SHUTTER MOMENT

by Tom Nugent

After months of grueling preparation, it was time to take the "photo," time to snap a picture, with an immense X-ray "camera," of some of biophysicist Sarah Woodson's (Kalamazoo College class of 1982) favorite molecules.

Not your ordinary photo shoot, and not only because of the extraordinary camera. The truly "hold-your-breath" nature of the moment comes from the importance of Woodson's work. She seeks to understand the connections between gene-triggered diseases and ribonucleic acid (RNA) in human cells so that we can learn more about how those cells respond to threats posed by some pretty devastating diseases. And the time to take the picture - right now - was a moment of high drama. It was, after all, the fourth try.

Operated by the Argonne National Laboratory near Chicago, the giant "Synchrotron Radiation" camera is an electron-accelerating ring that stretches for more than half a mile across the rolling Illinois landscape. It was here, on a mild spring afternoon, that Woodson and her colleagues had gathered in the hope of "catching a sample of ribonucleic acid [RNA] in the act of folding."

Their extraordinary scientific goal: to track the activity of molecules of RNA as they change shape. (Like its better-known cousin "DNA," RNA is involved in the transmission of genetic information. In addition, other RNAs make new proteins or act as "switches" to help cells grow in the proper way. This second class of RNAs must "fold" into a particular three-dimensional shape in order to do its work.)

A veteran scientist with a growing international reputation in the field of biophysics, the former Kalamazoo College chemistry major - now a 47-year-old science professor at Johns Hopkins University in Baltimore - has spent the past 20 years in a quest to better understand the biochemistry of RNA.

Ribonucleic acid has become increasingly important to geneticists and molecular biologists in recent years. RNA plays a key role in the flawed biochemical processes that can lead to such disorders as Alzheimer's disease, Parkinson's disease, and cancer.

"I think we were all holding our breath a little bit, because our first three attempts at capturing the RNA folding had completely failed," she said.

"We were running out of time, and we really needed this to work. It seemed to take forever, but we finally got everything set up. Then the technicians opened the shutter, and X-ray light from the Synchrotron started bombarding the RNA. These X-rays deflect - or 'scatter' - off the RNA molecules, and this allows you to observe their movement during the few thousandths of a second in which the folding actually takes place."

Woodson and her teammates intently watched a flood of data emerge from the "scattering" of the X-rays. In visual terms, what they saw that day was "a big loose clump of spaghetti" suddenly contract into "a tight little ball," as each RNA molecule changed shape.

"On that fourth try, we finally got it right," she said. "Within a minute or so, we could tell that we were going to be able to walk away with some beautiful data, and we all had big smiles."

"A lot of the time when you conduct scientific experiments, you know that you probably won't get the results you want - at least not at first. That's a given. That's how it has to be, if you're really working on problems that you don't yet understand. Occasional failures are part of the process - and they certainly aren't much fun. But when you do get an outcome like the one we experienced that day at the Argonne Laboratory . . . well, that's when it all fits together and you're extremely happy.

"Those moments are very nice, of course, but they don't last too long - because you soon have to get back to work!"

"Keeping All The Balls In The Air"

Woodson conducts research of mind-boggling, scientific complexity, mentors up to dozen grad students and postdoctoral fellows at a time, gives frequent seminars on "RNA folding" at universities and medical schools, attends scientific conferences all across the country, and also raises hundreds of thousands of federal research dollars for her projects each year.

"I do have a lot of balls in the air," she says. "And there's no doubt that keeping them all up there requires a lot of time and attention.

"But I really love teaching and interacting with students. It's also true that if you're hoping to do any significant research, you must be prepared to raise money for it!"

The Genetic Analysis System - and the basic research it helps support - are costly. "We use this tool for the RNA 'foot-printing' studies that have been one of our major research initiatives in recent years," Woodson explains, "and those studies are very exciting because they've opened a new window on the three-dimensional shape of ribosomal RNA, which is part of the cell's machinery for making new proteins.

"Unfortunately, it has been difficult to find the resources for this kind of basic research in recent years. That fact has helped to create a discouraging environment for science, but many scientists are now cautiously optimistic that there will be more support for science research and education in the future."

