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John Scott Award Goes to NIDDK's Bax

By Anna Gillis

NIDDK's Dr. Adriaan Bax is keeping fine company. He recently joined the ranks of scientists and inventors who have won the John Scott Award. Previous winners include Thomas Edison, the Wright brothers, Jonas Salk, and Nobelists Marie Curie, John Bardeen, Baruch Blumberg and Kary Mullis.

The award, which is given by the board of directors of City Trusts in Philadelphia, recognizes Bax's contributions to structural biology. Bax, whose techniques are used by scientists all over the world, was cited for developing methods to determine protein structures in solution using nuclear magnetic resonance (NMR). In naming him, the board said, "His research has enabled the three-dimensional structures of large proteins to be obtained at atomic resolution with an accuracy that was inconceivable just a few years ago." Bax received his copper medal and $10,000 recently at a ceremony at the College of Physicians in Philadelphia.

Dr. Adriaan Bax

Ad Bax is chief of the biophysical nuclear magnetic resonance spectroscopy section in NIDDK's Laboratory of Chemical Physics. A physicist by training, he has sought ways to use NMR to get better "pictures" of large biomolecules such as proteins and nucleic acids since his arrival at NIH in 1983.

NMR, like magnetic resonance imaging (MRI), is a method that relies on radio waves emitted by atomic nuclei in a sample or subject when placed in a very strong magnet. Whereas MRI obtains its image contrast primarily from water hydrogens and the changes in the amount of water at various positions in the human body, NMR derives its molecular image differently. NMR investigators dissolve their sample in a liquid, usually water, and then put this into a super-strong magnetic field. The samples are showered with radio waves that are absorbed and emitted in patterns. Typical proteins emit thousands of signals, one for every hydrogen atom in the molecule. The intensity and interrelationships of the signals contain information about the distances among the various hydrogens in the molecule, provided they are close. From that information scientists reconstruct the protein's shape.

The idea is straightforward, but, in practice, identification of the individual signals is so complex that only the smallest proteins can be studied this way. Key to the advances developed by Bax and his colleagues in extending NMR to larger proteins is the replacement of the standard, "NMR-invisible" carbon and nitrogen atoms in the protein with stable isotopes that provide additional NMR signals. Remarkably, Bax showed that these additional signals allow for new experiments that make the analysis of all the signals much simpler. The improvement can be compared to the difference between putting together a jigsaw puzzle relying just on the shape of the pieces and putting it together using the pieces' shapes and colors.

NMR structures of proteins determined simply from distances between hydrogens also tend to be of limited resolution, somewhat like a photograph that is slightly out of focus. To produce sharper images, Bax and his associate Nico Tjandra (now in NHLBI) developed another method that determines the orientation of chemical bonds relative to the magnetic field. Normally, molecules tumble randomly in solution and generally their chemical bonds are not oriented to the magnetic field. But Bax showed that alignment of proteins can be induced by adding microscopically small, disc-shaped fat particles known as bicelles to the sample. These bicelles are weakly magnetic and therefore align with the magnetic field, causing the nearby proteins to align also. This method is now used worldwide to create better pictures of a wide range of proteins.

Another advance by Bax's group allows researchers to quantify the flexibility of proteins using NMR. The methods were used in a recent collaboration between the National Institute of Dental and Craniofacial Research and NIDDK. The study of HIV protease highlighted how the enzyme changes its mobility upon binding various types of drugs.

With his first batch of scientific problems solved, Bax is looking at the next technical hurdles. "We need to make protein structure determinations faster. Right now, it can take 6 months or a year to get a structure. We also need higher quality pictures, and we would like a way to get to membrane proteins." Proteins moving and signaling through membranes are especially difficult to study using NMR because they are insoluble in water.

Bax attributes much of his success to the generous support he has received from NIDDK and NIH's HIV-targeted antiviral program. "Much of this work was based on close collaboration with the other protein NMR groups at NIH, in particular those of Dennis Torchia in NIDCR and Marius Clore and Angela Gronenborn in NIDDK," says Bax. "And none of this would have happened without a large number of very bright postdocs."

In addition to Bax, Dr. Clay M. Armstrong of the University of Pennsylvania and Dr. Mary-Dell Chilton of Novartis Agricultural Biotechnology Research, Inc., were named winners of the Scott Award. The award was created in the early 1800's with funds from John Scott, an Edinburgh druggist, who called upon "the Corporation of Philadelphia entrusted with the management of Dr. [Benjamin] Franklin's legacy" to bestow a prize not to exceed $20 upon "ingenious men and women who make useful inventions." The fund has since grown.

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