Nobel squared

Stockholm calling

Linda A. Cicero

Andy Fire keeps his cool at a morning press conference on the day his Nobel Prize was announced. The award honored his work on RNA interference, which gives scientists a way to turn off nearly any gene.


If biological research is a high-stakes game of poker, then the School of Medicine gained a pair of aces during the first week of October: Andrew Fire was awarded the 2006 Nobel Prize in Physiology or Medicine on Oct. 2, and Roger Kornberg the Nobel Prize in Chemistry on Oct. 4.

The Nobels complemented three 2006 NIH Director’s Pioneer Awards, given to David Relman, Karla Kirkegaard and Kwabena Boahen. Taken together, the honors herald a new generation of extraordinary biomedical accomplishment at Stanford medical school.

Over the past five years, faculty members at the school have earned seven of the 34 NIH Director’s Pioneer Awards, the Kyoto Prize (which went to Leonard Herzenberg in 2006) and the Welch Award (awarded to Kornberg in 2001). Furthermore, medical school faculty continue to rank among the highest in terms of per-investigator NIH funding.

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The accomplishments of this year’s two Nobel winners underscored that trend with a flourish. In Dean Philip Pizzo’s words: “We celebrate the achievements of two extraordinary scientists whose findings cut to the foundation of life — the elegant elucidation by Roger Kornberg and his colleagues of the molecular machinery that permits DNA to transcribe its genetic code to messenger RNA in order to make protein, and the insightful discovery by Andy Fire, Craig Mello and their colleagues of a previously unrecognized double-stranded RNA that in essence silences genes to prevent the production of protein. Together these discoveries represent a yin and yang of genetic control.”

Fire, PhD, had already spent a little time at Stanford before he joined the faculty in 2003. The molecular biologist was born at Stanford Hospital, attended public schools in Sunnyvale and graduated from the University of California-Berkeley after being turned down by his only other college choice: Stanford. All pretty normal, he pointed out self-deprecatingly — not mentioning that he completed high school at age 15 and college at age 19.

Linda A. Cicero

News travels Roger Kornberg speaks with reporters and well-wishers from his office on the morning the Nobel committee announced his prize. He worked for close to 20 years to depict one of biology’s most important molecules.

Fire shares the prize with Craig Mello, PhD, of the University of Massachusetts medical school. The announcement from the Nobel Assembly at the Karolinska Institute came a mere eight years after they published their breakthrough discovery of RNA interference. The relatively rapid recognition is unusual in the Nobel world, which often rewards researchers decades after their initial findings. Such prompt accolades are one indication of how their finding has turned the field of molecular biology on its head.

Fire, 47, and Mello, 45, are part of a team of researchers credited with recognizing that certain RNA molecules can be used to turn off specific genes in animal cells. The discovery, made while Fire was at the Carnegie Institution’s Department of Embryology in Baltimore, marked the first time that biologists were able to selectively “silence” the voice of one gene in the cacophony of the tens of thousands that give a cell its marching orders from development to death. Their description of the process, called RNA interference, or RNAi, in Nature in 1998, jumpstarted a new biological field by opening up previously inaccessible areas of research.


Programming brains, battling viruses and getting to know the microbes

For the second year in a row, in 2006 Stanford University School of Medicine researchers snagged three of the National Institutes of Health’s Director’s Pioneer awards, one of medicine’s top prizes.

The new Stanford recipients were Kwabena Boahen, PhD; Karla Kirkegaard, PhD; and David Relman, MD. With three of the total 13 winners in 2006, Stanford had more awardees that year than any other institution — and the largest total since the award was established in 2004. The prize provides each winner with $2.5 million over five years to pursue new research directions.

Stanford’s new recipients:

  • Kwabena Boahen, associate professor of bioengineering. In his previous work, Boahen built computers that work like brains. Now he wants to make these computers programmable so neuroscientists can use them to learn even more about the brain..
  • Karla Kirkegaard, professor and chair of microbiology and immunology. She intends to investigate how the dengue, West Nile, hepatitis C and polio viruses develop drug resistance and how to reduce the frequency of such occurrences.
  • David Relman, associate professor of microbiology and immunology and of medicine. Relman aims to discover the ecological principles at play in the microbial communities that live within us.

“It was clear from the first week that I met Andy that he was destined to do something great,” says a longtime friend and Carnegie Institution colleague David Schwartz, PhD, professor of genetics and chemistry at the University of Wisconsin-Madison. “He was just such a natural about it. There are people who are excellent at sports; you just put a baseball bat in their hands and the ball flies. Andy is like that with science; without a fuss, it just happens.”

