Living cells don’t fret about their weight, even though it may go up and down all the time. So, they probably won’t mind that scientists have created a scale that can weigh individual cells in real time, capturing tiny fluctuations, the increases and decreases in water, proteins, lipids, carbohydrates, and nucleic acids. Although cells may not adhere to exercise programs, they can gain or lose weight as they go about their ordinary routines, which include metabolism, proliferation, and gene expression.
The scale is a tiny, transparent cantilever, a “picobalance,” that incorporates an optically excited microresonator. It can measure the total mass of single or multiple adherent cells over days with millisecond time resolution and picogram mass sensitivity, revealing mass fluctuations that accompany dynamic cellular processes. Already, the scale has been used by its creators, scientists based at ETH Zürich, to link mass fluctuations to adenosine triphosphate (ATP) synthesis and water transport. Also, the scale has revealed that growth and cell cycle progression are arrested in cells infected with vaccinia virus, but mass fluctuations continue until cell death.
Cells are weighed under controlled conditions in a cell culture chamber. The weighing arm, a microscopic silicon cantilever coated with collagen or fibronectin, is lowered to the floor of the chamber, where it nudges and picks up a cell. “The cell hangs on the underside of a tiny cantilever for the measurements,” says doctoral student Gotthold Fläschner, a co-inventor of the new scale.
The microscopic cantilever is induced to oscillate slightly by means of a pulsing blue laser at its fixed end. A second, infrared laser measures the oscillations at the other end, where the cell hangs—first without and then with the cell. “The cell's mass can be calculated from the difference between the two oscillations,” explains David Martínez-Martín, Ph.D., the main inventor of the cell scale.
A computer screen shows the changing weight as a curve. Readings can be taken from this over the whole measuring period—whether that's milliseconds or days. As the measuring apparatus, including the cell culture, is mounted directly on the object plate of a high-performance fluorescence microscope, internal processes in the cell can also be observed and filmed while measurements take place.
Additional details appeared October 25 in the journal Nature, in an article entitled “Inertial Picobalance Reveals Fast Mass Fluctuations in Mammalian Cells.” The article noted that while technologies have emerged in recent years that make it possible to track the masses of single suspended cells and adherent cells, no available technologies have been able to track individual adherent cells in physiological conditions at the mass and time resolutions required to observe fast cellular dynamics.
The new scale, however, can monitor how a cell’s weight changes over time. And it can do so with a resolution of milliseconds and trillionths of a gram.
“Our measurements suggest that all living cells show fast and subtle mass fluctuations throughout the cell cycle,” wrote the authors of the Nature article. “As our cell balance is easy to handle and compatible with fluorescence microscopy, we anticipate that our approach will contribute to the understanding of cell mass regulation in various cell states and across timescales, which is important in areas including physiology, cancer research, stem-cell differentiation and drug discovery.”
“We established that the weight of living cells fluctuates continuously by about 1% to 4% as they regulate their total weight,” said Martínez-Martín. Measuring errors have been ruled out. The biophysicists were able to prove that cells only stop these second-by-second fluctuations upon dying. The researchers are visibly excited. Fläschner: “We're seeing things that nobody else has yet observed.”
“A cell's mass is a very good indicator of its physiology,” explained Martínez-Martín. So, it makes sense that biologists of all stripes are interested in the new measuring method. It may also be relevant to the medical and pharmaceutical sectors, as it could be used to investigate the pathological growth of cells and the influence of drugs on this growth.
More surprisingly, material scientists are also interested in the device. “For them, it's about the functionalization of nanoparticles—in other words, changing the surface of very small particles,” stated Martínez-Martín.