Kári Stefánsson (born 6 April 1949) is an Icelandic neurologist and founder and CEO of Reykjavík-based biopharmaceutical company deCODE genetics. In Iceland he has pioneered the use of population-scale genetics to understand variation in the sequence of the human genome. His work has focused on how genomic diversity is generated and on the discovery of sequence variants impacting susceptibility to common diseases. This population approach has served as a model for national genome projects around the world and contributed to the realization of several aspects of precision medicine.
Biography Kari Stefansson was born in 1949 in Reykjavík, Iceland. He was the second youngest of the five children of Sólveig Halldórsdóttir and Stefán Jónsson, a radio personality, writer and democratic socialist member of parliament.Obituary notice for Stefán Jónsson, Morgunblaðið, 18 September 1990, accessed at http://timarit.is/view_page_init.jsp?pageId=1729310 He completed his secondary education at Reykjavik Junior College and received his M.D. in 1976 and his Dr. med. in 1986 from the University of Iceland. He was married to Valgerður Ólafsdóttir from 1970 until her death on 11 November 2021. In June 2012, his daughter, Sólveig "Sóla" Káradóttir, married Dhani Harrison, son of the late George Harrison and his wife, Olivia Harrison. Stefansson says that he owes much to his brother, who has schizophrenia. He initially thought of becoming a writer, and attests to being a voracious reader. His favorite author is Isaac Bashevis Singer."What if You Knew When You Were Going to Die?" Haaretz
Academic career Following his internship at the National Hospital of Iceland, he went to the University of Chicago to work under Barry Arnason (coincidentally a Canadian of Icelandic descent). There he completed residencies in neurology and neuropathology, and in 1983 joined the faculty. In 1993 he was appointed professor of neurology, neuropathology and neuroscience at Harvard University and division chief of neuropathology at Boston's Beth Israel Hospital. While in Boston, he and his colleague Jeffrey Gulcher decided to return to Iceland to perform genetic studies to determine multiple sclerosis risk.Executive Profile from BusinessWeek magazine Stefansson resigned both positions in 1997 after founding deCODE and moving back to Reykjavík. Since 2010, he has held a professorship in medicine at the University of Iceland. He is a board-certified neurologist and neuropathologist in both Iceland and the US.
From biology to genetics Stefansson's academic work was focused on neurodegenerative disease.His particular focus was myelin degeneration in multiple sclerosis. A selection of his publications from this period can be searched on Google Scholar. The protein biology approach to this research involved trying to map complex processes using limited samples, mainly of brain tissue from deceased patients. Although publishing steadily, Stefansson was frustrated by the pace of progress and often by not knowing whether the proteins he was characterizing were involved in causing disease or the product of the disease process.Adam Piore, "Bring us your genes: A Viking scientist's quest to conquer disease," Nautilus, 2 July 2015 He and his colleagues came to question even the accepted definition of multiple sclerosis (MS) as an autoimmune disease.Gulcher, JR, Vartanian, T, and Stefansson K, "Is Multiple Sclerosis an automimmune disease?" Clinical Neuroscience 2(3-4):246-52 (1994)
When he was recruited from Chicago to Harvard, Stefansson began to think that the genome might provide a better starting point than biology. Genes encode proteins, so identifying the genes and specific genetic variations that patients tended to share more often than healthy individuals should provide a foothold in the pathogenesis of disease.For contemporary views of this potential, MS Guyer and FS Collins, "The Human Genome Project and the future of medicine," American Journal of Diseases of Children, 147(11):1145-52 (November 1993) In doing so they might point to biologically relevant targets for new drugs and predictive diagnostics.An authoritative mid-1990s view of the promise of genetics in diagnostics, Min J Khoury and Diane K Wagener, "Epidemiological evaluation of the use of genetics to improve the predictive value of disease risk factors," American Journal of Human Genetics, 56:835-844, 5 January 1995
However, in the mid-1990s the tools for reading the sequence of the genome were primitive. Data was scarce and expensive to generate, and a major early focus of the Human Genome Project was to develop better methods.FS Collins et al., " New Goals for the U.S. Human Genome Project: 1998 –2003," Science, Vol. 282, pp. 682-689, 23 October 1998 In the meantime, one solution was to use genetics – how the genome is mixed and passed from one generation to the next – as a means of deriving more information from the available data.An influential early – and at that time still largely theoretical – discussion of different possible approaches to common rather than rare diseases is ES Lander and NJ Schork, "Genetic dissection of complex traits," Science, Vol. 265, Issue 5181, pp. 2037–2048, 30 September 1994 Siblings share half their genomes; but cousins one eighth, second cousins one thirty-second, etc. Studying patients linked by extended genealogies should therefore make it possible to more efficiently find the inherited component of any phenotype or trait, even using low-resolution markers.
