Cells in Motion

by Alison Davis

Elaine Bearer is a pathologist at Brown University in Providence, Rhode Island. Bearer is fascinated by how cells in the body move around and change their shape.

Photo credit: John Forasté

When it comes to research, Elaine Bearer says one thing is for sure. "You never know what you'll find!"

To Bearer, the excitement of science is all about the adventure of discovery. Each experiment she carefully plans yields a new piece of information, and every discovery poses a new challenge. That's not only in trying to understand what the new information means, she explains, but also in deciding what is the best experiment to do next.

Yet despite all the challenges and hard work, the Brown University pathologist cannot imagine doing anything else.

"Every day, I still get a thrill putting the key into the lock of my lab door," admits Bearer, who is fascinated by how cells in the body move around and change their shape. "When I open that door and enter my lab, I'm following my own imagination," she says.

Once inside her lab, Bearer spends her time trying to unlock secrets about how changes in cell shape make the body tick, and how other changes in cell shape underlie disease. She began the quest as a graduate student at the University of California, San Francisco (UCSF) in the early 1980s.

Turning to Science
Bearer arrived at science somewhat later than many students, having already established herself as a composer of music. She also has a faculty appointment in the Brown University music department.

Bearer still actively writes music, with recent performances in New York City and Boston. She earned a bachelor's degree from the Manhattan School of Music in New York City and a master's degree in music from New York University. She studied composition while playing French horn with the Pittsburgh Symphony.

Bearer uses squid, which have extremely thick and long nerve cell extensions, to study movement of the herpes virus.

Photo credit: Elaine Bearer

But while Bearer has always loved to write music, she hated teaching it, and at age 25 she decided to pursue another, simultaneous career in medical research.

Bearer went to Stanford University as a student in the Human Biology program, where she became a teaching assistant to environmental scientist Donald Kennedy, who is now editor-in-chief of Science magazine. She went on to UCSF, where she was accepted into the Medical Scientist Training Program (MSTP), which is sponsored by the National Institute of General Medical Sciences and leads students to earn a combined M. D.-Ph. D. degree. In 1983, Bearer was the very first UCSF graduate of the MSTP. The program's overarching goal is to train students to have the skills and knowledge to perform research and help translate findings to the clinic.

With Bearer, it worked. Her research on cell movement has uncovered important knowledge about how cell motion normally works, as well as about the errant cell movement that can provoke disease. Bearer credits much of her current scientific success to having lofty early ambitions.

"I was arrogant and naïve," she says more than two decades later, without apology. "I had big-picture aspirations. I wanted to understand everything there was to know about how cells change their shape."

After receiving her M.D. and Ph.D. degrees and completing a 1-year postdoctoral research fellowship in Switzerland, Bearer returned to UCSF to learn to become an anatomic pathologist, a type of physician who diagnoses disease based upon telltale alterations in tissue structure.

Elaine Bearer composed The Nicholls Trio as a commissioned piece honoring the 65th birthday of renowned neuroscientist John G. Nicholls.

Photo credit: Elaine Bearer

"Day after day, I looked through a microscope, searching for changes in cell shape," Bearer says. She yearned to take a more systematic approach, not just to diagnose disease by recognizing what unhealthy cells look like, but also to understand the roots of how and why cells get unhealthy in the first place.

"I had a more global idea about pathology," Bearer says, now recognizing the long-term gains of thinking that way

during her early training years. "Over time, I have achieved much more than I would have if I had set my sights lower," she says.

Bearer says that side-by-side training in doing basic research and practicing medicine gave her an eye for thinking about problems in very fundamental ways, while keeping a focus on the medical relevance of such problems.

Moving Along
Take herpes, for example. Bearer has recently been investigating just how it is that the herpes simplex virus traverses nerve cells to do its dirty work of causing an infection. Scientists have known for some time that the herpes virus hitches a ride into the body by entering a nerve ending in the mucous membrane of the lip, eye, or nose, then journeying along the long and winding nerve to its control center near the brain. Here, the virus takes hold and copies itself. Bearer recently shed light on how this works by recreating the virus transport process in the giant axons of squid taken from local waters off the coast of nearby Massachusetts. Axons are spindly extensions of nerve cells that transmit electrical signals over great distances in the body.

