Driven to Discover
by Emily Jensen
If you ask Shelley Grimes what she wanted to be when she grew up, she’ll tell you she had her sights set on being a veterinarian. At a young age, Grimes enjoyed the sciences and felt that a career in that field would be the best fit for her.
But that all changed after she got her first pet.
“We had gerbils and I didn’t like them one bit,” Grimes said. “They’d bite and scratch, and when I discovered I was shy around other kinds of animals, I decided that a career as a veterinarian was not for me.”
Grimes continued taking science classes in high school and also in college, and as an undergraduate at St. Olaf College she became especially interested in two fields: microbiology and genetics.
“My teachers in those subject areas were really inspiring,” said Grimes. “For them, it wasn’t just about making students memorize things––they made the material come alive.”
Grimes completed her undergraduate studies, entered graduate school at the University of Minnesota, and continued to pursue her interest in genetics. She began working in the lab of Dwight Anderson, a School of Dentistry scientist who was studying a simple virus that infects soil bacteria––bacteriophage phi29 (pronounced fee 29). During the previous two decades, Anderson had developed the phi29 experimental system into one of the premier research tools to study the fundamental principles of virus assembly. Specifically, his team studied how the viral RNA and DNA utilizes proteins and enzymes of the host cells to replicate and assemble new virus particles that can be transmitted to infect other cells. It was research that might one day lay the foundation for a better understanding of how similar viruses like the herpes viruses make us sick. It could also inform the field of the basic rules for how macromolecules in all living cells interact, assemble and function.
Grimes completed her Ph.D. in Anderson’s lab before moving on to a one-year postdoctoral position in Phoenix. In 1990, she accepted a full-time position back in Anderson’s lab and continued exploring phi29.
Meanwhile, in New Brunswick, Canada, a graduate student named Paul Jardine was earning his Ph.D. in biology. He was particularly interested in virology, and knew of Anderson’s work through numerous academic conferences.
“Dwight had the best experimental system and the best lab,” said Jardine. “Several of my colleagues spoke highly of the environment at the University of Minnesota and also about how Dwight makes science fun.”
After completing his Ph.D., Jardine applied for a post-doctoral position in Anderson’s lab and began working alongside both Anderson and Grimes in 1997.
In addition to adding Grimes and Jardine to his research team, Anderson sought partnerships with multi-disciplinary experts in structural biology and single-molecule biophysics from Purdue University and from Berkeley. “We wanted to do things that were unprecedented––not run of the mill stuff, but approaches that would have impact in other areas,” Anderson said.
Together, they focused much of their investigations on how strands of viral DNA were packaged into protein shells, a critical step in the assembly of infectious virus particles that deliver viral DNA from cell to cell. Major breakthroughs came with the characterization of a “molecular motor” that drives this process. Utilizing chemical energy within the cell, this motor packages DNA into virus particles. By combining classical genetics and biochemistry with state-of-the-art structural biology and single molecule biophysics, the Minnesota group and their collaborators discovered that the phi29 packaging motor is one of the strongest force-generating molecular motors ever reported––with a power-to-weight ratio 20 times greater than a car engine. Not only have their studies contributed to a better understanding of the mechanisms of virus assembly and DNA packaging, their research has found a broad audience in the scientific community of those studying the enzymes and motor complexes that drive all cellular processes.
“One of Dwight’s gifts was his vision––he was always looking to the horizon and where we would be going next,” Grimes said. “He saw that we needed additional expertise to move the science forward, and that’s exactly what this multi-disciplinary collaboration did.”
Passing the Torch
In 2004, when it came time for Anderson to retire, he had two bright and productive colleagues to take over. Grimes and Jardine rose to the occasion right away, knowing it would not be an easy road to take.
“We knew it would be a challenge. Even though there are two of us, to replace someone with such a history and momentum in science isn’t easy,” said Jardine. “It was a tremendous learning process and we felt like we were filling some pretty big shoes.”
After Anderson retired, the dental school provided some support for the team as the two worked on renewing grants for a few years to keep their program functioning and moving forward in a particularly difficult funding environment. Ultimately, after much effort, they were able to successfully renew their research funding and continue the science of phi29 in Minnesota.
Getting Under the Hood
Over the years, the research team has completed a number of high-risk, high-yield projects. With each breakthrough, the group reveals a little bit more about the virus and uncovers more and more questions that need to be answered.
“If you were to compare it to ten years ago, we’ve gone from cartoon-like ideas to complex atomic models of tens of thousands of atoms in a structure,” Jardine said.
For example, recently they found that the molecular motor has five subunits that communicate and coordinate with each other in order to properly package the DNA. If there’s a defect in one of the subunits, it affects the function of the others. The motor also senses defects in the DNA, making multiple attempts to pass modified sections to continue packaging the DNA.
It’s these advancements that excite Grimes and Jardine and motivate them to continue in their studies. In many ways, Jardine says the ongoing project is a lot like a mechanic understanding the inner workings of a car.
“When we get into a car, we put the key into the ignition and the engine starts. Somewhere under the hood is your engine,” he said. “For a long time, nobody was able to get inside and see the ‘engine’ of this virus. But now we’ve opened the hood and are starting to take the engine apart to understand how it actually works.”
So, what does it take for a group to pioneer more than four decades of research and receive 42 consecutive years of NIH-funding?
“Good students, good post-docs, 60 hour work weeks, and always the mindset that we’re going to be on the cutting edge,” said Anderson. “Our intent is to publish in the best places; Nature, Cell, the Proceedings of the National Academy of Science. And we have. This contributes to keeping our funding.”
Grimes and Jardine point to Anderson’s enthusiasm and excitement as inspiration to continue searching for answers.
“One thing I have witnessed from Dwight, and been able to model my behavior on, is perseverance,” said Grimes. “If you persevere, you’re going to get there. It’s a long road, but it’s definitely a worthy road.”
For Jardine, it is Anderson’s long-term vision that has made his lifetime research project successful.
“Dwight’s a ‘big ideas’ guy. He’s always done exceptionally long-term, high-risk and high-yield projects,” said Jardine, “and few labs have the resources or the courage to attempt these sorts of projects.”
Keeping the Inspiration Alive
Grimes and Jardine chose to pursue careers in the sciences because of mentors who inspired them, and both point to their scientific community for removing barriers between junior scientists and those who are world-renowned in their field.
“When I’d go to conferences as a grad student, I’d sit before a generation of researchers who developed the field,” says Jardine. “We’d go to meetings and I was in awe that they’d sit down and talk about my project with me. It was very humbling, and it’s still the same way today. The level of interest and support for first- and second-year grad students is the same as it is for those who have been in the field for decades.”
When Grimes works with junior scientists in her lab, she understands the importance of instilling positive impressions. She always tries to put their work into context and show them how it fits as a piece into the bigger picture. That way they stay motivated and understand the important role they’re playing in the project.
As for what keeps Grimes and Jardine inspired, Grimes points to continuous breakthroughs in their research.
“Every time we discover something new, all of a sudden another door opens and there’s a whole new pathway,” says Grimes. “And that’s what makes it exciting to stay in this research for 20 years.”
For Jardine, what keeps him inspired is the feeling that he’s doing something that’s important and meaningful. “It’s not about saving the world or making money––it’s about wanting to do the best science. And by working with phi29, we get to do that with an elegant, beautiful system.”
(This story appeared in the Fall/Winter 2011 edition of Dentistry Magazine)