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One week, two Nobels: Roger Kornberg wins in chemistry

L.A. Cicero

Roger Kornberg speaks with reporters and well-wishers Oct. 4 a few hours after winning the Nobel Prize.

BY KRISTA CONGER

"Reason for ticket cancellation?" asked the Travelocity operator. After a short pause, Roger Kornberg went with the best excuse he could muster. "Well, I, uh, just won the Nobel Prize in chemistry."

It wasn't quite like "the dog ate my homework," but in the pre-dawn hours of Oct. 4 it sounded nearly as outlandish. But that was just one of the perils that came with recognition by the Royal Swedish Academy of Sciences of Kornberg's multidisciplinary research into how DNA is converted into RNA, a process known as transcription.

Kornberg, a 59-year-old professor of structural biology, had been scheduled to travel to Pittsburgh later that morning to accept the Dickson Prize in Medicine. His plans changed after the 2:30 a.m. phone call from Sweden.

Kornberg's research and Nobel award are a family affair: His father, Arthur Kornberg, was awarded the Nobel Prize in physiology or medicine in 1959 for studies of how genetic information is transferred from one DNA molecule to another. The younger Kornberg is also the second newly minted Nobel laureate at the Medical School in one week; two days earlier, Andrew Fire, professor of pathology and of genetics, had been awarded the 2006 Nobel Prize in physiology or medicine for his discovery of RNA interference.

"I'm simply stunned," Kornberg said. "There are no other words."

Together the two Nobel Prizes are a clarion call announcing RNA's arrival in the scientific and medical spotlight.

"Roger has been one of my role models for many years," said Fire. "We did our post-docs at Cambridge in the same institute, and he's been a tremendous help to me since I came to Stanford in 2003. Our fields are interestingly intertwined."

In 2001 Kornberg, PhD, the Mrs. George A. Winzer Professor in Medicine, published the first molecular snapshot of the protein machinery responsible for transcription in yeast—RNA polymerase II—in action. Because RNA polymerase in yeast is similar to its human cousin, the finding helped explain how cells express all the information in the human genome, and how that expression sometimes goes awry, leading to cancer, birth defects and other disorders.

Nearly every cell has the same complement of genetic information in its DNA. It's the selective transcription of a cell's tens of thousands of genes from double-stranded DNA to single-stranded RNA that determines whether it becomes a neuron, a liver cell or a stem cell—and whether it develops normally or becomes a runaway cancer.

The picture of RNA polymerase at work provided an atomic-level window into how the protein complex unzips the double-stranded DNA at the site of a gene, uses its internal code to generate a complementary strand of RNA and then re-zips the DNA like a Ziploc® bag. For many scientists it was a thing of beauty.

"We were astonished by the intricacy of the complex, the elegance of the architecture and the way that such an extraordinary machine evolved to accomplish these important purpose," said Kornberg of the images he and his colleagues created. "RNA polymerase gives a voice to genetic information that, on its own, is silent." Learning how that voice is amplified—and shushed—through the selective expression of genes is a critical stepping-stone to many areas of biological and medical research.

The path to the pictures involved a highly specialized yet multidisciplinary field, called crystallography, that lies at the intersection of chemistry, biology and physics. The technique traditionally involves evaporating a concentrated, highly pure solution of a molecule to encourage the development of highly structured, three-dimensional crystals. Powerful X-rays are then used to pinpoint the position of individual atoms and the data are used to produce a computer-generated representation of the molecule.

Successfully crystallizing one molecule is a feat worth congratulating. Embarking on a quest to capture the 10 subunits of RNA polymerase—in action, no less—was daunting for three main reasons: It was difficult to get the very pure mixture of the complex necessary to make crystals, it was difficult to get enough of the complex to make crystals, and both the X-ray and computing power of the day fell far short of what was required.

"The problem was obviously impossible to solve when we first started," said Kornberg. "The means did not exist."

The scientists plowed ahead despite the obstacles. After a decade-long process devising a way first to initiate the process of transcription in a test tube and then to stall it by withholding one of the building blocks of RNA, they spent the next decade purifying and crystallizing the complex by exploiting a phenomenon called bilateral lipid diffusion.

The technique, which Kornberg discovered in the 1960s as a Stanford graduate student in the laboratory of Harden McConnell, involves applying the complex to be crystallized to a bed of uniformly charged lipid (fat) molecules. Attraction to the lipids keeps the complex in a single layer without restricting the two-dimensional shuffling necessary for the formation of an orderly, but very thin, crystal film.

"This was a technical tour de force that took about 20 years of work to accomplish," said Joseph Puglisi, PhD, professor and chair of structural biology at the School of Medicine. "Like other great scientists, Roger doesn't quit. He's stubborn. A lot of scientists would have given up after five years." Kornberg's determination, coupled with his expertise in both crystallography and biochemistry, finally cracked the code.

"Professor Kornberg's seminal research on transcription has been an exceptional contribution to the body of knowledge in fundamental biology," said Stanford President John Hennessy on the day of the announcement. "His work settled long-open questions about how genes communicate the information needed to make proteins and will help us understand a variety of diseases that can be caused by a failure in the transcription process."

"Roger Kornberg has dedicated his life and career to elucidating the molecular mechanism of transcription," said Philip Pizzo, MD, dean of the School of Medicine. "His remarkable studies have been acclaimed for their elegance and technical sophistication as well as their unique insights. His work has deepened our understanding of the 'message of life' and how it contributes to both normal and abnormal human development, health and disease."

Kornberg emphasized that the work required the contributions of many people in a variety of fields. "I am indebted to my colleagues," he said. "This is not something that I did alone, or even with a small number of people."

Born in 1947, Kornberg was the first of three children of Arthur Kornberg and his wife, Sylvy, also a biochemist. "Both my parents had fine scientific minds and taught by example how to approach questions and problems in a logical, dispassionate way," Kornberg once said. "Science was a part of dinner conversation and an activity in the afternoons and on weekends. Scientific reasoning became second nature. Above all, the joy of science became evident to my brothers and me." Kornberg was able to indulge his scientific bent early as a high school student working in the laboratory of Paul Berg, PhD, a colleague of his father's at Stanford who won the Nobel Prize in Chemistry in 1980.

Arthur Kornberg, the Emma Pfeiffer Merner Professor of Biochemistry, Emeritus, said he had not imagined decades ago that there would be a second Nobel laureate in the family. "But nature is so broad, profound and mysterious—one doesn't know where it leads," he remarked. "And I would say among the people I know—and I have trained many hundred—he has the clearest vision, sense of purpose and direction."

Roger Kornberg received his undergraduate degree in chemistry from Harvard in 1967 and his doctorate in chemistry from Stanford in 1972. He was a postdoctoral fellow and member of the scientific staff at the Laboratory of Molecular Biology in Cambridge, U.K., from 1972 to 1975. He joined Harvard Medical School in 1976 as an assistant professor in biological chemistry and returned to Stanford in 1978 as a professor in structural biology. He served as department chair from 1984 until 1992.

Kornberg is no stranger to recognition. On Oct. 4, it was also announced that he had been awarded the Louisa Gross Horwitz Prize, which recognizes outstanding contributions to basic research in the fields of biology and biochemistry.

It's been a busy week, and there's still much to look forward to—including a December trip to Sweden by the Kornberg family to watch Roger Kornberg accept his latest, and greatest, award.

"I'm looking forward to being in Stockholm, where we have many friends," said Arthur Kornberg, remembering his own award 47 years ago. "They put on a great party."

Time for another call to Travelocity?