Purnell Choppin, HHMI president emeritus, recalls the enthusiasm among the Trustees and the scientific community for the Institute’s commitment to structural biology.

Steitz and his colleagues needed help, and assistance arrived in the form of an HHMI initiative. In 1986, the Institute created a program to fund structural biology research around the country. Over the next quarter century, the initiative produced three Nobel laureates (see sidebar, “A Trio of Accolades”), five high-powered x-ray beamlines, scores of innovations in microscopy, hundreds of protein structures, and answers to long-standing questions in biology.

		A Trio of Accolades Three HHMI structural biologists have won Nobel prizes, studying three very different structures. Read More

“From the very beginning it was a very popular program with the Trustees and it was absolutely welcomed with great delight by the structural biology community,” says Purnell Choppin, who was then chief scientific officer of HHMI and became president in 1987. “Many people have told me that the Hughes program really transformed structural biology, not only in the United States but abroad as well.”

The Dawn of Structural Biology

Architects like to say that form follows function—a building’s shape should be based on its intended purpose. The same concept applies to the structure of biological molecules: their forms reflect their functions. Learning what a molecule such as a protein looks like can lead to ways to encourage or hinder its activity, which might be especially helpful if that protein lowers blood cholesterol levels, for example, or is part of a virus.

Unfortunately, protein molecules are much too small to be seen by light microscopes and even most electron microscopes. Structural biologists have developed technical workarounds, however. One of the earliest and most powerful techniques is x-ray crystallography, which involves the often arduous process of coaxing millions of copies of a molecule to organize themselves into a repeating three-dimensional pattern—a crystal. After working for weeks, even months, to grow a protein crystal, scientists then pelt it with intense beams of x-rays, thereby destroying their hard work but also obtaining valuable data.

Each atom in the crystal scatters the x-rays, producing what’s called a diffraction pattern. By rotating the crystal in the beam, scientists can gather diffraction data from many angles. With help from a high-powered computer, the data are translated into a three-dimensional map of the coordinates of each of the molecule’s atoms.

Linus Pauling and Robert Corey at the California Institute of Technology were the first scientists to use x-rays to probe the structures of amino acids—the building blocks of proteins. Combined with information from other groups, what they found was simple, yet profound: an elegant spiral of amino acids called an alpha-helix—one of the fundamental structures found in almost all proteins. They published their results in 1951.

Less than a decade after Pauling and Corey’s remarkable discovery, Max Perutz and John Kendrew of Cambridge University went bigger. They solved the structures of the proteins hemoglobin and myoglobin with x-ray crystallography, a feat for which they were awarded the 1962 Nobel Prize in Chemistry.

“There were a number of rods in the original myoglobin structure and everyone believed those rods were alpha-helices,” recalls David Davies, a structural biologist at the National Institutes of Health who was at that time a visiting scientist in Kendrew’s lab. “Pauling had proposed the alpha-helix in 1951 but no one had actually seen one. So, in 1959 John and I [analyzed] a section through one of these rods in a higher resolution model of myoglobin and there was an alpha-helix. It was fantastic.”

		Molecular Mimicry See how the field of molecular illustration has evolved over the past 50 years.

In addition to publishing his work in the Proceedings of the Royal Society of London, Kendrew described the myoglobin structure in a 1961 Scientific American article. To help nonscientists understand this groundbreaking discovery, he enlisted the talents of scientific illustrator Irving Geis to create the first molecular illustration meant for a general audience (see sidebar, “Illustrating the Invisible”).

		Illustrating the Invisible Over the years, scientists and artists have used an assortment of techniques to showcase molecular structure. Read More

The ’80s Tech Boom

Those first few discoveries made clear that x-ray crystallography would be a huge player in deciphering the nature and function of molecules. Although it took Kendrew more than 10 years to deduce the structure of myoglobin, subsequent technological advances sped the pace of discovery. “When I first started as a postdoc, if you could determine a structure in three to five years you were doing well,” recalls Brian Matthews, a biophysicist and HHMI alumnus at the University of Oregon. “By the time I came to Eugene in 1970 to start my own lab, the first structure we worked on took three of us a year. That was considered extraordinarily quick.”

Photo: Paul Fetters

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