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MIT-Harvard study yields insight into cell growth and division
CAMBRIDGE, Mass.—An article recently authored by scientists at the Massachusetts Institute of Technology (MIT) and Harvard Medical School (HMS) sheds light on the causal relationship between cell growth and size regulation. The finding offers a possible explanation for how cells determine when they start dividing, according to the research team.
Previously, technical problems or limited precision associated with measuring mammalian cell growth over time have hampered the study of cell growth. That all began to change in 2007, when the laboratory of Scott Manalis, a professor at MIT's Koch Institute for Integrative Cancer Research and departments of biological and mechanical engineering, developed a microfluidic system for simultaneously measuring single-cell mass and cell cycle progression over multiple generations. Known as a suspended microchannel resonator (SMR), this technology pumps cells in fluid through a microchannel that runs across a tiny silicon cantilever. That cantilever vibrates within a vacuum. When a cell flows through the channel, the frequency of the cantilever's vibration changes, and the cell's buoyant mass can be calculated from that change in frequency.
Since then, Manalis and his colleagues have used the SMR to measure a wide range of physical properties with a precision and throughput that would have been possible with existing technologies.
"In the beginning, we never anticipated the idea of weighing cells," Manalis says. "And when we stumbled upon this, we had no clear idea on how it would be useful."
But because the original SMR offered limited control over the motion of cells in the channel, Manalis' lab tweaked it so the scientists could trap cells over a much longer period of time, track cell growth and relate it to the timing of cell division by measuring the cells' mass every 60 seconds throughout their lifespans.
The result, as described in an article that was published in the Aug. 5 online edition of Nature Methods, was the observation that mammalian cells divide not when they reach a critical size, but when their growth rate hits a specific threshold. A cell devotes itself to growth in a phase called "G1." A critical transition occurs when the cell enters the "S" phase, during which DNA is replicated in preparation for division. The researchers found that growth rate increases rapidly during the G1 phase. This rate varies a great deal from cell to cell during G1, but converges as cells approach the S phase. Once cells complete the transition into S phase, growth rates diverge again.
"The rapid increase in growth rate per mass in G1 indicates that the growth rate is not simply proportional to cell mass and suggests that there may be unique regulation mechanisms established during the G1 phase of the cell cycle," the scientists concluded.
Manalis' company, Affinity Biosensors of Santa Barbara, Calif., has sold instruments to many research labs in both academia and industry. Affinity Biosensors has turned the SMR into a benchtop instrument called Archimedes, which is named after the Greek mathematician, physicist, engineer, inventor and astronomer.
"Right now, the commercial unit is used to facilitate the development of antibody-based drugs by monitoring protein aggregates," Manalis says.
Next, Manalis' lab will measure the cell's response on short timescales to various perturbations, such as depleting a particular nutrient or adding a drug, he says.
"We believe this could offer new types of information that could not be obtained from conventional proliferation assays," he notes.
Manalis' co-authors were former MIT grad student Yaochung Weng; Amit Tzur, a former research fellow at HMS; Paul Jorgensen, a former HMS postdoctoral student; Jisoo Kim, a former undergraduate student at MIT; and Marc Kirschner, a professor of systems biology at HMS.