For his groundbreaking research on gene expression, Dr. Michael Grunstein wins the “American Nobel,” the Albert Lasker Basic Medical Research Award.
The biography of Michael Grunstein, PhD, that is posted online by the UCLA Department of Biological Chemistry offers a lengthy list of awards and honors that he has received throughout the long arc of his career in science. But the one that he received in New York this fall — the 2018 Albert Lasker Basic Medical Research Award — is unique.
The Lasker Award is known as the “American Nobel” — its recipients often go on to win the Swedish prize. Eighty-eight Lasker winners (including one of the two recipients of the 2018 Nobel Prize in Physiology or Medicine) have been awarded Nobels since the Laskers were first given in 1945 to recognize researchers, clinical scientists and public servants who have made major advances in the understanding, diagnosis, treatment, cure or prevention of disease. Dr. Grunstein, Distinguished Professor of Biological Chemistry at the David Geffen School of Medicine at UCLA, received the award for his groundbreaking research that revealed the vital role of histones, the proteins around which DNA molecules are coiled for more efficient storage — he playfully refers to histones as “packing material” — in regulating gene activity in living cells. He shared the award with another scientist, C. David Allis, PhD, of The Rockefeller University, who conducted parallel but separate research.
If DNA is the thread from which the tapestry of life is woven, then histones, while present in every type of organism with a nucleus (the so-called eukaryotes), were thought to be little more than the spools that hold that thread — useful and necessary accessories but with no greater role in the grand design. But Dr. Grunstein’s work with lowly yeast revealed that histones, far from being a bit player, help control which genes are turned off or on. His research, and that of Dr. Allis, ultimately led to the realization that hundreds of diseases, including cancers, neurobiological disorders and congenital heart disease, are linked to malfunctions in the histone machinery — malfunctions that might be repaired, leading to new treatments for those conditions.
Dr. Grunstein arrived at UCLA in 1975, and he spent decades in his campus lab conducting his histone research. But he was not originally motivated by a desire to rewrite texts on the subject. “I went into the field thinking that a whole field is working on the regulation of gene activity [and] I didn’t want to go in the same direction that many already were pursuing,” he says.
DR. GRUNSTEIN WAS BORN IN ROMANIA IN 1946, the child of Holocaust survivors. When he was 6 years old, his family settled in Montreal, Canada. His parents, like most immigrants, labored to build a successful life. His mother sewed in a factory until rheumatoid arthritis forced her to stop in her mid-40s; his father worked seven days a week, running a tire shop and then a taxi company. “It was a tremendous amount of work,” Dr. Grunstein recalls. “He’d have to get up in the middle of the night in the Montreal winter to retrieve a car that somebody had left in a ditch. That was not uncommon, and I or my mother would sometimes accompany him. Their experiences during the war and in the period after immigration affected me tremendously. As I was growing up, I didn’t want to have anything to do with that. What I really wanted to do was play baseball and be normal.”
In high school, his passion was for plays, not science. “I would find and read every play I could by different playwrights,” he recalls. Even then, he was something of a contrarian: “I had two good friends who were each focused on their own intellectual problems and goals, and I was drawn to the written play, which required the reader to fill in the blanks left by the playwright. Pursuing my own direction appears to have been a recurrent theme in my life.”
After high school, Dr. Grunstein attended McGill University. He worked a number of jobs between semesters to help pay for college, often in various research facilities. Each job sparked new interests — biology, immunology, genetics. “I realized the fun that you could have doing research, and I decided to apply to graduate school,” he says. “I only applied to one place: the Institute of Animal Genetics at the University of Edinburgh. Fortunately, they accepted me, because I didn’t have a plan B.
“My parents were self-educated and well-read, but they had no idea what I was doing,” Dr. Grunstein says. “The main thing my father saw was that when I worked in the labs during the summers, it was clean. He worked in his tire shop before he started the taxi company, and when he came home, he would cough up bits of rubber from the tire retreading process. He saw me working in very clean, respectable conditions. I think he thought that was better.”
After postdoctoral studies at Stanford University, Dr. Grunstein came to UCLA as an assistant professor. He initially intended to study the gene structure of immunoglobulin proteins, immune system molecules that attack invading pathogens and viruses. It was a hot subject at the time, but it was generating a new field, one populated by some very large labs. Nor did he want to study another booming topic of the time, gene transcription, the process by which the genetic material encoded in our DNA is copied into RNA. He wanted to chart his own path — to again do something different. That led him to histones.
