RESEARCH BRIEFS

Stressed to the Bone

According to Newton, “For every action, there is an equal and opposite reaction”—a concept familiar to anyone who has ever played tug-of-war. But even a couch potato faces a constant bombardment of mechanical stress, from the daily necessities of physical activity to the unavoidable pressures of gravity. This stress affects skeletal tissue, triggering bone growth or bone loss as the body tries to maintain structural equilibrium. While this effect on skeletal development has long been noted, scientists are still trying to unravel the molecular response to these outside forces.

Researchers in the lab of Bjorn Olsen, dean of research and professor in the Department of Developmental Biology at HSDM, have uncovered one piece of this puzzle. Reporting in the June 2009 issue of Bone, they describe how a gene called Pkd1 contributes to the body’s response to mechanical stress.

The researchers gently stretched the palates of mice using midpalatal suture expansion, a process that triggers measurable new bone formation. Since mice deficient in the Pkd1 protein PC1 were already shown to have difficulty with bone development, the researchers used the technique to test Pkd1’s involvement in the body’s response to mechanical stress.

The researchers measured new bone formation in four groups of mice. The first group had normal Pkd1 activity while the others had Pkd1 deleted in selected cells. The team found that when Pkd1 was suppressed in neural crest cells—progenitor cells that give rise to bone and cartilage—the mice lacked the expected bone formation exhibited by the control and other Pkd1-deleted groups.

“The findings show that Pkd1 is clearly important to the progenitor cells’ ability to respond to mechanical stress,” said first author, Bo Hou, a former PhD student in the Olsen lab and a resident in orthodontics and dentofacial orthopedics at Tufts School of Dental Medicine. “We think PC1 may act as a mechanical sensor, helping to initiate bone tissue activity in response to mechanical stress, though more studies are needed to confirm this.”

This study establishes midpalatal suture expansion as a method for testing the genetics of bone development, with implications for skeletal diseases such as osteoporosis and osteoarthritis, as well as orthodontic and orthopedic treatments.

“If we can understand the process better,” Hou explained, “we could develop improved strategies to manage these kinds of cases, which would be good news for the patient and for our healthcare system.”

—Veronica Meade-Kelly

Students may contact Bjorn Olsen at bjorn_olsen@hms.harvard.edu for more information.

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Bioengineers Teach Cells to Count

Taking one step forward toward designing synthetic life, researchers have assembled the first cells that can count. A team from Harvard, MIT and Boston University mounted two different gene networks inside E. coli that helped the bacterial cells count up to three biochemical processes.

The study, published in the May 29 Science, achieves an elusive goal in the field of synthetic biology, which attempts to assemble cells and bacteria with programmed behaviors. The technique is still in its very early stages, but it holds promise for a vast range of uses including drug production, toxin detection and environmental cleanup. Timothy Lu, an MD–PhD student in the Harvard–MIT Division of Health Sciences and Technology, and Ari Friedland, a graduate student at Boston University, are lead authors of the study. Co-authors include George Church, HMS professor of genetics, and James Collins, professor of biomedical engineering at BU, both members of Harvard’s Wyss Institute.

The researchers developed two different counters based on dominolike gene processes that ended with the production of a fluorescent protein. Each successive tick of the counter was induced by arabinose, a kind of sugar that moved gene transcription one step forward at a time when injected into the cell. Both models were first tweaked to send their fluorescent signal when two steps were completed. Then they were extended to send the signal after a three-step reaction. One of the counters proved more effective at accounting for events happening within short time spans while the other was able to detect changes within a period of up to 12 hours. The latter counter was also able to store its state in memory based on DNA orientation within the genetic network and be activated with three different inducer molecules, the researchers said.

The first counter might be used to program cell death once a specific number of cell divisions had taken place, which would be useful as a safety measure to control new treatment and diagnostic applications. The second counter might be programmed to count day–night cycles and track genetic chain reactions in the study of organism development.

—Nuño Domínguez

Students may contact James Collins at jcollins@bu.edu for more information.

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Family Genetic Studies Still Matter

After Mendel worked out the math to predict the genotype of offspring from the parents’ genes, scientists relied for a century on family pedigrees to trace the genetic basis of inherited diseases and disorders. In the last few years, the gene-hunting strategy has changed with the advent of reliable whole-genome association studies, which compare unrelated strangers with and without the disease.

But family-based studies remain valuable tools in the search for the multiple genetic variations that contribute to common diseases, especially for less-common variants, said Nan Laird, HSPH professor of biostatistics, even in the era of reliable genomewide association studies.

Laird and her colleagues have developed software and expanded the most common family-based approach to accommodate real-world situations like missing parents, unaffected offspring, multiple traits and gene–environment interactions.

For any given circumstance, a scientist must make the best guess about how to examine the genetics underlying a disease process. Ultimately, only the end results will reveal which statistical tool describes the truest model, said Laird, who advised trying different methods for the same problem.

“If you can’t get rid of the family skeleton, you may as well make it dance,” she said.

Laird’s April 27 talk at Brigham and Women’s Hospital was part of the Harvard Catalyst colloquium series, a forum for state-of-the-art scientific and educational exchange at the cutting edge of clinical and translational research.

—Carol Cruzan Morton

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Shortening the Distance Between Lab and Clinic

Once today’s undergraduates retire, they will likely continue living, on average, to age 102. And if they’re lucky, they may benefit indirectly from the recent HMS Dean’s Symposium on Clinical and Translational Research, held April 30 and May 1 at three locations in Boston and Cambridge.

“Your hair thins, your skin wrinkles, and your brain ages,” pointed out psychologist and neuroscientist Randy Buckner in a morning session at the HMS Martin Conference Center. Of this terrible triad, science has been the least successful at understanding and intervening in the processes that lead to severe memory loss and cognitive disorders.

The symposium aimed to help speed up the translation of scientific advances into the clinic. Three sessions covered the economic and informational structures of collaboration and innovation, the brain, and nanotechnology.

The symposium was sponsored by Harvard Catalyst, a University-wide enterprise based at HMS that helps investigators from disparate disciplines and institutions find each other, form teams, access tools and technologies, and obtain seed funding. A new video by Jesse Dylan laying out the big idea behind Harvard Catalyst premiered at the symposium.

The first tangible outcome of the event is an application by Harvard Catalyst for National Institutes of Health stimulus funding to support Buckner’s work. If funded, Buckner, a Howard Hughes investigator and HMS lecturer on radiology at Massachusetts General Hospital, will have the resources to connect data from three MRI scanners in the greater Boston area and two at other translational research sites nationally. The project is an affordable bid to find the genetic and biological correlates of brain function and dysfunction of thousands of people who normally undergo the brain scans for other reasons.

—Carol Cruzan Morton

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