Until Bearer completed these experiments, scientists did not have a model system in which they could study the individual viral proteins involved in transport along axons. This was partly because human nerve cells are small and finicky to grow in the lab, and human axons are too small to inject with test transport proteins. Squid axons are very thick and nearly 3 inches long — much, much longer and fatter than those in people.

Researchers had thought that herpes made its way toward the brain by successively infecting other cells along the way. Bearer and her coworkers at the Marine Biological Laboratory in Woods Hole, Massachusetts, injected the huge squid axons with a modified form of the human herpes virus. The researchers were amazed to measure its travel speed at 2.2 micrometers per second (1 micrometer is a thousandth of a millimeter). This speed can only be achieved, Bearer explains, by a single virus whipping down a nerve cell on a "track," being driven by a protein "motor."

The finding has plenty of practical importance, Bearer says. Understanding this movement process may allow scientists to send safe forms of herpes viruses with helpful genes attached into the nervous system, where the genes could treat certain neurological disorders. More fundamentally, the findings revealed how similar the nerve cell parts are between squid and humans.

"This kind of research is so powerful," Bearer says, about the process of making connections by studying normal cellular and molecular events and linking them to diseases.

The Arp2/3 complex helps a cell form actin filaments (left).

Photo credit: Elaine Bearer

Taking Shape
In addition to studying the movement of viruses along nerve cell tracks, Bearer investigates other kinds of cell motion, such as changes in cell shape. To this end, she has had a long-standing interest in platelets. In truth, platelets are not actually cells — they are rounded cell-like particles that are pinched off from the edges of cells in the bone marrow called megakaryocytes. As such, platelets do not contain all the usual components a cell has, like a nucleus. Nevertheless, these "mini-cells" are the parts of our blood that make a clot and keep us from bleeding excessively when we get a cut.

According to Bearer, platelets are incredibly interesting to study when it comes to shape changes — they undergo dramatic maneuvers when the body sends a signal that it's time to make a clot. When we cut ourselves, the wounded area of our skin sends messages that trigger platelets to snap into action, a process called activation. When platelets receive this activation signal, the normally smooth, disc-shaped cell particles stretch out, forming tendril-like "fingers" that grab onto tissue surfaces and other platelets. With their ragged edges, the activated platelets help to form a clot: a sticky, gel-like mass. The clot literally plugs up a wound and prevents blood loss. Activated platelets are also prompted to spill their contents, which include among other things a soup of clot-forming molecules. Despite intensive study, scientists do not know exactly how this happens.

In the lab, researchers like Bearer can trick platelets into activating themselves by spreading them onto a glass slide. Researchers know that the platelet activation process hinges on a cellular scaffolding protein called actin. All cells have actin molecules, and there are several different types of actin proteins. Actin is globe-shaped and can assemble itself into filaments that resemble a string of pop beads (see figure at top of page). In preparation for making a clot, a ring of actin filaments circling a platelet squeezes tightly, helping to dump clotting factors out of the platelet.

In smooth, unactivated platelets, actin proteins keep apart from each other. However, upon getting the activation signal, first two and then three actin molecules come together, forming a small group, or "nucleus." After this initial step, other actin molecules follow suit, lining up alongside the nucleus and forming a long string. This filament-like assembly of actin forms the underlying structure for the foot-like extensions of the activated platelet cells that make clots.

For 15 years, Bearer has been searching for the molecular machine that causes actin molecules to come together, or "nucleate," during the activation of platelets. She believes she has finally found it, and it is actually an assembly of several proteins, called a complex. This complex, found in many different creatures spanning evolutionary time, is named "Arp2/3."

The Arp2/3 complex is a relatively recent discovery by scientists who study how cells move. Preparations of platelets like the ones in Bearer's experiments have been used by other researchers to discover that the Arp2/3 complex is also the machine that helps certain disease-causing bacteria to move around inside cells. The complex works by bringing together actin proteins into a highly organized network at the rear of a bacterium. This network pushes these one-celled organisms forward.

Actin filaments also help cells move around in our bodies, for example, helping to propel white blood cells toward the site of an infection. The Arp2/3 complex allows them to shift direction rapidly in response to changes in their environment.

The Arp2/3 complex (arrows, bottom) helps actin proteins get together as platelets stretch out during activation (top).

