In memoriam of Professor Timothy H. Bestor

Our dear colleague and mentor Timothy H. Bestor passed away on July 29, 2026, at the age of 74. He was preceded in death by a few years by his beloved wife, Kathryn Anderson, Professor and Chair of the Developmental Biology Program in the Sloan Kettering Institute. Together, they shared a life devoted to science, art, and the rich cultural life of New York City. Tim was also an ardent and accomplished fly fisherman, finding peace and quiet reflection on rivers around the world during moments away from the laboratory or while attending scientific conferences.

Tim was born in Cocoa Beach, Florida, on the shores of Banana River. He began his scientific career as a cell biologist, earning his PhD from Florida State University in 1981 for his work on microtubule-mediated nuclear movements during fertilization, under the supervision of Gerald Schatten. He then trained in biochemistry as a postdoctoral researcher with Vernon M. Ingram at the Massachusetts Institute of Technology, where he became interested in DNA methylation and DNA methyltransferases. In 1988, Tim was appointed as Assistant Professor at Harvard Medical School. In 1995, he joined the Department of Genetics and Development of Columbia University, where he remained until he became emeritus in 2021.

Tim was an extraordinary scientist and personality, one of the pioneers who shaped the field of modern epigenetics.

He was the first to purify and clone a eukaryotic DNA methyltransferase, DNMT1, proving the physical existence of the maintenance methylation enzyme that Riggs, Pugh, and Holliday had theoretically envisioned. His subsequent collaborative work with Rudolf Jaenisch on a breakthrough mouse Dnmt1 knock-out model revealed that DNA methylation is absolutely indispensable for mammalian development, notably through the control of transposable elements. Continuing his exploration of the biological function of DNA methyltransferases, his lab demonstrated that mutations in DNMT3B cause the human immune disorder ICF (Immunodeficiency, Centromeric anomalies and Facial anomalies), and identified the catalytically inactive DNMT3L co-factor as essential for fertility by stimulating DNA methylation, shaping genomic imprinting and silencing transposable elements in germ cells. In another unexpected twist, Tim and colleagues revealed that the long-thought DNA methyltransferase DNMT2 was actually an RNA methyltransferase, specialized in tRNA protection.

Tim also made invaluable contributions to our understanding of how DNA methylation is shaped during development and disrupted in diseases. He uncovered key crosstalks connecting DNA methylation to histone modifications. In collaborative work with histone-pioneer David Allis and structural biologist Xiaodong Chen, they found H3K4 methylation repels DNMT3L binding, explaining why active gene promoters are protected from DNA methylation. Tim's group also identified the chromosomal protein FBXL10 as a mediator of the antagonistic relationship between H3K27 methylation and DNA methylation. Applying a rigorous and skeptical lens to cancer genomes, he proposed that focal hypermethylation of gene promoters in tumors most often represents accidental passenger epimutations rather than driver events, whereas global hypomethylation unleashes transposable elements, triggering the genomic instability that hallmarks advanced cancers.

Crucially, Tim used his discoveries to challenge the dominant view that DNA methylation evolved primarily to orchestrate routine developmental gene expression. Instead, he championed the genome defense model, showing that the vast majority of DNA methylation resides within intragenomic parasites, such as transposons and endogenous retroviruses, and proposing that its central evolutionary function is protecting genome stability against these elements.

Indeed, Tim was renowned for his willingness to challenge assumptions. He was a rigorous thinker, an enthusiastic contrarian, and was never reluctant to defend an unpopular opinion when he believed the evidence warranted it. His fierce debates, especially at scientific meetings, helped shape the evolution of the epigenetics field. Although not everyone agreed with his views, he was deeply respected and widely admired for his intellectual rigor, conviction, and unwavering commitment to scientific inquiry.

That same commitment extended beyond his own research. Behind his reserved exterior, Tim was a loyal, generous, and deeply supportive mentor. He was passionate about fostering the scientific community and creating opportunities for the next generation of researchers, a motivation that notably led him to co-found the Gordon Research Conference on Epigenetics in 1995.