Back to Iceland An important question was whether and where such extended genealogies might be found. It was not one that occurred to many leading geneticists to ask with regard to common diseases.This was not an obvious thing to look for. Even prominent experts who predicted the future power of population genetics and association studies seem not to have considered that linkage analysis could be extended to common diseases, and aid in association studies, through population-wide genealogies. Neil Risch and Kathleen Merikangas, "The future of genetic studies of complex human diseases," Science, Vol. 273, No. 5281, pp 1516–1517, 13 September 1996; Aravinda Chakravarti, "Population genetics: making sense out of sequence," Nature Genetics 21, pages 56–60, 1 January 1999 As an Icelander, Stefansson knew the country's passion for genealogy first hand and had grown up with and trained in its national health system. In 1995, he and his colleague and former graduate student, Jeffrey Gulcher, decided to go to Iceland to study multiple sclerosis. Working with doctors in the national health system they identified hundreds of patients and relatives who gave them blood samples to begin their research. As Icelanders they were almost by definition related, and due to the national pastime of genealogy those relationships could be established.
When Stefansson and Gulcher returned to Boston, their grant proposal was turned down by the NIH, which had little experience of funding work using distantly related patients. But Stefansson saw potential in Iceland for using the same approach to find the genetic component of virtually any common disease.Nicholas Wade, "SCIENTIST AT WORK/Kari Stefansson; Hunting for Disease Genes In Iceland's Genealogies," New York Times, 18 June 2002 This was beyond the scope of an academic laboratory, and he made contact with venture capital firms to find out if such an enterprise could be funded as a private company. In the summer of 1996 he raised $12 million from several American venture capital funds to found deCODE genetics.from Alta Venture Partners, Polaris Venture Partners, ARCH Venture Partners, Atlas Venture, among others. A complete list of early investors is in the Icelandic business paper Frjals Verslun from 1 March 1998, p. 37 He and Gulcher moved to Iceland to set up operations and resigned their positions at Harvard the following year.Announcement of deCODE starting operations on the front page of Morgunblaðið, 31 May 1996
deCODE and the population approach Stefansson conceived deCODE as an industrial-scale enterprise for human genetics. Unlike the prevailing academic model of scientists undertaking discrete projects in their separate labs, he proposed to gather and generate as much genealogical, medical and genomic data as he could from across the population. Using bioinformatics and statistics, deCODE could then combine and mine all this data together for correlations between variation in the sequence and any disease or trait, in a nearly hypothesis-free manner.An early description of the discovery model and process by Stefansson and Gulcher when they still planned to build the IHD, in "Population genomics: laying the groundwork for genetic disease modeling and targeting," Clinical Chemistry and Laboratory Medicine 36(8):523-7, 1 August 1998 The business model was to fund this effort through partnerships with pharmaceutical companies who would use the discoveries to develop new drugs.A good early outline of Stefansson's vision and the business model in Stephen D. Moore, "Biotech firm turns Iceland into a giant genetics lab," Wall Street Journal , 3 July 1997
Iceland had the data sources required for this "population approach": a high-quality single-payer healthcare system; a relatively homogeneous population that would make finding disease variants less complex;Gulcher, J, Helgason A, Stefansson, K, "Genetic homogeneity of Icelanders," Nature Genetics volume 26, page 395, December 2000. One example of the relative genetic homogeneity but global utility of studying the Icelandic population is breast cancer. Around the world there are many variants in the BRCA2 gene known to confer substantial increased risk of breast cancer, but in Iceland there is essentially one disease-linked variant, which was published on the eve of deCODE's operational launch in Iceland: Steinnun Thorlacius et al., "A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes," Nature Genetics , Volume 13, pages117–119, 1 May 1996. deCODE now has a website that enables Icelanders to find out if they carry the mutation. an educated citizenry that was willing to contribute DNA and medical and health information for research; and most uniquely, comprehensive national genealogies.The resources and their utility for gene discovery is concisely summarized in deCODE's first press release: "Icelandic Genomics Company Identifies Location of Gene for Essential Tremor," 25 August 1997, on the company website. Mary Clare King, who had used family pedigrees to identify BRCA1 in breast cancer, was among the scientists who recognized the potential of these records. As she told the New Yorker, "to be able to trace the genealogy of an entire nation for a thousand years...and obtain samples of blood and tissue from healthy living people...could become one of the treasures of modern medicine."Quoted in Michael Specter, "Decoding Iceland," The New Yorker , 18 January 1999