A druid with white hair, a well-trimmed beard and an entire character, famous for his legendary tantrums and his totally oversized ego. Kari Stefansson, the leader of the Icelandic company deCode Genetics, has a little Didier Raoult side. The same propensity to co-sign all the publications that come out of his research center, to appear in all the photos that illustrate his company’s website, and to cling to his post despite his advanced age. But the comparison stops there, because the septuagenarian is also a recognized scientist, to whom we owe many advances in genetics. And it took a strong personality to lead the project he launched twenty-five years ago: to collect DNA and health data from the entire population of the Nordic island. At the time, he aspired “to discover the origin of diseases there, and to develop drugs to cure them”. If our biology ended up being much more complex than he anticipated then, the genes of the Icelanders did contribute to advancing medicine. But not quite the way Kari Stefansson imagined a quarter of a century ago.
This scientific adventure was not a long calm river. It started in 1996, when this neurologist working at Harvard University in the United States returned to the country to found the company deCode. He had to face a real outcry: part of the medical profession and members of the clergy opposed him. Abroad too, his project surprises, and many are worried about the risks associated with the creation of such a database, national, exhaustive, and managed by a private company. After many twists and turns, and despite the support of the Prime Minister, parliament vetoed. But Kari Stefansson knows how to do it. It plays on national pride, emphasizes the specificities of this small people, in particular its homogeneity due to a limited number of common ancestors, “which facilitates genetic research”, he explains. He will end up gaining the trust of his fellow citizens, and their voluntary participation in his database.
A small people descended from a limited number of ancestors, well-kept medical records since 1915, a local passion for genealogy: three assets for genetic research. credit: Luc Melanson
Luc Melanson
The result is there, behind an armored door in the basement of deCode’s headquarters, just outside the capital Reykjavik. More than 500,000 tubes of blood, taken from some 180,000 people – nearly 70% of adults on the island – and stored in a gigantic freezer at -24°C. David and Goliath, two robots, officiate there 24 hours a day to take out the precious bottles as the researchers need them. More often than not, entire families have entrusted their DNA to deCode, from grandparents to grandchildren. “Having genetic and health data over several generations is unique in the world”, underlines Sir Rory Collins, scientific manager of UK Biobank, the British biobank. The Icelanders have indeed medical records dating back to 1915. And, above all, they are fond of genealogy. Nowhere else are the family trees so complete and ancient, some dating back to the 9th century. Above all, in this small population, it is a question of avoiding ending up frolicking with a cousin or a cousin in the third degree… But this passion has become an asset for geneticists, in order to follow the evolution of diseases within families.
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With this mine of information, the Icelandic pioneers multiplied the discoveries, and collected over the years the front pages of the prestigious newspaper Nature. Protective variants against Alzheimer’s or against coronary heart disease, risk factors for cancer or glaucoma, genes involved in the size or pigmentation of the skin, mechanisms of appearance of mutations…, the publications are linked. The working methods invented here inspire many other research institutions abroad. On the other hand, advances that can be monetized, in other words that can be used to create treatments, are long overdue. “We were able to discover a few genes linked to rare diseases. But for common pathologies, it turned out to be much more complicated. When we started, nobody knew that most cancers, diabetes or cardiovascular pathologies do not depend on not a single mutation, but many variations across a multitude of genes,” said Dr. Unnur Thorsteinsdottir, vice president of genetics research at deCode. Time passes, and the company runs out of funds. It was swept away in the turmoil of the 2008-2009 financial crisis, and was on the verge of bankruptcy when the American pharmaceutical company Amgen bought it in 2010.
With the evolution of research, the population of the island is no longer sufficient
At the same time, genetic research is evolving. The highly polygenic nature of many conditions requires ever greater statistical power to identify the multiple variants involved in common diseases. Huge databases are needed, bringing together information from populations of various origins. Iceland is no longer enough: deCode has multiplied partnerships abroad over the years. In its freezers, the company now stores the DNA of 250,000 English, 600,000 Danes, 250,000 Norwegians and 65,000 Swedes, not to mention a few thousand Scots and Dutch. However, it was not just this mountain of information that interested Amgen.
“Their database remains one of the richest in the world, but we know this advantage will erode. [NDLR : du fait de la multiplication des projets de séquençage de génomes à grande échelle]. In contrast, deCode has built very powerful tools to store, manage, and cross-reference hundreds of thousands of patient profiles with millions of genetic data, and then distinguish interesting correlations from those that are arguably coincidental. This experience is not going to erode,” says Dr. Ray Deshaies, vice president in charge of research at Amgen. Not to mention that, in recent years, it has also become apparent that the exploration of our heritage genetics could have multiple applications for pharmacy, well beyond the sole search for genes involved in this or that pathology.
Few direct returns for the Icelandic people
For example, DNA helps identify the patients most likely to benefit from a treatment, in order to better target clinical trials. “This generates significant savings in time and money,” emphasizes Dr. Deshaies. In some cases, genetics can also help predict or improve drug safety. The use of advanced techniques, such as transcriptomics (the study of gene expression) or proteomics (the analysis of proteins circulating in the blood), makes visible the body’s responses to a molecule. But that’s not all. The deCode experts also sift through the many scientific publications presenting discoveries in genetics. “In 75% of cases, they are not reproducible, and therefore have no interest for a pharmaceutical laboratory”, observes Kari Stefansson. Conversely, Amgen may learn of all deCode advancements before they are made public, a legal requirement.
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And the Icelanders, what did they gain by offering their DNA to a private company? The pride that their island is known for something other than its sumptuous landscapes and its fishermen. The satisfaction of participating in the progress of science. And not much more. Because except for the BRCA2 gene (involved in breast cancer), the law prohibits the sharing of sequencing results with participants, in the name of the “right not to know”. No drugs have so far been developed directly from targets discovered by deCode, although some are reportedly in preclinical testing, according to Amgen. But it doesn’t matter in the end, for Kari Stefansson: “Here, we don’t make products, we make discoveries”, he insists today. For this precursor, there is no doubt that over the next quarter century we will understand everything about our genome. The medical revolution he foresaw twenty-five years ago will then take place. Just a little later than expected.
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