It was an all-or-nothing moment. Titia de Lange, a newly hired assistant professor at the Rockefeller University, had months of prep work and her entire grant's supply budget in hand as she waited to cross York Avenue, the busy north-south street on Manhattan's Upper East Side that separates Rockefeller from Memorial Sloan-Kettering Cancer Center, where a collaborator was waiting to sequence de Lange's protein distillate. "We walked with all the protein we had from 1,500 liters of HeLa cells," de Lange recalled. "If we had tripped it would have been a problem. "It was a potentially self-destructive experiment, but it worked."
But de Lange made it across York Avenue and the sequencing led to the first of her key discoveries about how chromosomes are protected from damage by telomeres, repetitive sequences at the end of chromatids. Defects in telomeres can lead to cancer and loss of telomeres leads to aging. Her telomere discoveries led to the announcement last week that de Lange, a longtime ASCB member and now full professor at Rockefeller, was one of six recipients of the 2014 Canada Gairdner International Award. The prestigious Gairdner comes with a prize of $100,000 CDN.
De Lange started studying telomeres back in 1980 by accident, she says. She was a graduate student at the University of Amsterdam working with Piet Borst working on how trypanosomes, parasites that cause diseases such as African Sleeping Sickness, evade the host's immune system by changing their surface proteins. Borst and de Lange suspected that the genes responsible for this evasion were in the telomeres at the ends of chromosomes. "My first project was to prove that [the genes] were at telomeres. I read the telomere literature, which was four papers at the time," de Lange said. "I thought [telomeres] were really cool."
Her interest in telomeres led her to the U.S. where she was a postdoc with Harold Varmus at the University of California, San Francisco, looking for proteins that could bind to telomere DNA. "I spent four years trying to purify the factor," de Lange said. "It was really difficult and no one in my lab believed in the project." De Lange brought the project with her to Rockefeller where she finally purified the protein, but it wasn't easy.
"We needed 1,500 liters of HeLa cells to purify enough [protein] at the time," De Lange explained. It was far more than her lab could handle. "At some point I spent my whole supplies budget from my one NIH grant on HeLa cells. I couldn't grow that volume on my own, but I could buy it. I bought 1,500 liters of HeLa cells for my full supplies budget. We had done endless purifications from smaller volumes that I could grow, like 40 liters or 100 liters, so we knew how to purify it when we did the big prep."
When it was done, de Lange walked the results across York Avenue to the Memorial Sloan-Kettering Cancer Center lab of sequencing collaborator Paul Tempst. The sequencing led her lab to identify a protein that binds and maintains telomeres.
De Lange's work has been pivotal in advancing understanding of telomeric control, an achievement that was recognized last year when de Lange was named a winner in the first round of Breakthrough Awards, a new bioscience prize bankrolled by a group of Silicon Valley entrepreneurs. Despite the acclaim, de Lange says she was dumbfounded by the call from Gairdner President and Scientific Director John Dirks. "I thought he'd probably made a mistake calling me," De Lange said. When Dirks confirmed that he had called the right person, de Lange was thrilled but quickly sworn to secrecy. De Lange could finally celebrate with her lab only last Wednesday after the Gairdner announcement was made in Toronto.
De Lange is the only woman on this year's Gairdner prize list. It's not a problem per se with selection committees or that women aren't doing great science today, de Lange believes. "It's hard for prize committees to get a reasonable representation of women. Most prize committees that I know are trying very hard, but they rely on nominations and I think what needs to happen is that women get nominated more in order for them to get recognized at the level where they should be recognized."