When you are looking for something very rare, e.g. a genetic disease found only in one out of 10,000 people, you have to look for a very long time.
Today large groups of children or adults are usually screened with one gene test per person. This makes it very expensive to test large groups for rare diseases. But imagine if we could test 10,000 people with just 200 tests. That would save society
9,800 tests and it would help ensure that far more people with serious rare diseases, including new-borns, can be diagnosed and treated before their illness advances, or perhaps even before a patient has the first symptoms.
Danish researchers have found a new method of DNA screening that makes this scenario a reality. The method is called Double Batched Sequencing (DoBSeq) and it was developed by researchers from Copenhagen University Hospital – Rigshospitalet in collaboration with researchers from the University of Copenhagen, Statens Serum Institut (SSI) and the Danish Cancer Society. The method provides unique possibilities to test large groups of people for serious, rare, genetic diseases simply, efficiently and cheaply.
Cross-tests
In brief, the newly developed DNA screening entails mixing thousands of blood samples in a number of test tubes in a carefully orchestrated system, so that each individual’s blood sample only occurs in exactly two sample tubes. With just a few analyses, it is possible to see whether there is one among the many with the rare genetic the disease, and to identify which individual it is. Instead of testing DNA samples (genetic material) per person, as is normal practice, the innovation lies in mixing DNA samples twice across the samples. This means that you can quickly and much more cheaply find precisely the people with rare gene mutations.
The new method developed by the research group is so efficient and promising that Innovation Fund Denmark has decided to invest DKK 23 mill. in developing and testing the method. The method will be tested as a research project conducted collaboratively by the researchers involved.
Børnecancerfonden has provided DKK 10 mill. in funding, while the Novo Nordisk Foundation has granted almost DKK 4 mill. to develop the new screening method.
Can make screening of large groups of people financially feasible
Ulrik Stoltze, is a consultant and researcher at the child cancer laboratory (Bonkolab) at Copenhagen University Hospital – Rigshospitalet, and he is one of the main players behind developing the method. He explains:
"Even though there has been great interest in screening for genetic diseases, one of the fundamental problems has been that it would be too costly to examine all new-borns through a gene test, for example. This new method makes screening of all new-borns for numerous serious genetic diseases financially feasible, meaning in turn that we’ll be able to treat these patients for a large number of diseases much better than we can today,” said Ulrik Stoltze, who along with his researcher colleagues, including Jonas Bybjerg-Grauholm from Statens Serum Institut (SSI), has spearheaded development of the method.
Ground-breaking method
Professor Kjeld Schmiegelow from the Department of Paediatrics and Adolescent Medicine at Copenhagen University Hospital – Rigshospitalet has also been involved in development of the method, and he agrees that this method is ground-breaking and opens up for many new possibilities.
“Our method makes it possible for us to begin to examine whether we can and should test all newborns and many other Danes for selected genetic conditions. There are prospects to both improve and save lives for children and adults, but it is also a new area, and there is a risk that this new knowledge about diseases could entail a psychological strain for many,” explained Professor Kjeld Schmiegelow, and he continued:
“Most people don't think about the fact that we’ve been screening all Danes for genetic disease for more than 50 years. It began with a metabolic disorder called Følling’s disease (PKU), which, if left untreated, leads to serious brain damage. Since then, more diseases have been added to the Danish screening programme for new-borns, but we have lacked cheap technology so we can screen for many more diseases. Screening based on cheap analyses of DNA is the next step, and it could significantly increase the number of diseases we can screen for, thereby preventing children from dying or being seriously harmed by these diseases.
Right now, large projects are being conducted in the US and the United Kingdom to test whole genome sequencing (i.e. tests of the entire genetic material), but this is an extremely costly strategy for screening newborns. In the British Newborn Genomes Programme, which is costing approx. DKK 1 bn., they’re examining 100,000 people, or just one-third of the number we’ll be examining - and at a fraction of the price,” stresses Kjeld Schmiegelow.
The new Danish method was described in the recently published prestigious journal Genome Medicine under the title "Combinatorial batching of DNA for ultralow-cost detection of pathogenic variants."
Facts about the method and the research project
Video and illustration
The Double Batch Sequencing method
- Double Batch Sequencing (DoBSeq) is a new, cheap method to find rare pathogenic gene mutations in the large groups of people.
- The method works by testing batched DNA from many people, so that an individual’s blood sample and no others will occur in just two specific batches. This means the rare gene mutations can be traced back to the individual.
- The method is described in a scientific article published in 2023 in the international journal Genome Medicine
The research project
- With support from Innovation Fund Denmark, Børnecancerfonden and the Novo Nordisk Foundation the method will now be scaled up in a new project called PREDiSPOSED, and the method will be tested on 300,000 Danes.
- The project aims to identify the technical and medical possibilities and examine the human implications through an anthropological and bioethical arm.
- The 300,000 adult Danes included in the research project to test the method will be randomly selected and contacted via e-Boks with an offer to take part in the research project and a more detailed description of what participation involves. Participation in the project is 100% voluntary and participants will only included in the research project if they agree to participate.
The research group
The group behind the new method and the PREDiSPOSED project consists of leading researchers:
- Henrik Hjalgrim from the Danish Cancer Society
- Ayo Wahlberg and Simon Rasmussen from the University of Copenhagen
- Jonas Bybjerg-Grauholm, David Hougaard, Christian Munch Hagen and Marie Bækved-Hansen from Statens Serum Institut (SSI)
- Kjeld Schmiegelow, Ulrik Stoltze, Thomas v. Overeem Hansen, Karin Wadt and Allan M Lund from Copenhagen University Hospital – Rigshospitalet.
The group covers the research fields: clinical genetics, paediatrics, oncology, bioinformatics, anthropology, molecular biology and epidemiology, all of which are fundamental for the project.
The project is being headed by Prof. Kjeld Schmiegelow, Copenhagen University Hospital – Rigshospitalet, who is a professor on paediatrics and expert in cancer diseases in children and adolescents. Read more on the project website.
Further information
For further information or contact with the research group, contact
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