2016 Genetics Prize
Michael Grunstein was born in Romania in 1946. His parents, both Holocaust survivors, immigrated four years later to Montreal, where Grunstein’s father ran a taxi company and his mother worked in clothing factories. While growing up, the young Grunstein gravitated toward biology, “but, like most immigrant students, I thought I would go to medical school,” he recalls. He began to change his mind, however, after he got his first between-semesters job at an industrial laboratory, doing gas chromatography. Soon, he was volunteering to work in science laboratories at McGill. “I quickly found out how much I enjoyed research,” he says. While at McGill, Grunstein also developed a deep interest in genetics, a field he decided to pursue after graduation. “My parents were disappointed that I was giving up medical school, but they were always supportive of my choice," he says.
Grunstein was particularly interested in developmental genetics, so, on the advice of a faculty member at McGill, he decided to cross the Atlantic and attend graduate school at the University of Edinburgh in Scotland, the academic home of C. H. Waddington, the renowned British developmental biologist who coined the term epigenetics. While there, Grunstein worked with molecular biologist Max Birnstiel to characterize the first chemically isolated genes of an eukaryote (an organism whose cells contain a nucleus), specifically, the ribosomal RNA genes from the toad, Xenopus laevis. “It was an involved, difficult procedure,” Grunstein recalls, “but it was very exciting because it was testing key principles of biology and raising basic questions: What is a gene? How is it controlled? And where in the DNA sequence is the control coming from?”
After receiving his PhD, Grunstein returned to North America for postdoctoral research with Larry Kedes at Stanford University. While there, he began to study genes and messenger RNAs (molecules that carry the DNA code to other parts of the cell) for the histone proteins. Stanford was the right place to be for that research, for it was pioneering what was then a new approach for studying genes called recombinant DNA cloning. The technique, however, had limitations that made it difficult to isolate cloned DNA that contained an individual gene of interest. To overcome that problem, Grunstein, then in the laboratory of David Hogness, developed “colony hybridization,” a tool that makes it possible for researchers to isolate a single gene encoding an individual mRNA. “It was a game-changer,” Grunstein recalls. “It made everything else possible.” Soon, scientists were using colony hybridization to clone genes in bacterial viruses, bacteria, yeast, and even human cells.
In 1975, Grunstein left Stanford to establish his own laboratory at the University of California, Los Angeles (UCLA), where he began studying histone mRNAs in sea urchins. Working with sea urchins was challenging, especially when bad weather made them difficult to obtain. Then one day he attended a lecture about yeast, and quickly realized it would be an ideal model organism for histone studies. “I had a revelation, and so I switched,” says Grunstein. “It was wonderful.” Yeast allowed the geneticist to make DNA sequence and resultant protein sequence changes in a living cell and test hypotheses fairly rapidly.
At that time, the study of histones lacked genetic analysis. It had been known since the 1960s that histone acetylation (a protein-modification process that modulates gene transcription within a cell) and gene activity were correlated, but it was not known whether that acetylation was a cause or a result of transcription. Many scientists, especially those working with bacteria (which lack histones) believed that histones were nothing more than inert structures around which DNA was wrapped to form nucleosomes, the building blocks of the chromatin complex that forms chromosomes. In 1988, Grunstein shattered that belief. It was already known that nucleosomes repressed transcription initiation in vitro, in the test tube. But would this also be the case in the living cell? In a seminal paper published in Cell, Grunstein provided the initial evidence that nucleosomes repress transcription in yeast. A second study showed that without a section (the N-terminus) of the tail of a major histone protein, H4, the yeast could live, but it could not reproduce sexually. These were the first demonstrations of a causal relationship between histones and gene regulation in living cells. A few years later, he demonstrated that while nucleosomes are generally repressive, the acetylation sites on histone H4, are actually required for gene activity. He also showed that a single lysine (an amino acid used in the biosynthesis of proteins) on H4 was critical for silencing genes. Together, these studies unequivocally demonstrated that histones have important and varied regulatory roles separate from their role as DNA “packaging.”
Other important findings followed. In 1995, Grunstein showed that silent information regulatory (Sir) proteins mediate transcriptional repression by interacting with the histone tails. This was the first demonstration that histones themselves are the immediate targets of certain transcriptional regulatory proteins. Grunstein also showed that the Sir proteins, once recruited to their target sites, can spread over larger regions of the genome. This helped explain heterochromatic spreading, a phenomenon that occurs in other forms of heterochromatin (densely packed DNA) in the cells of mammals. These and other groundbreaking findings from Grunstein’s lab helped launch a new era in the studies of chromatin structure and, more broadly, the field of modern epigenetics.
Grunstein continues to work at UCLA, where he is a former chair of the Geffen School of Medicine’s Department of Biological Chemistry, although he plans on becoming professor emeritus later in 2016. Grunstein has received numerous honors and awards for his work, including memberships in the National Academy of Sciences and the American Academy of Arts and Sciences. He lives in the Los Angeles area with his wife, Judith, who is a dentist. They have two grown children — a daughter, Davina, and a son, Jeremy — as well as two grandchildren.