23 December 2022 - “It would be very surprising if you ever had a mechanism in nature that would be 100%. Biology never seems to be so clear cut.” That was Roger Reddel’s reaction to his then Ph.D. student Tracy Bryan’s discovery that many cancer cell lines do not express the enzyme telomerase, but still maintain long telomeres throughout the immortalization process. Their 1995 paper “Telomere elongation in immortal human cells without detectable telomerase activity” has been cited over seventeen hundred times. It is included in The EMBO Journal’s 40th-anniversary collection of ground-breaking articles, all free to read. On this episode, Reddel and Bryan discuss how the project began, the key experiments, and the consequences of Alternative Lengthening of Telomeres (ALT) for cancer research. Miguel Godinho Ferreira discusses the paper’s impact in the broader setting of genome instability and DNA repair.