutation in human DNA that is several thousands of years old, it is by no means certain that the individual in question contracted CADASIL.
‘The disease usually presents after the age of 50, and average life expectancy in the past was very much lower than it is today,’ says Anne Joutel, and she adds:
‘If I can in any way help trace CADASIL in the ancient DNA, I’ll gladly volunteer.’