Photo credit: Elaine Bearer

So why is understanding how the Arp2/3 complex works in platelets so important, you wonder? For starters, knowing what nucleates actin molecules during the activation of platelets means that scientists can look for ways to block that process. Take the logic one step further and you can imagine new treatments to control clotting. Clotting is a key process that's essential to life, but clotting gone wrong can also cause serious health problems, such as strokes and heart attacks, if a clot happens in the wrong place at the wrong time.

Platelets can't reach out and touch each other when the Arp2/ 3 complex is missing, Bearer explains, describing experiments she has done with platelets growing on glass coverslips.

Bearer could not be more thrilled with the results. Just as with her herpes virus research, Bearer's work studying actin in platelets has both practical worth and fundamental value.

"There are definitely two sides of the coin," Bearer says. "These results help us understand cardiovascular disease and atherosclerosis, but they reveal a basic mechanism of action in cells."

Practice Makes Perfect
Teaching, thinking of experiments, doing those experiments, and turning the results into scientific publications takes a lot of time, and Bearer also fits her musical life in between. How does she do it all?

"I have a lot of energy," Bearer concedes, adding that she doesn't watch television and reads the newspaper only twice a week, on Tuesdays and Sundays. She gets 9 hours of sleep every night and exercises every day, often riding 35 miles on her bike on a Sunday.

In Bearer's busy life, science and music co-exist, although she admits there is a certain "dynamic tension." She believes that for her, music and science work well together. Bearer's music emerges all the time, she says, sometimes in the middle of an experiment. She believes that her musical persona enriches the way she thinks about science, even helping her to write better scientific papers reporting her research data.

Don't for a second think it's easy, though, Bearer says. Years and years of diligence — musically and scientifically — have enabled her to do both music and science so well. In addition to rigorous scientific training, Bearer had strong musical influences early in life. One was Nadia Boulanger, the Parisian composer and mentor to a whole generation of 20th century composers, with whom Bearer studied when she was very young.

"Boulanger had a huge impact on my life," Bearer says, adding that the composer taught her to "think like Bach." Bearer learned how to listen to a complicated Bach fugue (a musical piece with multiple themes that appear and repeat in a complex pattern) and hear each musical "voice" independently, all at once.

It took a lot of work to acquire such a talent, Bearer says, but the work has paid off. "I can do an experiment and think music at the same time," she says.

Bearer juggles two careers, writing music and using pathology research as a window into understanding disease and normal cell behavior. She acknowledges the strong influence of superb scientific mentors, who guided her not only through her training years in California, but beyond.

"They really inspired me, and I still remember their terrific ideas," says Bearer.

One of those mentors, Donald Kennedy, remembers Bearer's spirit during her college days at Stanford.

"She was an outstanding student," Kennedy recalls, "but what I found remarkable was the way in which she could pursue serious interests in science and music at the same time. What is more remarkable still is that she has managed to continue both interests and develop them into an exceptionally rich, dual professional career."

Mountain Medicine Photo Credit: Joe Di Giorgis As a combined physician-scientist, Bearer is hooked on basic science but also committed to practicing medicine. At Brown, she teaches pathology (" No medical student graduates from Brown Medical School without passing my course," she states matter-of-factly). In addition, Bearer directs an elective "clerkship" (clinical rotation for medical students) that serves the community of San Lucas Toliman, a poor Mayan population living in the highlands of Guatemala. The program, called the San Lucas Health Project, is sponsored by the Department of Community Health at Brown University, and involves doctors, nurses, dentists, and social workers from her local community of Providence, Rhode Island, in addition to medical students from Brown and all over the world. Nine years ago, Bearer began the clerkship program in part to satisfy her own need to supply medical care to needy populations. The project's mission is multifaceted. In addition to providing direct medical and dental care and educational support to local health care personnel in Guatemala, the Brown University team also gathers health-related data and provides financial and material support for instituting local programs to improve health, nutrition, and hygiene. In recent years, Bearer has learned that AIDS has seriously impacted this Central American population, and since that time the group has set up HIV testing and counseling programs. Bearer is now trying to establish a research program there to learn more about the social relationships and family commitments that can play a big role in risk factors for AIDS and other sexually transmitted diseases. — A. D.