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UCLA scientist shares 2018 Lasker Prize for figuring out how genes turn on and off

UCLA scientist shares 2018 Lasker Prize for figuring out how genes turn on and off
UCLA's Michael Grunstein shares a 2018 Lasker Prize for his work on genes and how they are turned on and off by histones. (Reed Hutchinson/UC)

Michael Grunstein, a longtime professor of biological chemistry at UCLA who uncovered the key role that DNA’s “packing material” plays in turning genes on and off, has won the Albert Lasker award for basic medical research.

He shares the prize with Rockefeller University biochemist C. David Allis, who extended Grunstein’s findings on how certain proteins modify gene expression and identified how one such route can lead to childhood cancers.

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The prize, announced Tuesday, is one of three awarded each year by the Albert and Mary Lasker Foundation. It’s often called the “American Nobel” because some 87 recipients have gone on to be honored by the Swedish Nobel committee.

Grunstein’s and Allis’ exploration of histone proteins has deepened geneticists’ understanding of how an organism’s DNA, identically copied in every cell, can behave so differently from cell to cell — giving rise to the exquisite complexity of, say, a human being.

Working with single-cell yeast, Grunstein and Allis showed how the string of proteins around which strands of DNA are wrapped contains chemical instructions for which genes should be active and which should stay dormant until called upon.

In the mid-1970s, when Grunstein began studying these specialized proteins in sea urchins, genomic science was still in its infancy. Frederick Sanger had only just developed techniques to sequence DNA, for which he would go on to win a Nobel Prize in chemistry in 1980. It would be a decade before the Human Genome Project was born.

As for histone proteins, geneticists saw them as building blocks that arranged themselves into an inert spool around which DNA was wrapped.

“They were packing material, and therefore not very interesting,” said Grunstein, who retired from UCLA in 2015.

But Grunstein wanted to understand how histone proteins, which are found in the nucleus of every complex organism’s cell, act to package DNA. In certain spots along that spool, chromosomes were packed tightly, while at others, they wound around more loosely. Grunstein suspected the varying packing patterns affected how genes functioned.

“We thought they were worthy of a good look, but you needed evidence that they were a more dynamic structure than people thought,” Grunstein said.

His path to answering those questions was set by the convergence of a weather event and a career necessity.

In 1977, he arrived at UCLA as a scientist studying histones in sea urchins, a simple organism with a large complement of histone genes. Grunstein knew he’d be considered for tenure in three years, and that, if he were to be asked to stay on at UCLA, he’d need to have made some progress in clarifying histones’ role.

But there was a problem: In 1978, the weather pattern known as El Niño decimated the population of sea urchins available for his research.

That’s when Grunstein attended a talk in which a fellow scientist working with yeast described pulling apart the threadlike structure of chromosomes and revealing how all the genetic material was wrapped around a spool of histone proteins.

“It so impressed me you could do this,” Grunstein said. And he knew that unlike sea urchins, which had 200 histone genes, yeast had only two. It would be the simplest possible organism in which to test whether histone proteins were turning genes on and off all along the chromosome.

What followed was a series of experiments in which Grunstein and his lab members introduced mutations in yeast histone genes. They found that the supposedly inert packing material — the spool around which DNA was wound — was repressing gene activity in some places and, by extension, prompting genes to turn on in other places.

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It was dynamic indeed.

Grunstein’s first paper on the subject was published in 1980, and the studies clarifying histones’ role in gene regulation continued from there. Allis would go on to demonstrate that other histone modifications — methylation and phosphorylation — also regulate gene expression.

The pair’s work would set the cornerstone for the study of the so-called epigenome, the chemical signalling process that makes a single strand of DNA capable of giving rise to such complexity.

“We have shown how a simple protein can have a lot of complexity by being modified differently at different sites on the genome,” Grunstein said. “It’s a whole new level of regulation that we didn’t know existed.”

Allis’ research also linked certain histone modifications to some forms of cancer, opening new avenues for battling aggressive malignancies. Among them is a “histone deacetylase inhibitor” known as Zolinza that treats certain types of lymphoma. Other similar chemotherapy agents are under development.

Grunstein, a Romanian-born child of Holocaust survivors, credited hard work, persistence and a perverse interest in pursuing science’s less-appreciated questions for putting him on the path to scientific honor.

There was also luck, he said. At the University of Edinburgh, where he conducted some of his graduate studies, a work marathon that left his desk a mess prompted a supervisor to dispatch him to another lab where he believed the director would welcome his industry and tolerate the resulting untidiness. That lab belonged to Max L. Birnstiel, a Swiss molecular biologist whose focus was on gene regulation.

Finally, Grunstein thanked yeast.

“I appreciate their simplicity,” he said. ”I started working on humans and frog cells, then went on to sea urchins, then onto yeast. I certainly found the yeast the most satisfying.”

Among the other winners announced Tuesday was Scottish veterinarian John B. Glen, who received the Lasker-DeBakey Clinical Medical Research award for his development of the sedative propofol, which has become the world’s most widely used anesthetic drug.

Yale University biologist Joan Argetsinger Steitz received the Lasker-Koshland Special Achievement Award in Medical Science for her “pioneering discoveries in RNA biology, generous mentorship of budding scientists, and vigorous and passionate support of women in science.”

As a young microbiologist, Steitz believed she had no prospect of ever leading a university research lab. As a result, she said, she was not afraid to explore scientific questions that might not pan out.

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She studied ribonucleic acid, or RNA, molecules, which perform many functions in the cell, including communication with DNA. She “generated a cascade of discoveries that have illuminated wide-ranging and unanticipated functions for RNA molecules within our cells,” the Lasker committee said.

And over the four decades that she’s done so, she has been a generous mentor to almost 200 students and postdoctoral fellows, including many women. Of the 360 papers that have originated from her laboratory, 60 of them do not include her name in the list of authors.

That, she has said, reflects her belief that students and postdoctoral fellows who work completely independently should be allowed to publish on their own. It’s a conviction not universally shared among academic scientists.

As a member of the Committee on Maximizing the Potential of Women in Academic Science and Engineering, Steitz in 2007 helped outline steps to draw more women into the fields of science, technology, engineering and medicine.

Glen’s work on anesthetics is felt every day. As the scientist most responsible for bringing the sedative propofol to the market, he has made outpatient surgeries ubiquitous and long, complex surgeries safer and less arduous. Through his vision and persistence over more than 20 years, “Glen ushered into the world’s medical arsenal a powerful and versatile anesthetic that acts quickly and produces minimal side effects,” the Lasker Committee said

In 1973, the anesthetics at doctors’ disposal limited surgery time and left many patients addled and ill for days after an operation. Glen took over a program at Imperial Chemical Industries to find a better induction agent, a sedative that serves as a bridge to deeper anesthesia. He overcame scientific, clinical and commercial hurdles to make propofol into something the World Health Organization deemed “an essential medicine.” As of 2016, more than 190 million people had received the drug.

Glen is now retired from AstraZeneca, the pharmaceutical firm that, through a succession of mergers, subsumed ICI.

Each award carries a prize of $250,000.

9:15 p.m.: This story has been updated with additional detail about the work of winners John B. Glen and Joan Argetsinger Steitz.

This story was originally published at 2:10 p.m.

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