If you're trying to discover the secrets to long life, studying people who live to age 100 and beyond -- centenarians -- is a good place to start. Recent research on centenarians, including a paper published in Science last year, has pinpointed numerous genetic variants that might account for their extra years.
The ability to sequence a person's entire genome has raised the bar for studies like these, enabling researchers to take a closer look at centenarians' DNA. Postdoc Elizabeth Cirulli of Duke University in Durham, North Carolina, and her adviser David Goldstein have launched the first whole-genome sequencing study of centenarians. The project is part of the Measurement to Understand the Reclassification of Disease of Cabarrus/Kannapolis (MURDOCK) Study, which is trying to find new ways to treat and prevent diseases by meshing health records and genomic information for the residents of the North Carolina city of Kannapolis and the surrounding county of Cabarrus. "Surviving to 100 means that you have avoided or made it past all of the diseases that might have killed you at a younger age," says Cirulli. "Therefore, discovering genetic variants related to longevity may provide information about general health at all ages."
Although still early in her career, Cirulli has already worked on studies that tracked elusive disease-resistance genes in hot peppers, probed why some people infected with HIV are better at keeping the virus in check, and identified the cause of a rare genetic disease. Along with this broad experience in genetics, she brings to the centenarian study her expertise in whole-genome sequencing.
A passion for genetics
Cirulli, 28, grew up in the town of Endicott in upstate New York. Her interest in a scientific career bloomed late, only after she'd abandoned plans to become an architect or a novelist. In the 8th grade, she even went so far as to write a novel and submit it to several publishers. "Looking back, it is hardly surprising that it was rejected," she remembers, "but at the time it was quite crushing."
Focus on Aging Research
Researchers in many different disciplines are looking at how to make our aging population stay healthy for longer. Throughout the month of May, Science Careers will publish profiles of scientists studying healthy aging from the perspective of genetics, sociology and psychology, engineering, and neurology.
Cirulli got hooked on genetics during her A.P. biology course in high school. She pursued the subject as an undergraduate at Cornell University. For 3 years, she worked in a lab headed by plant geneticist Margaret Jahn, who has since relocated to the University of Wisconsin, Madison. Cirulli says her task there was to help other members of the lab carry out their research. "Everyone figured out that if you could get your project to [Cirulli], she could get it to work," says Michael Mazourek, then a graduate student in Jahn's lab and now a plant geneticist at Cornell. Jahn adds that Cirulli was able to hold her own intellectually in a lab that contained up to 30 people, including graduate students and postdocs who had more scientific experience than she did.
Cirulli got her first crack at analyzing genomes by helping out with the lab's study of disease resistance genes in hot peppers and their relatives, which include tomatoes and potatoes. The researchers wanted to determine whether certain pathogen-fighting genes reside at the same place in the genomes of different species, a tricky question to answer because over evolutionary time, the genes can be copied or lost, or swap segments with other genes. By scrutinizing DNA sequences of the genes and amino acid sequences of the proteins they encode, Cirulli identified similarities among the genes, providing key findings for the group's 2009 Genetics paper showing that three of these genes are located at the same position across species. Mazourek says that the discovery might help plant breeders identify seedlings that are good at fighting off disease and thus could be sources for new strains of crops.
Her time in the Jahn lab shaped Cirulli's later decisions about what projects to tackle, Cirulli says. "I think the most important things I learned … were what kind of work environment works for me and what I cannot tolerate," she says. "There was no micromanaging in the Jahn lab. You were trusted to do your job on your own, a characteristic I have found is essential for my happiness in the workplace."
"Like a lot of people, I went to grad school because I didn't know what to do next but I loved learning," Cirulli says. She chose Duke University because of its academic strength and proximity to her family, who had moved to South Carolina. As a bonus, the Southern climate was congenial for her hobby: breeding king snakes.
At Duke, Cirulli performed her dissertation research with Goldstein, a molecular geneticist. Her main project was a genome-wide association study (GWAS), a type of analysis that attempts to link particular genetic variants to certain traits, such as susceptibility to heart disease or asthma. Instead of a disease, Cirulli focused on cognitive ability, asking more than 1600 subjects, mostly Duke University students, to provide blood or saliva samples and take two standard tests that measure attention, verbal fluency, different aspects of memory, and other mental abilities. Cirulli and colleagues then analyzed the samples for single nucleotide polymorphisms, or SNPs, small changes in the DNA code. The idea was that certain genetic variants might boost or reduce a person's score.
Cirulli and her colleagues found that none of the 500,000 to 1 million SNPs they evaluated related to people's proficiency on the tests. The results weren't surprising, she says: Other GWASs on different traits have come up dry. But the negative result was dismaying. "If I had hated the work I did and lived only for the results, then I could see that being a point in my career when I might have given up and changed course. Fortunately, I love the work I do and found other projects and other aspects of that project that I could analyze and enjoy," she says. For example, Cirulli has been investigating the mental tricks and personal habits that help some people perform well on these tests, which she will detail in two upcoming papers.
After Cirulli finished her Ph.D. research, she stayed at Duke for her postdoc, again working with Goldstein, whose lab is a leader in a new and more revealing type of analysis, whole-genome sequencing. Instead of just scanning the genome for SNPs, researchers sequence an individual’s entire DNA sequence, which allows them to identify rare changes that might underlie certain diseases or traits but wouldn't show up in SNP studies. This exhaustive technique has only recently become feasible because of faster, more powerful, and cheaper DNA sequencing technology.
Along with colleagues at Johns Hopkins School of Medicine in Baltimore, Maryland, Cirulli and Goldstein have already used whole-genome sequencing to nail down the faulty gene that causes metachondromatosis, an inherited disease in which patients develop bony lumps on the hands and feet and benign tumors in the leg bones and hips. Cirulli counts this finding as one of the most rewarding of her career because the results were positive.
The MURDOCK study is trying to find molecular signatures that would help doctors identify which patients’ health is likely to get worse and who would benefit from treatments. Goldstein and Cirulli's centenarian portion of the study, which began last year, differs from previous analyses of centenarian DNA because it's relying on whole-genome sequencing instead of SNP analysis.
Other genetic studies of centenarians have sought to identify specific beneficial variants that boost longevity. For example, a 2009 paper identified two SNPs in centenarians that might slow down the thyroid gland, a factor that stretches the life spans of lab animals. But Cirulli and Goldstein want to determine whether these folks survive so long in part because they carry fewer harmful genetic variants, such as those that might lead to faulty or nonfunctional proteins. So the scientists will be scanning the genomes of centenarians to determine whether they inherited fewer bad genes than the general population. The researchers have already sequenced the genomes of 10 centenarians, all participants in the MURDOCK study, and plan to complete as many more as possible.
Off the beaten path
Cirulli appears to be on the path to a tenure-track job at a top school. But that's not her plan. Even though she's happy in academia, she says her next step will probably be an industry job. For one thing, the pay is better, she says. And she has no interest in becoming a principal investigator (PI) who is responsible for a whole lab. "I love running projects and being in charge of my own analysis." But she says doesn't want the pressure of having to dream up new projects. Jahn endorses the choice. In science, "you can play a pivotal role without being a PI," she says.
Cirulli says that with her background, the transition to aging research hasn't been difficult. "Genetic tools and methodologies can be applied to just about any trait," she says. But she likes the work because unlike other traits she's studied, this one is personally relevant: Everybody ages.
Mitch Leslie writes about cell biology and immunology for Science. He wrote about centenarians in 2008 in "Searching for the Secrets of the Super Old."