HISTONES WERE FIRST DISCOVERED IN THE LATE 19TH CENTURY, although their role as the building blocks of the chromosome wasn’t revealed until the 1970s. The DNA/histone complex is known as a nucleosome. From the pioneering work of Roger Kornberg, PhD, at Stanford University, it was known that every nucleosome consists of two copies each of four different histone molecules — dubbed H2A, H2B, H3 and H4 — linked together to make a larger protein spool around which the long strand of a DNA molecule winds. Collections of nucleosomes, strung together like beads, make a compound called chromatin. Chromatin can be further classified as either euchromatin (a form that is loosely packed, allowing cellular machinery to access and transcribe genes) and heterochromatin (tightly packed and not transcribed).
The genetic sequences of the histone proteins have changed little over the 2 billion years of eukaryote evolution. In plants and mammals, the sequences of the H4 protein differ by just two out of 102 amino acids, or one change per billion years. “That put off a lot of people about histones, because if that’s the case, then any change you make should be lethal, and then you can’t study histone function very easily,” Dr. Grunstein says. He, however, was intrigued. “People thought that histones are so incredibly conserved that they must be boring. Whereas I thought, ‘They’re so conserved, every amino acid must be important.’”
In the 1960s, Vincent Allfrey, PhD, a researcher at The Rockefeller University, discovered that RNA synthesis (gene expression levels) was higher in cells whose histones were studded with chemicals called acetyl groups. He suggested that the changes in histone structure produced by these so-called acetyl modifications might be involved in switching genes on and off. The problem was that there was no way to tell if the modifications were actually the result or the cause of gene transcription.
Two decades later, in the 1980s, Dr. Grunstein and his team used yeast to help uncover the regulatory role of histones in living cells. For one key study, the team created a yeast strain in which cells were depleted in the H4 histone and in nucleosomes. “When we did that, you’d think everything would go wrong,” he says. Instead, “Every gene we looked at that should have been repressed was activated.” That showed that nucleosomes normally prevent the cell’s transcription machinery from making RNA from DNA. Through other experiments, the team discovered that deleting a section of the tail (or N-terminus) of the H4 histone resulted in the activation of genes in heterochromatin that had otherwise been repressed. This was due to an interaction between the histone H4 N-terminus and a known repressor, an interaction that was regulated by the acetylation state of one of the H4 N-terminal amino acids. Independently, Dr. Allis identified an enzyme that added acetyl groups to histone N-termini, and this enzyme was a known protein involved in transcription. This cemented the link between these modifications and gene regulation.
“Once scientists began to check the box next to the idea that histones are a player in gene regulation, it became clear that some of this machinery was altered and very dysfunctional in human cancers,” Dr. Allis says. “That spawned the idea that maybe that’s something that can be reversed. Researchers now have begun to develop small molecule inhibitors to target these machines that operate on the histone proteins, and that’s led to FDA-approved drugs and novel cancer therapies.”
In the beginning, Dr. Grunstein had no idea that his work eventually might lead to such clinical advances. “We thought of it as basic research at its most primitive,” he says. “We had no feeling that it would be taken up by the pharmaceutical industry and become clinically significant. It was just fun to do.”
Ultimately, however, he’s not all that surprised at the outcome. “Science is looking for the truth,” he says. “That’s what it’s all about. Determining how biological mechanisms work leads to medical advances that you never would have thought of.”
NOW IT IS UP TO DR. GRUNSTEIN’S SUCCESSORS TO CARRY FORWARD the work that he pioneered. He retired in 2016, and, among other pursuits, he has taken up boxing. He has Parkinson’s disease, and the coordinated and controlled movements of boxing help with his symptoms. Three times a week, he goes to a gym for lessons. Sometimes, his wife Judith accompanies him.
Dr. Grunstein acknowledges that he’s not going to win any bouts as a pugilist. Yet, there are other joys for him to experience, the most prominent of which is the pleasure of seeing the study of chromatin evolve as new technologies are developed and new questions are asked by new generations of scientists. One of Dr. Grunstein’s former post-docs, Siavash K. Kurdistani, MD, is among those continuing that story at UCLA, where he is chair of the Department of Biological Chemistry and conducts histone-related research.
Asked which of his accomplishments makes him most proud, Dr. Grunstein offers a simple answer: “Our role in the study of histone function. This has become a field in which histone modifications and histone protein interactions with other factors provide a novel level of gene regulation. That this area has been recognized by a Lasker Award is very humbling, and it makes me very happy.”
Kathy Svitil is director of research communications at the California Institute of Technology.