"If I have a message for the public today, it's that we perhaps need to start thinking about our budgetary priorities. If we continue to reduce our national investment in scientific research the way we have been, how are we going to stay competitive with the rest of the world - to say nothing of continuing the battle against diseases such as cancer and HIV/AIDS, and even influenza?

"These are questions that badly need to be addressed, and as a biophysicist who does basic research, it's my obligation to help ask them!" Another ball to keep in the air.

Complicated Research, Simple Goal: Better Health

Born and raised in the Detroit suburbs, Sarah Woodson was the oldest of four children. Her father was a high school music teacher who taught her the joys of "playing Bach and Scarlatti" on the harpsichord. Her family was by no means rich, but thanks to "a very attractive financial aid package" (along with a campus job and student loans), the science-loving Woodson arrived at "K" in the fall of 1978 and soon found herself neck-deep in the rigors of physical chemistry.

"I studied the basics of chemistry with [Professor] Ralph Deal, and the classes I took were terrific. He was a real stickler for being rigorous, especially when it came to lab experiments, and the discipline and concepts I learned from him have stood me in good stead ever since. And I also think I was very fortunate to take a senior-level course in instrumental analysis that was taught by Richard J. Cook. I actually wound up as a teaching assistant in his class, and it was my responsibility to make sure that all
"...our first three attempts had completely failed....We were running out of time..."
of the instruments worked each day!"

Woodson also cites the importance of other K-Plan components on her scientific education. During her career development quarter, she worked as a cancer-research lab assistant at the National Institutes of Health. She completed her Senior Independent Project in inorganic chemistry in a lab at Wayne State University in Detroit. She earned her Ph.D. in Yale University's renowned biophysics program.

After completing two years of postdoctoral research with Professor and Nobel laureate Thomas Cech at the University of Colorado, Woodson became assistant professor of chemistry and biochemistry at the University of Maryland. By the late 1990s, she was already gaining a national reputation for her experiments and publications.

Her studies of such esoteric-sounding processes as "Concurrent nucleation of 16S folding and induced fit in 30S ribosome assembly" (to read the abstract, see Nature, 30 October 2008) are designed with a very practical purpose in mind. By better understanding how RNA molecules control the cell's use of genetic information, she said, researchers will soon be in a much better position to begin finding the biochemical medicines that will one day help to shut down genetic triggers for diseases like cancer and Alzheimer's.

"Sarah Woodson is a top-notch scientist and she's got one of the most productive and groundbreaking scientific groups now working in RNA research," says Robert M. Briber, Ph.D., the chair of the University of Maryland's Department of Materials Science and Engineering and a major authority in his field. He has collaborated with Woodson on several research projects in the past: "Scientists are realizing the crucial importance of RNA in the transmission of genetic information," he added.

"A key part of that transmission involves the 'RNA folding process' - which has been at the heart of Sarah's research. I don't think there's any doubt that her studies are going to become even more important in the next few years, as our knowledge of gene expression and its relationship to diseases and human disorders continues to expand."

"Just during the past few years, we've begun to understand much more about how RNA turns genes on and off," Woodson said. "And we now know that this function is extremely important, in terms of a cell's decision to become a liver cell, or maybe a brain cell.

"Right now, it seems very possible that malfunctioning RNA actually underlies some of the degenerative diseases that involve nerve tissue, such as ALS and Parkinson's."

Unlocking the mysteries of cellular self regulation may be a scientific challenge for generations. "But it's a struggle that is thrilling and worthwhile." It's a good thing as well that, along with enjoying her research, Woodson gets "a great deal of pleasure out of helping the next generation of scientists to develop their own research skills.

"For me, teaching graduate students and working on research problems that relate directly to potential therapies for diseases provide all the motivation I need to keep working hard each day - in spite of the occasional experimental failures that are part of the job."

Picture 1
Sarah Woodson, Ph.D.
Picture 2
Equipment like the Genetic Analysis System are a vital-and expensive-component of basic research.

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