October 2002
Popular Science: Writing About S&T for the Public

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Understanding Life by Understanding Proteins

Summer at the Bench

The Roundabout Path

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Bryn Mawr College
A quarterly newsletter on research, teaching, management, policy making and leadership in Science and Technology

Understanding Life by Understanding Proteins
By Jennifer Fisher Wilson

Carolyn Cohen ’50
photo: Mike Lovett

The summer before her senior year at Bryn Mawr College, Carolyn Cohen ’50 was serving breakfast at a resort located in Pennsylvania’s Pocono Mountains. Recalling the isolated location, the demanding vacationers, the required hairnet and the paltry tips, "it was awful," she says. A friend from Bryn Mawr who was working at the Marine Biological Laboratory at Woods Hole, Mass., heard how miserable she was and found her a job there instead. Cohen’s new job still required her to work in food service, but Woods Hole turned out to be "heaven, absolute heaven," Cohen says. In addition to being surrounded by scientists every day, she was free to do some laboratory work in the afternoon and attend scientific talks in the evening. And at one of the talks, Cohen found the inspiration for what would become her long and successful career in science.

The talk was given by Dr. Dorothy Wrinch, a British-trained mathematician, who presented striking diagrams of her ideas about how proteins are constructed. Wrinch was convinced that protein structure held the secret of life. It was 1949, still a few years before Linus Pauling deciphered one of the key patterns for protein folding called the "alpha helix" in 1952, and before James Watson and Francis Crick discovered the double helical structure of DNA in 1953.

"I was intrigued with the idea that in seeing protein structure, we were seeing the details of the inner workings of the cell," Cohen explains. She was hooked. After graduating from Bryn Mawr in 1950, she pursued graduate studies in biophysics at MIT, focusing on the analysis of the structure of proteins, and that’s what she’s been working on ever since.

Cohen’s research has helped to establish the basic structures and functions of certain proteins and to clarify in what ways they can indeed be considered key to "the secret of life", as Wrinch observed all those years ago. Her early work focused on the X-ray diffraction of fibrous proteins, first collagen and then muscle. She later carried out electron microscopy studies of various muscle proteins, such as myosin and paramyosin, to learn how they are designed to form highly ordered fibers in the cell. More recently, Cohen’s focus has been higher-resolution X-ray crystallography of these muscle proteins.

Cohen did much of her early work with a small group of colleagues over two decades at the Jimmy Fund (or the Children’s Cancer Research Foundation) in Boston. Together, they formed one of the earliest structural biology laboratories. During that time, she was also a lecturer in biophysics at Harvard Medical School. In 1972, the laboratory moved to Brandeis University in Waltham, Mass., where Cohen has been a professor of biology for 30 years.

"I’ve been blessed by the help of marvelous colleagues, postdoctoral fellows and students over the years," Cohen notes. Findings from Cohen’s laboratory have earned her some of the highest honors in science, including memberships in the prestigious National Academy of Sciences and the American Academy of Arts and Sciences.

Proteins Rule

In order to appreciate Cohen’s work, it’s necessary to understand that proteins are the fundamental functional units of every living organism. Knowledge of protein structure is essential for understanding life at its most basic level. Genes in the nucleus of the cell encode the information required for the linear amino acid sequences that make up proteins, which then fold into specific shapes.

Starting with her postdoctoral work, Cohen has focused for the most part on the architecture of muscle proteins, which have both dynamic and structural roles in the cell. Among other advances, she and her co-workers have discovered assembly and regulatory properties of the muscle proteins that control movement in the thin filaments (actin) and thick filaments (myosin) that make up muscle tissue. Cohen’s current research attempts to obtain atomic images of the complex motor portion of myosin, the myosin "head", as it moves through different stages of contraction.

"We want to visualize how myosin moves the actin filaments," Cohen explains. "By visualizing these large structures in precise detail, we are beginning to understand how these molecular machines work." Related research focuses on visualizing the protein interactions that lead to the assembly of a fibrin blood clot at the site of a wound.

Another focus of Cohen’s laboratory is on protein folding. Many proteins, including those involved in muscle and blood clotting, fold into extended three-dimensional shapes in which two alpha helices wind around one another. This simple "coiled coil" structure reveals features of protein design in a far more accessible way than does the structure of complicated globular proteins. Cohen and her colleagues have shown how certain amino acid sequences affect a protein’s shape and, in so doing, they have established some of the principles of protein folding.

Creating Protein Pictures

Current work in Cohen’s laboratory employs X-ray crystallography to capture atomic-level images of proteins. This method uses the X-rays diffracted by crystals to determine where atoms are located in the protein structure.

When Cohen began her doctoral work, X-ray crystallography was very arduous — for example, it could take many years to determine the structure of a protein, such as hemoglobin. Today, advances in practical and theoretical techniques and the use of computers have allowed scientists to produce increasingly complex and detailed images. They can now visualize the structure of certain large protein molecules all the way down to the atoms that make up their amino acid sequences. From this work, they can make beautiful, colorful, three-dimensional computer diagrams that reveal how atoms interact to determine the molecular architecture.

Reductionist Insights

"I’m a great reductionist," Cohen says, noting the paradox that as we learn more precise information about the structure of individual proteins we become better able to generalize about how they function. For example, protein research is beginning to provide clues about a wide variety of diseases such as cancer, cystic fibrosis and Alzheimer’s disease, which may arise from malfunctioning proteins. Cohen’s work has special relevance to various neuromuscular and cardiovascular diseases. Increased knowledge of protein structure may lead to the development of new therapeutic agents and drugs.

Cohen and her colleagues have made much progress in understanding protein structure and protein folding, but many questions still remain. After 50 years in research, she finds that her work is "endlessly interesting." Cohen paraphrases Albert Einstein’s description of his own devotion to science: it is her driving force, the pivot of her emotional life, with her efforts coming straight from the heart.

Although Cohen’s work has taken her to London and Paris and throughout the United States, she says that she prefers to spend most of her days in her laboratory at Brandeis University, working with fellow researchers. From the age of 12, when Cohen built her first small lab in her bedroom, and including her years at Bryn Mawr majoring in biology and physics, this is how it has always been for her. And this is how she intends to continue, although at 73, Cohen has passed the usual age of retirement.

"Some people think that science is a grim business, but it is neither grim nor a business," Cohen says. "There can be enormous playfulness, terrific imagination and wonderful human interactions in the laboratory. In fact, one of the great pleasures now in science is the connectedness of the scientific community — one’s colleagues are truly international."

About the Author

Jennifer Fisher Wilson is a contributing editor for The Scientist. She writes frequently about science and medicine for various publications, including Lancet Neurology, Science and UCLA Magazine.

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