Siebel Scholar Rachel Miller using calcium imaging to examine a dorsal root ganglion, a cluster of nerve cell bodies that brings pain signals from the knee to the spinal cord.
Image credit: Lauren M. Anderson, Rush University Medical Center

Siebel Scholar Rachel Miller (MIT BioE ’10) spends her days in the laboratory contemplating the knee and its mysteries. The knee joint, where bones, cartilage, mass and movement all come together, will cause pain associated with osteoarthritis to an estimated 40% of Americans at some point in their lives.

“Osteoarthritis is such a common disease that it’s kind of strange that we don’t have a better understanding of what causes the pain,” says Miller, an assistant professor in the departments of internal medicine and biochemistry at Rush University Medical Center in Chicago.

The chance to use her training in bioengineering in combination with a new exploration into neuroscience led Miller to establish her own research lab at Rush. She is now focusing on explaining the origins of osteoarthritis pain associated with mechanics.

“Almost everyone knows someone suffering from osteoarthritis but there’s really not much you can do about it. It seems like there’s definitely an opening there to help people,” said Miller.

Knee pain may be chronic, or it might come and go with no rhyme or reason. It is the puzzle of what is actually happening in the complex ecosystem of the knee that drives Miller. Her latest work, in collaboration with her mentor at Rush, Ann-Marie Malfait, has focused on what processes result in knee pain, looking at the intersection of how the nervous system interacts with the musculoskeletal system.

It’s the mystery of the mechanics behind such a common ailment that makes the work continually interesting, Miller says. “I’m trying to understand why, when you have a musculoskeletal problem, it can suddenly hurt when you go for a run when it never used to.

Ultimately, the basic research she is doing on mechanisms of pain in the knee could result in the development of a drug targeted to those pathways. “It’s not going to happen overnight,” she says. “It’s probably more like a 10- to 20-year timeline.”

Day-to-day activities in the lab vary for Miller. “I like that every day is different. I can get there in the morning and decide what I want to do that day.” There are mundane tasks to running a lab, such as supervising mouse colonies. Other days she might be designing a new experiment or troubleshooting what’s wrong with a piece of equipment or a protocol.

To truly understand osteoarthritis, Miller believes, researchers will need to look at both the traditional joint damage mechanics along with the pain. “That’s still kind of a novel concept in the osteoarthritis world,” she says.

Having her own lab is a huge accomplishment, though it’s requiring a lot of fundraising. Miller spends a substantial amount of time writing grant proposals. But it doesn’t bother her. “I find the work I’m doing exciting enough that it’s OK for me to spend a lot of time writing grants.”

Hooked on Bioengineering

When Miller was in high school she had a chance to see artificial hearts being designed during a school trip to the nearby Penn State’s Hershey Medical Center labs, and she was hooked on bioengineering. Little did she know that just a few years later she would be working in those labs helping researchers on nanotechnology projects.

“As a high school kid I found that awesome and it got me excited about doing research,” recalls Miller. She attended Penn State and wasted no time getting into the lab; she became an undergraduate research assistant in biomaterials research at her own university while also helping out at Hershey Medical Center’s lab.

But Miller found her passion when she went to MIT for graduate and PhD work in Alan Grodzinsky’s cartilage mechanics laboratory. There she was introduced to the biomechanics of the human knee.

As a graduate student, she studied cartilage and how it works. Cartilage is made up of “extracellular matrix proteins,” Miller explains – “it’s actually not very dense in cells.” That’s what gives cartilage its unique properties. And yet, a lot of time is spent in school learning cell-based biology; “to learn this whole different matrix side was very interesting to me.”

Her time at MIT was especially enjoyable because of the sense of innovation and an environment full of smart people. “Pretty much anything you want to do you can find somebody with the expertise and the equipment to make it happen,” Miller says. “Whatever crazy idea you come up with you can test it out.”

Grodzinsky’s lab is working on issues such as musculoskeletal tissue regeneration to repair cartilage injuries and studying the nanoscale structure of extracellular matrix molecules.

Bridging Two Fields

While Miller finds these structural topics interesting, the fact that the pain around osteoarthritis is not well understood drew her to Chicago in 2010 to work with Malfait, for whom she was a post-doctoral research fellow for five years. Now the two work collaboratively from their own labs. “Now I’m trying to more closely address how the different cells and tissues are reacting to mechanical forces and what about that could be painful,” she explains. “A lot of top neuroscience labs are trying to figure out the receptors for stimuli such as touch and itch. There are plenty of mechanoreceptors to be discovered whether on nerves or other types of cells. It’s a hot field at the moment and there are implications for osteoarthritis as well.”

Moving from tissue engineering to neuroscience has required Miller to educate herself quickly in a new field.

Because she is working in both fields, Miller finds herself going to more meetings and working with a variety of collaborators. “I find biomedical science to be social these days because the scope of projects tends to be so broad that you need collaborations, whether at your own university, nationally or internationally,” she says.

Miller was drawn to the wide range of expertise at Rush, which has both a strong cartilage biochemistry research group and a strong orthopedics department on the clinical side.

Being able to see where her basic research will translate into help for real people is inspiring. “If you want to get the clinical point of view you just have to walk across the street and talk to people who really know what patients are suffering from, and that can give you ideas for your research.”

Another source of scientific community has been the Siebel Scholar program, to which Miller was named in 2010 while completing her doctoral work at MIT.  “It was great to be introduced to a national network of other bioengineering students so that in the future if I needed something I could work within that network and contact someone, and if someone from the Siebel network contacted me I would be happy to help them. That was a pretty cool idea.”