Tim leaves not only an indelible imprint on the fields of DNA methylation and epigenetics, but also a united community of scientists, whom he mentored and inspired, and through whom his remarkable legacy will continue to live on.

From Mary Goll, University of Georgia and former PhD student: Tim believed in my abilities long before I fully believed in them myself. His confidence in me and his encouragement over the years helped shape both my career and my approach to science. He taught me to think critically, question accepted wisdom, and defend my ideas, even when they were unpopular. By giving me the freedom to find my own path, he instilled a confidence and independence that continue to guide me today. I will always remember the shared excitement we felt when we figured out what DNMT2 did! Beneath his often reserved exterior was a deeply supportive mentor whose influence on my life and career will remain with me always.

From Mathieu Boulard, EMBL, Italy, and former postdoc and research associate: I had the immense privilege of working in Tim's lab for nearly nine years. Tim's lab was a very special place because of his original and unique research vision. Tim created an environment where rigorous science and intellectual honesty were the foundation for exploring the unknown and challenging dogma. Those of us fortunate enough to work alongside him learned how to pursue our own ideas, and many of us became independent investigators. Those years were formative in ways I am still discovering, and I try to transmit to my mentees. Tim will be sorely missed for his sense of humor, his original ideas, and his strong scientific opinions.

From Deborah Bourc’his, Institut Curie, France, and former postdoc: I always knew that I would do my postdoc with Tim; there was no other possibility in my mind, and I never considered any alternative. I was fascinated and highly impressed by his signature, sharp writing style, the clarity and force with which he expressed his ideas, his strong convictions, and keen sense of scientific debate. The truth is, there was never a proper recruitment process; I did not visit the lab, did not meet people beforehand. It was a done deal between Tim and I, and I basically showed up one day in October 2000 in his lab, while nobody even knew I was coming! Tim quickly renamed all computers after French names (jambon, pamplemousse) to make me feel at home. Tim has been extraordinarily protective of me throughout my career. In return, my constant motivation has been to make him proud.

From Anne O’Donnell-Luria, Boston Children’s Hospital and Broad Institute of MIT and Harvard, and former MD/PhD student: I trained with Tim because he had such clarity of scientific vision, from the hypotheses to project development to communication of the results. He had big opinions and ideas, along with the confidence to share them and his reasoning. I was in awe from our first meeting and excited to train in the Bestor lab. Tim imparted this rigorous and inspiring approach to research to me and the others who had the opportunity to train or collaborate with him. I remain grateful to Tim for providing me with this solid foundation and am privileged to be a Bestor lab alum.

From John Edwards, University of Washington, St. Louis, and former postdoc: Tim was one of, if not the most, instrumental mentors in my career, and he played a key role in supporting my transition to a faculty position. Even after starting my own lab, we continued to collaborate on various projects up until he closed his lab. Over the years, we kept working together in part because we had similar scientific interests and complementary expertise. The science was always stimulating, but to be honest, I kept working with him mainly because it was always fun. Warm greetings followed by intense science, peppered with light teasing and jokes. Memories of shared laughter will bring me a smile for the rest of my days.

From Olya Yarychkivska, Rockefeller University, and his last PhD student: When I was graduating from his lab, Tim took me to lunch and shared insights that have guided me ever since. He said that one should always work on interesting biology. Indeed, Tim never got tied down in complicated mechanisms; he always looked to the core issue - did this have biological meaning? He also advised us to work on problems relevant to human disease. In fact, Tim was a walking medical encyclopedia, knowing about even the rarest disorders. By his constant example, he taught me to be respectful and kind to others. I consider him my scientific father, who accepted me as an eager, inexperienced student and gave me the freedom to explore and grow independent. I was Tim’s final PhD student, and despite his illness, he sent his last letter of recommendation for me from his hospital bed. I feel immensely grateful that I was able to tell him in person, just before he passed away, that I got an offer for a faculty position.