2016 Genetics Prize
C. David Allis
C. David Allis was born in 1951 in Cincinnati, Ohio, where his father was a city planner and his mother was a homemaker and, later, an elementary school teacher. While growing up, Allis was not particularly interested in science, but he found he excelled in those classes, so when he entered the University of Cincinnati in 1969, he declared biology as his major. He intended to go to medical school, but his cell biology professor, Steven Keller, suggested he first spend some time working in a research lab with Michael Bharier at the university’s medical school. “Everything I had learned in class came to life for me,” he recalls. “It was so much fun. I never looked back.”
Allis enrolled at Indiana University in Bloomington for graduate studies, a choice he made in part because he needed to stay within a few hours’ drive from his parents’ home. But Indiana also had a great embryogenesis program, “and I was hooked on developmental biology,” says Allis. Under the tutelage of Anthony Mahowald, Allis did his doctoral research on the early Drosophila (fruit fly) embryo, focusing on pole cells and polar granules, which are essential to the development of the fly’s germline. But it was while researching a presentation for a “dreaded” genetics course that Allis first became hooked on what was to become his life’s work: the study of the DNA-histone protein complex called chromatin.
“Chromatin was not a hot area at that time. In fact it was thought to be a boring area, but to me it was cool,” Allis recalls. After finishing his PhD in biology in 1978, Allis began searching for a postdoc laboratory where he could pursue chromatin studies in the context of developmental biology, preferably with Drosophila. “None of the ‘fly’ labs was interested,” he says. A friend suggested that he consider a different model organism for his chromatin studies, the ciliated protozoan Tetrahymena, which has the odd distinction of having two nuclei with very different collections of genes. That led Allis to the University of Rochester lab of Martin Gorovsky, who had learned how to grow the organism and separate its nuclei. Allis spent three years in Rochester, using Tetrahymena to learn about the various histone proteins and about histone acetylation, a protein-modification process that modulates gene transcription within cells.
In 1981, after his postdoctoral research was completed, Allis took a position as assistant professor in the Department of Biochemistry at the Baylor College of Medicine in Houston. He remained committed to chromatin research, specifically to the goal of finding proteins that modify histones, even though most scientists at that time continued to consider histones as just passive “spools” around which DNA was wrapped. Despite some periods of doubt, Allis persisted. That tenacity paid off in 1996, when his lab identified the first direct link between transcription activation and histone modification. In a groundbreaking paper published in Cell, Allis and his graduate student, Jim Brownell, reported that they had isolated an acetyltransferase (HAT) — a protein known to add an acetyl chemical “tag” to DNA — on the tails of histones in the macronuclei of Tetrahymena. A few weeks later, Schreiber and colleagues (Harvard) reported that they had found another protein that removed the acetyl. “It was a one-two punch, and it changed everything, for it meant that histone modifications play a direct role in gene regulation,” says Allis. “You couldn’t now just dismiss histone proteins as packaging only.”
Allis’ research helped launch modern epigenetics, the study of how molecular chemical “switches” in the chromatin complex turn genes on and off. In 1998, Allis moved his lab to the University of Virginia in Charlottesville, Va., and in 2003, he moved it once more to The Rockefeller University in New York City. He continued to make groundbreaking discoveries in diverse areas of epigenetic regulation. These included the identification of a chromatin methyl “reader,” known as a PHD finger, on the tail of histone H3. Later, Allis demonstrated that genetic mistakes made in PHD fingers cause improper readings of the chromatin in ways that link them to a human cancer, leukemia. His lab also showed, for the first time, that a histone “variant” (one slightly different from the main histone type) can have an effect on both gene activation and gene silencing, depending on where it is located in the genome. This “split personality” of a histone variant has been linked to human diseases, including neurological syndromes. More recently, Allis’ lab has described the mechanisms behind deadly histone mutations in a rare pediatric brain tumor. “Before I retire for good, I want to learn how to detoxify these mutations,” says Allis. “I want to learn how to make it better for these very sick children.”
In a series of highly cited articles, Allis has also formulated the “histone code hypothesis,” which predicts that histone modifications, working in different combinations, act to dictate downstream biological processes, such as gene expression and silencing. These concepts have stimulated an immense worldwide effort to understand the structural and functional principles underlying the writing, reading, and erasure of posttranslational histone modifications (the part of gene expression that occurs after transcription) and the “cross-talk” in such processes.
At The Rockefeller University, Allis is currently the Joy and Jack Fishman Professor and Head of the Laboratory of Chromatin Biology and Epigenetics. He is the recipient of numerous professional honors, including memberships in the National Academy of Sciences and the American Academy of Arts and Sciences. In addition, he is renowned for inspiring and mentoring a long line of graduate students and postdoctoral researchers who are now at leading academic institutions around the world. Allis lives in New York City with his wife, Barbara. They have three grown children, Laura, Brian, and Michael.