|FEATURES Spring 2003|
In her biomedical engineering laboratory Assistant Professor Shelly Sakiyama-Elbert has created a viscous gel that delivers protein cues for regenerating nerves damaged by disease or trauma.
"A large part of discovery is coming up with the right questions," says Shelly Sakiyama-Elbert. As the Joseph and Florence Farrow Assistant Professor of Biomedical Engineering, Sakiyama-Elbert is in the business of asking questions. The answers she's found provide people with hope for regrowing severed nerves, healing spinal cord injuries, and slowing the progress of degenerative diseases.
Currently when a nerve is damaged, new nerve tissue is grafted onto the surviving old tissue. Although the grafted nerve cells are dead (even when taken from a living donor), they carry proteins that the living tissue can detectand follow through the gap where the damaged cells used to be. Essentially, the graft becomes a scaffold upon which new cells can grow. Grafts have problems of their own, though. Graft cells either come from within the patient, in which case their excision creates a new injury elsewhere, or they come from cadavers and run the risk of rejection.
Sakiyama-Elbert's lab tackles these problems by using an artificial nerve guide tube instead of a graft, filled with a sticky gel that bears protein cues of its own. The guide tube is not unusual, but the gel within it is. To engineer that gel, Sakiyama-Elbert asked questions about existing nerve behavior. She saw that nerve cells already send fibrin bridges across guide tubes at the start of regeneration. This fibrin, which is also the protein component of blood clots, takes about a week to form. "We put fibrin into the gel from day one," Sakiyama-Elbert explains. "That cuts a week off our regeneration time from the beginning."
She puts growth factor proteins into the gel as well. These proteins normally act and disappear within minutes, but since nerves require weeks and months to grow, Sakiyama-Elbert needed to slow the process down.
"So we made the gel very sticky," she says. Because of this stickiness, only a small amount of the protein can act at a given time; the rest remains bound to the gel. "It's as if you tried to walk across the room, but I'd put down a bunch of mousetrap sticky boards," Sakiyama-Elbert says. "If there weren't very many boards, you could weave around them and get across the room. But if I put down a continuous sheet, eventually you'd start stepping on them, and it would take you much longer to get your foot off the floor for each step. Therefore, it would take you a lot longer to cross the room."
Initial studies of this affinity-based delivery system, conducted on rats, have shown promising results; injured sciatic nerves treated with nerve guide tubes regenerated at the same rate as sciatic nerves receiving nerve grafts.
Making Nerve Tissue Functional
The next question, Sakiyama-Elbert says, is whether the new nerve tissue is functional. While anatomic regeneration takes only about six weeks, functional regeneration takes three to six months, depending on the injury. Sakiyama-Elbert is currently designing follow-up studies.
"The prospect of being able to regenerate nerves damaged by disease or trauma is tremendously exciting," says Frank Yin, chair of the Department of Biomedical Engineering and the Stephen F. and Camilla T. Brauer Professor of Biomedical Engineering. "And [Sakiyama-Elbert] is indefatigable, undaunted by even the most difficult challenges."
She rarely faces these challenges alone; in addition to the graduate students, undergraduates, postdocs, and technicians in her lab, Sakiyama-Elbert also works with colleagues at the School of Medicine. "One of the things I enjoy most about the University is that people are very open to collaboration," she says. In fact, this collaborative spirit helped encourage her to come to Washington University, almost three years ago.
In her work with nerve guide tubes, Sakiyama-Elbert collaborates with members of the laboratory of Susan Mackinnon, who is both head of the School of Medicine's Division of Plastic and Reconstructive Surgery and the Sydney M. Shoenberg, Jr. and Robert H. Shoenberg Professor of Plastic and Reconstructive Surgery. "Professor Sakiyama-Elbert has been a tremendous role model for the University's medical students and research fellows," Mackinnon says, adding that School of Medicine surgeons trained in nerve surgery are working to translate Sakiyama-Elbert's work into clinical practice. Sakiyama-Elbert appreciates Mackinnon's clinical expertise in turn. "The opportunity to work with clinicians, to find out what they really need, is very helpful when developing technologies that are so interdisciplinary," she says.
Sakiyama-Elbert also collaborates with John McDonald, assistant professor of neurology and neurological surgery, and head of the School of Medicine's Spinal Cord Injury Program. McDonald says he enjoys her "passion and high motivation," as well as her "no-barriers approach to science." Their work together does not require a nerve guide tube; instead, the researchers make a small hole in the membrane around a damaged section of spinal cord, letting that membrane act as a natural conduit for the gel.
"Spinal cord regeneration is very challenging," Sakiyama-Elbert says, because scars tend to form around spinal cord injuries, creating a barrier to new nerve growth. The fibrin in Sakiyama-Elbert's gel has helped reduce this scarring, however, and preliminary rat studies again look promising. The work has potentially promising applications for accident victims, as well as for victims of degenerative disorders such as Parkinson's diseasethough the road to clinical applications there is likely to be longer.
Helping People Recover
As an undergraduate chemical engineering major at Massachusetts Institute of Technology, Sakiyama-Elbert once considered entering medical school and becoming a clinician herself. She ultimately decided to combine her interests in biology and engineering by focusing on biomedical engineering instead; she went on to pursue graduate work first at the California Institute of Technology, then at the Swiss Federal Institute of Technology.
Now at Washington University, she teaches courses in Tissue Engineering and the Engineering Aspects of Biotechnology. Yin says her students consider her tough but fair in the classroom, and supportive of them in the laboratory.
In both settings she encourages her students to ask questions of their own. "One of the things they learn is to be very critical of the literature," she says. "You need to think: 'What experiments would I have done? How would I have analyzed these data?'"
Sakiyama-Elbert continues to enjoy asking her own questions and designing the experiments to answer them. "The potential for coming up with a new idea, a new way to approach a problem, is very exciting," she says.
"And so is thinking about the ways in which work you're doing might one day be able to help people."