SPANNING THE BIOLOGY-TECHNOLOGY BRIDGE
WORDS BY EVE JACOBS / PHOTOGRAPH BY ANDREW HANENBERG
A young graduate student in the joint UMDNJ-NJIT Biomedical Engineering Doctoral Program is already making his mark researching bisphosphonates (marketed as Actonel, Aredia, Boniva, Didronel, Fosamax, Reclast, Skelid and Zometa) prescribed to increase bone by reducing the bone-loss part of the bone life cycle. But scientists are finding evidence that long-term use of the drugs can cause harm to the very bone they are intended to support.
XUDING CONFIDENCE AND POISE, 25-YEAR-OLD biomedical engineering graduate student Joseph Geissler walks calmly through the large, open laboratory on the G level of the NJMS-UH Cancer Center on South Orange Avenue in Newark that has literally become his second home. Sometimes he spends 16 of 24 hours there, with no complaint — he finds it a comfortable place to work, think, write, plan, and hammer away at sticky problems of bones and muscles, cells and beams. His science portends a wave of the future, where such distinct disciplines as biology, chemistry and engineering lose their hard edges and meld to create strikingly new approaches to previously "unsolvable" human problems that have stumped some really good minds. "A natural bridge" is what Joshua Berlin, PhD, NJMS/GSBS professor and founding co-director of the shared NJIT-UMDNJ biomedical engineering doctoral program, calls this marriage of biosciences and technology. Biomedical engineering students are riding a mighty wave into a really promising future.
With a degree in chemical biology from St. Joseph's University in Philadelphia earned in May 2009, Geissler was originally headed to medical school, at least in part because that's what biosciences majors often do. But when biomedical engineering was presented as an option, he "got" its potential value and the field intrigued him. He completed three courses as a non-matriculated student — bioinstrumentation, tissue engineering and biomechanics — to make sure it was a fit, then applied and was accepted into NJIT's Master's degree program.
|A SINGLE CORTICAL BONE BEAM READY FOR MECHANICAL TESTING. THE BLUE DOTS INDICATE AN ANATOMICAL ORIENTATION FOR LOADING. THE BEAM IS 10 MM IN LENGTH.|
Currently, Geissler is "just" completing his first year as a doctoral student. However, he's not a beginner in the field. His Master's thesis research on bisphosphonates — medication often used to treat osteoporosis and cancer — plunged him headlong into the heart and soul of his upcoming career. As technology officer and then president of the Graduate Biomedical Engineering Society during his first two years at NJIT, he helped to line-up industry and university lecturers who could present students with a clearer picture of the array of professional options in the field. Geissler himself "clicked" with one of these speakers, Chris Fritton, PhD, an assistant professor of orthopaedics at NJMS, who directs a lab in the NJMS-UH Cancer Center, and the Master's student came to work in Fritton's lab in late 2010. It has proved to be a very productive partnership.
Their research has focused on the long-term effects of this drug on bone strength and has even earned Geissler a NASA-sponsored New Jersey Space Grant Consortium graduate fellowship. "NASA has been looking at techniques to overcome the adverse effects of weightlessness on the musculoskeletal system. Because bisphosphonates have been effective for treating osteoporosis, they have been seen as an attractive countermeasure for astronauts on long-duration space flights," he explains. In the U.S., 55 million prescriptions for bisphosphonates are written annually, according to a 2007 report in the journal Osteoporosis International.
The UMDNJ research has focused on animals that were given bisphosphanates for three years. "I received the right 11th rib of all 36 animals for my studies," Geissler explains. Bone samples were provided by collaborators at the Indiana University School of Medicine.
The challenges of the research were many. The first — fabricating from the ribs "really small micro-beams, the size of two toothpicks side by side," to be tested — was "very tough," he says. But after mastering the skills taught to him by lab-mate and postdoctoral fellow, Devendra Bajaj, PhD, Geissler cut 90 beams for mechanical testing. Then he did what is called "cyclic loading," applying a small force over and over and over again until the bone fractures, because, he says, "This is how we load our bones, in walking, for instance." The UMDNJ group was the first to do a cyclic loading study looking at the effect of bisphosphonates. In other studies of the drug, a high level of mechanical force was applied in a continuous fashion to bone specimens until they fractured.
More and more fractures are being linked to long-time use of bisphosphonates, according to Geissler. "Where the femur goes into the pelvis at the hip is a region where you would expect to see osteoporotic fractures," he says. "But some patients who are on these drugs for longer than five years may increase their susceptibility to atypical fractures, such as a clean break right across the middle por- tion of the femur. A small subset of bones have snapped as the result of something as simple as getting up — not falling down. Some people get two breaks nearly simultaneously — one at the same point in each leg." Some rib fractures may also be due to weakening bone caused by the medication.