Before the discovery, the only method of removing a gene’s influence from a population of cells involved a laborious, time-consuming series of experiments with no guarantee of success. It was virtually impossible to “knock out” even a small fraction of genetic suspects in a particular pathway. Now researchers around the world are using RNAi techniques to quickly and randomly silence one gene at a time in swaths of cells. By plucking out those that act abnormally with regard to the pathway in question, they are able to identify even previously unknown genes involved in the pathway.

The technique has also shown clinical promise. RNAi-based treatments are being tested in many animal models of disease — high cholesterol, HIV, cancer and hepatitis, among others — and clinical trials have been launched in humans with specific types of macular degeneration and pneumonia. Although the potential applications of the research are vast, Fire emphasizes that he doesn’t deserve all of the credit.

“We came into a field where a lot was already known,” says Fire. “It was a complex jigsaw puzzle, and we were able to contribute one piece. Fortunately for us it was a very nice piece, but it would be really disingenuous to say we did the whole puzzle.”

Such demurring is standard for Fire; colleagues often describe him as remarkably modest.

During the media whirlwind accompanying the prize announcement, Fire credited “insightful and dedicated colleagues and students” with whom he has worked and “whose ideas and efforts are very much the subject of the prize.”

Fire added, “For me personally, the occasion of such an award is an opportunity to thank the many patient teachers and mentors who have opened doors to science and research, and especially my family, who have made everything possible.” Fire also thanked the National Institute of General Medical Sciences for providing the grants that suported the research.

“I like what I do,” Fire replies when asked how the Nobel might affect his life. “I like teaching, I like research and I like talking to colleagues. This brings another dimension: an opportunity to have a voice beyond my own lab and field. That’s a big responsibility, and I look forward to using that voice as needed. At the same time, I still want to do interesting and unusual experiments, while also making sure I don’t get too much credit.”

All things considered, Fire might have been relieved when, just two days later, he relinquished his place in the spotlight. That’s when Roger Kornberg received a similar early morning call from Sweden. Kornberg, a 59-year-old professor of structural biology, had planned to board a Pittsburgh-bound plane later that morning to accept the Dickson Prize in Medicine. Instead he hastily changed his plans to accommodate the Nobel-related media onslaught.

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, 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 this important purpose,” says 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 required expertise in a highly specialized field called crystallography that lies at the intersection of chemistry, biology and physics. Successfully crystallizing one molecule is a major feat. Proceeding, as Kornberg did, to tackle a protein made of 10 separate molecules seemed to most scientists impossibly daunting. Key among the challenges: Adequately purifying the complex needed to make crystals, obtaining enough of the resultant complex, and making sense of any crystals that might form despite the shortcomings of the computing and X-ray technology of the day.

The scientists plowed ahead despite the obstacles. They spent one decade first devising a way 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 — discovered by Kornberg as a Stanford graduate student in the 1960s — called bilateral lipid diffusion.

The technique involves applying the complex to be crystallized to a bed of uniformly charged lipid 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,” says 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.”

Like Fire, Kornberg emphasizes that the work required the contributions of many people in a variety of fields. “I am indebted to my colleagues,” he says. “This is not something that I did alone, or even with a small number of people.”

Dean Pizzo attributed the medical school’s spate of breathtaking accolades to a strong pedigree in basic science research, decades of careful hiring and a commitment to innovative, interdisciplinary projects.

The medical school’s illustrious ancestry can be traced back to its move from San Francisco to the Palo Alto campus in 1959. At the time, Stanford recruited Arthur Kornberg (Roger Kornberg’s father) and other leading researchers from Washington University to establish the biochemistry department. Among those accompanying Kornberg, who won the Nobel Prize in Physiology or Medicine that year, was Paul Berg, who went on to win the Nobel Prize in Chemistry in 1980. Roger Kornberg worked in Paul Berg’s laboratory as a science-loving high school student.

Also in 1959, the school established its Department of Genetics under Joshua Lederberg, who had won the Nobel Prize in Physiology or Medicine the previous year. “Nearly overnight Stanford went from a regional medical school to a nationally ranked, research-intensive one,” Pizzo writes in his Oct. 9 newsletter. That original group not only gave the medical school its strong base in basic science, but also established connections with other schools on campus.

“Drs. Kornberg and Lederberg began reaching out to faculty throughout the university — especially from the physical and engineering sciences — and this laid the foundations for interdisciplinary research,” he continues.

“The fact that two Stanford faculty have been awarded Nobel prizes this past week is of course remarkable but also not surprising, given the excellence of the medical school’s investigators and academic community."

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