Nobel in Chemistry Goes to 3 Whose Work Speeded Drugs

By KENNETH CHANG

hree scientists share this year's Nobel Prize in Chemistry for developing techniques to identify and map proteins, carbohydrates, DNA and other large biological molecules.

The techniques have sped the development of drugs and could lead to quicker diagnosis of cancer. They helped create a new field of biology, proteomics, in which scientists are trying to catalog the interplay of hundreds of thousands of proteins in human cells.

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Dr. John B. Fenn, 85, a research professor at Virginia Commonwealth University in Richmond, and Koichi Tanaka, 43, an engineer at the Shimadzu Corporation in Kyoto, Japan, share half of the $1 million prize. Working independently, they improved a technique known as mass spectrometry to identify proteins by how quickly they are accelerated in an electric field. Now, biologists can determine the proteins in a sample in seconds rather than weeks.

Mr. Tanaka is one of the youngest chemistry laureates, while Dr. Fenn did not begin his Nobel-winning research until he was in his 60's.

"I was dumbstruck," Dr. Fenn said of receiving the phone call from the Royal Swedish Academy of Sciences at 5:30 yesterday morning. "I'm still in a daze. I'm not entirely sure I'm coherent."

Dr. Kurt Wüthrich, 64, a professor of biophysics at the Swiss Federal Institute of Technology in Zurich, received the other half of the prize for using nuclear magnetic resonance — the same underlying science as in the familiar medical M.R.I. — to map the structure of proteins.

Among the molecular structures that have been determined by nuclear magnetic resonance are prions, the misfolded proteins that destroy brain tissue in mad cow disease and similar diseases.

"The possibility of analyzing proteins in detail has led to increased understanding of the processes of life," the academy said in its citation.

Mass spectrometry and nuclear magnetic resonance have long been part of chemists' toolbox, but were limited to small molecules. In mass spectrometry, an electric field accelerates a vapor of charged molecules into a detector. Smaller molecules with larger charges hit the detector first; heavier ones with less charge take longer. Thus, molecules can be identified by the time it takes them to reach the detector.

In the 1980's, scientists could use mass spectrometry for molecules weighing up to 1,000 times as much as a hydrogen atom. (A hydrogen atom weighs 60 billionths of a billionth of a billionth of an ounce.) Proteins typically weigh 30,000 to 100,000 times as much as hydrogen, with some weighing several million times as much.

The difficulty was how to turn proteins into a charged vapor without knocking them apart.

In 1987, Mr. Tanaka showed how a low-energy laser beam could nudge loose individual protein molecules without breaking them apart.

The next year, Dr. Fenn, then at Yale, demonstrated a different technique for turning proteins into vapor. He used a strong electric field to disperse charged droplets containing the proteins. As a droplet evaporates, the repulsion of electric charges grows stronger than the surface tension holding the droplet together. The droplet explodes into smaller droplets; the smaller droplets explode into yet smaller ones until they each contain a charged protein hovering in the vapor.

"We learned to make elephants fly," Dr. Fenn said.

He said that more than 1,700 scientific papers using his mass spectrometric method had been published.

Dr. Catherine Fenselau, a professor of biochemistry at the University of Maryland and an associate editor of the journal Analytical Chemistry, said Mr. Tanaka's and Dr. Fenn's work had given biologists a much more direct view of the chemical processes going on in a cell.

Previously, for example, scientists studying an anticancer drug could look only at the fragments that the drug was broken into and guess at how it was broken apart.

"Now we can look directly at what proteins and nucleic acids the drug interacts with," Dr. Fenselau said. "This enabled amazing questions to be asked in biology."

In her research Dr. Fenselau is looking at changes in cancer cells when they become drug-resistant.

"We found there are at least 100 proteins whose levels are changed," she said. Before mass spectrometry, measuring concentrations of that many proteins would have been impossible, she said, "or it would have taken decades. I'm so happy it happened during my career."

Because protein levels in normal cells differ from those in cancerous cells, measurements via mass spectrometry may one day provide quick diagnosis of cancer.

The function of a protein is largely determined by its shape. With nuclear magnetic resonance, Dr. Wüthrich can not only identify a protein, but also determine its three-dimensional structure.

Previously, scientists had mapped proteins by carefully stacking them into crystals and then bombarding them with X-rays. By watching how the X-rays bounced off the crystal, they could deduce the structure of the protein.

But some proteins cannot be stacked into crystals. In nuclear magnetic resonance, the molecules are placed in a magnetic field, causing the atomic nuclei in the molecule, which essentially act like tiny magnets, to line up with the field. A pulse of radio waves flips the magnets, which causes the molecule to emit radio waves. With hundreds to thousands of atoms in a protein molecule, scientists had trouble trying to interpret the avalanche of radio waves.

"It gets to be a very complex problem," said Dr. Adriaan Bax, the section chief for biophysical nuclear magnetic resonance spectroscopy at the National Institutes of Health.

Dr. Wüthrich said he overcame the problem "by careful bookkeeping."

He developed a technique to determine the distances between any two hydrogen atoms in the molecule. From the distances, the structure of the protein could then be deduced.

"It's essentially a big jigsaw puzzle," Dr. Bax said. "It's a 10,000-piece puzzle with all the same color pieces."