This drug stays in the body for a long time. "Your bone is like a sponge," explains the doctoral student. "It sucks the drug up and holds it in. Five, ten years after stopping the drug treatment, it's still in your bones." The growing data on bisphosphonates over the last few years has translated into better dosing, he says. However, there is not a clear scientific rationale for when the dose should be lowered or discontinued.
In lay language, the research demonstrated that while bisphosphonates do help strengthen osteoporotic bone in the short-run, long-term treatment with the drug may have the reverse effect. Geissler's abstract on this research was among the 200 chosen from several thousand submitted for a spotlight podium presentation at this year's Orthopaedic Research Society Conference in February, a "unique opportunity" for a young investigator to present his findings to a highly specialized research and clinical audience.
|A GROUP OF FOUR OSTEONS, EACH CONTAINING NUMEROUS OSTEOCYTE CELLS. NOTE THE
CIRCULAR STRUCTURE OF EACH OSTEON AND THE SINGLE CANAL THROUGH WHICH NUTRIENTS ARE SUPPLIED TO THE OSTEOCYTES OF THIS BASIC METABOLIC UNIT OF HUMAN CORTICAL BONE. THE OSTEON IS ALSO MECHANICALLY IMPORTANT TO FRACTURE RESISTANCE. THE LARGEST CANAL SHOWN IS APPROXIMATELY 40 μM IN DIAMETER.
The team made other significant findings. Bone micro-beams treated with higher doses of the drug failed more quickly (within fewer cycles of loading) and the specimens did not return to their original form after stress was applied because of reduced elasticity, also called plastic deformation. Deformation is an engineering term: when an object is changed temporarily due to applied force, it's called elastic deformation. When it's changed permanently, it's called plastic deformation.
In microstructural analyses, to determine why the mechanical properties were reduced, Geissler looked at the number and size of the osteons [the chief structural units of human cortical bone] and the space between them. He says that in high dose specimens, each indi- vidual osteon was smaller and the space between them was larger.
"The space between osteons is important. We form small cracks in bone called microdamage. Our hypothesis is that the damage accumulates in these spaces," he explains. "Perhaps treatment with bisphosphonates affects the size of these spaces."
CURRENTLY, GEISSLER IS "JUST" A FIRST-YEAR
doctoral student, but he's anything but a beginner in the field. His Master's thesis research on bisphosphonates — medication often used to treat osteoporosis and cancer — plunged him headlong into the heart and soul of his upcoming career.
According to the young researcher, the UMDNJ team has already collected enough data on this project to apply for a National Institutes of Health (NIH) grant. "But that type of funding is not easy to come by," he says.
The Indiana University Medical School collaborators are obvi- ously happy; they have recently shipped more bisphosphonate- treated bone to UMDNJ to continue this research. Once again, Geissler will create bone micro-beams, but this time will test the samples differently — looking at shorter testing methods that provide similar information as the cyclic loading. Some cyclic loading tests require greater than a week to complete. An even more clinically relevant test would require less time and might be completed without subjecting a patient to a painful biopsy. This would give both patient and doctor more definitive, scientifically based information on when a drug should be discontinued to avoid an oftentimes life-threatening fracture.
"The mechanical data is there," he states. "Now we're looking for the ‘why.' We're looking for the ‘research payoffs' for unraveling several chapters of this story."
Meanwhile, the life of the biomedical engineering student marches on. Soon to begin a research rotation in the lab of NJMS orthopaedics and cancer researcher Elizabeth Moran, PhD, Geissler wants to "branch out, try new things." This will help him decide on a dissertation topic. Additionally, he is applying for his next fellowship; he has sent out applications to the Department of Defense and NASA.
But rest assured that this young man does not spend all of his time in the Cancer Center laboratory. Over the last 10 months, two to three days each week, Geissler has found his way to Science Park High School in Newark, where he observes classes, teaches modules on biology, anatomy and physiology, and talks with stu- dents about their educational opportunities — all under the aegis of a National Science Foundation Graduate Teaching Fellowship.
"It's been wonderful," he says. "I've formed great relationships with students. I am very interested in education — especially in this city."
Now a resident of Society Hill in Newark, he is one of the city's greatest proponents, speaking out against negative stereotypes. He wants to help rebuild a sense of community and is working on a "trickle down mentorship" plan involving middle and high school students, their parents, and college undergraduates and graduates in Newark, who would provide mentorship, legal and tax advice, health information, educational direction and other practical help.
"I want to build a whole community of mentors who are networked, starting with kids in middle school," he says. "Mentoring is such an awesome skill to have. Why not take on that responsibility, have someone looking to you for advice?"
And why not? If doctoral student, researcher, teacher and ardent Newark advocate Joseph Geissler is ready to take on another complex task in his already crowded week, perhaps there are others who will join him in building more stable bridges for young people crossing into adulthood in New Jersey's largest city.