U.S. Biochemist Takes Nobel for DNA Work

Roger D. Kornberg, a biochemist at Stanford University, won the Nobel Prize in chemistry yesterday for figuring out the intricate way in which information in the DNA of a gene is copied to provide the instructions for building and running a living cell.

This "transcription" process, which is a cross between a waltz and a wrestling match on the molecular level, is essential for organisms as simple as yeast and as complex as humans. It allows a cell to select the genes it needs among thousands it does not, and to extract information from them efficiently and accurately.

Kornberg's Nobel, a relatively rare unshared one, completed an American sweep of the science prizes for physiology or medicine, physics and chemistry. That has occurred only twice before, in 1946 and 1976.

Kornberg, 59, also became the seventh winner to have a parent who won a Nobel. His father, Arthur Kornberg, won in 1959. There have been five previous father-son duos and one mother-father-daughter combination, the Polish-French Curie family.

"Transcription is key to reading the information that is in our genes. His work allowed us to look in snapshots at how transcription works, and to look in beautiful detail," said Jacqueline Barton, a nucleic-acid chemist at the California Institute of Technology.

Kornberg's work is unusual because it bridges three fields -- biochemistry, biophysics and X-ray crystallography -- that are each difficult and consuming.

Francisco J. Asturias, a cell biologist at the Scripps Research Institute, in La Jolla, Calif., said: "What sets Roger apart from every other researcher in the area is the fact that he was willing and able to put together every way of looking at the transcription system to obtain answers."

Understanding how gene transcription works mechanically in three dimensions -- a 30-year quest -- has no direct medical application. But the events Kornberg studies are so central to the function of cells that understanding them will undoubtedly have practical uses.

"I am of the opinion there is nothing of a fundamental nature that, once discovered, doesn't ultimately prove valuable," he told reporters in a conference call.

Organisms more complicated than bacteria store their genes in a nucleus, a compartment apart from the rest of the cell's machinery. These so-called eukaryotic cells face a fundamental problem. They carry thousands of genes -- in the case of humans, about 30,000 -- that together provide the instructions to make all the parts of all cells. But beyond the first few days of embryonic life, no cell needs all those instructions. It needs only a few hundred, or at most a few thousand, but it needs to be able to get them quickly.

But efficient retrieval -- finding a single tool in a garage, or a single book in a library -- is only the beginning of the problem.

The gene cannot be taken out of the nucleus, like a tool or a book. Instead, the information in it has to be copied. The copy is then sent to a distant part of the cell, where it is "translated" into a specific protein, the desired end product.

The information in genes is encoded in DNA, which has a twisted, two-strand structure. The copy that leaves the nucleus is made of RNA, which has a single strand. DNA and RNA are built of letter-like units, nucleotides, strung end to end. The RNA copy is made by separating the two strands of DNA and then using one strand as a letter-for-letter template to make the RNA strand.

The thing that does this is a giant enzyme called DNA polymerase II. Along with numerous other molecules, called transcription factors, and guided by cues that differ from one type of cell to another, DNA polymerase II finds a gene and makes an RNA message through a series of actions that include feeling, unfolding, sorting, shoving and releasing.

Kornberg's feat was to show how those steps occur on a physical, three-dimensional, nonmetaphorical basis.

He did so by removing the transcription machinery of baker's yeast from the yeast cell, copying it in huge quantities and letting it run in a test tube. He found ways to stop the action at various points. He also found ways to solidify those delicate "molecular complexes" into crystals, which could be studied via X-rays.

The X-rays, analyzed mathematically, ultimately revealed the location of hundreds of individual atoms -- information that can be used to build three-dimensional models (or computer images) of all the transcription machinery, caught in the act of doing its job.

Turning genes on and off selectively is the key task of embryonic development. When the process is disrupted in mature cells, many problems, including cancer, may arise. The models and pictures that Kornberg and his associates are continuing to produce are helping solve the mysteries of gene regulation. But the practical problems faced at each step have been enormous, he said in a telephone interview.

"Each advance that we make is contingent on solving a problem before moving on. In each case, it has taken not less than five years to meet those requirements concerning the nature of the material," he said.

Kornberg majored in chemistry at Harvard College and received a doctorate at Stanford. He has two sons, ages 20 and 11, and a 14-year-old daughter. His wife, also a biochemist, works in his laboratory.

The prize is worth about $1.4 million. He said he will use the money to pay debts and perhaps buy a new car. His 20-year-old Volvo was in the shop yesterday.

He said he has vivid memories of accompanying his father to the Nobel Prize ceremonies in Stockholm as a 12-year-old and is looking forward to taking his family there.

Arthur Kornberg shared his prize with Spanish-born biologist Severo Ochoa for their discoveries of how cells manufacture DNA.

It was work that, intellectually speaking, helped build the house that Roger Kornberg is exploring.