Sequencing the World’s Oldest Woman
by Clarence Lee - 06/02/14
My R&D colleagues and I were approached several years ago to participate in what would become one of the most fascinating projects in our careers – to sequence the genome of a woman who lived to be 115 years of age and to see what her genome might tell us about healthy aging. Not only did Hendrikje van Andel-Schipper, who resided in the Netherlands, live to an advanced age, but she did so while remaining remarkably healthy. This “supercentenarian” did not display any of the typical age-associated signs of cognitive decline; in fact, at 111 years old, tests run by a Dutch neurologist demonstrated that Ms. van Andel-Schipper retained mental faculties sharper than average 60 to 70 year old individuals. In addition, although she eventually succumbed to gastrointestinal cancer, Ms. van Andel-Schipper, also known as “Hennie,” had beaten breast cancer when she was 105.
Thanks to this woman generously donating her body to science, we had an opportunity to collaborate with Dutch scientists to examine her genome. One of the first questions we wanted to ask had to do with what we call mutation “load.” How many mutations did Hennie’s cells accumulate during her life and what might it tell us?
With Dr. Henne Hostege at Vrije University Medical Center in Amsterdam, we devised an experiment where we extracted DNA from blood cells, which multiply frequently throughout the lifetime of an individual, and also from brain cells, which do not frequently divide. We found something we had not expected – at the time of her death, it appears that the entire population of white blood cells were derived from just two stem cell clones. This finding raises an astonishing question about the limits of aging – could depletion of blood stem cells serve as an ultimate cause of death? This is a question that had not been anticipated or considered before.
We did find about 450 mutations in Hennie’s blood cells that were not present in her brain cells. These mostly occurred in regions of the genome that had not been implicated in cancer or other diseases, and considered harmless. This is interesting in of itself since it shows that mutations naturally build up as we age. And since DNA is frequently obtained from blood samples, the sequencing information from it is not necessarily representative of what can be found in different tissues and really is only a snapshot of the complex human body.
A final aspect of the study was to look at telomeres - “caps” that are found on the tips of our chromosomes and known to diminish with age. Telomeres on Hennie’s blood cells were approximately 17 times shorter than her brain cells. Perhaps it was telomere shortening that puts a final limit on age and death? We can not know that from only one study. But more and more people are living to be healthy centenarians, and our Dutch collaborators have launched a project, the 100-Plus Study, that will help us address this and other questions.
When I look back over the span of this project, I am struck by the surprising data we obtained and excited to see the results that continue to come from this and other projects in this fascinating area of research. But most of all, I am thankful to Ms. van Andel-Schipper for her generosity in donating herself so that others might benefit to live longer, healthier lives.