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Top | Introduction | Atomic Force Microscopy | Cell Motion | The AFM | Sonocytology

The Singing Cell

Andrew E. Pelling


Professor James Gimzewski and Andrew Pelling made the discovery of cellular sounds at the UCLA Department of Chemistry in 2002, while observing certain cells oscillating with specific audible frequencies at the nanoscale. “Sonocytology”, the study of sounds that various cells generate, is a completely new field of research.


Top | Introduction | Atomic Force Microscopy | Cell Motion | The AFM | Sonocytology


The cell is one of the oldest nanomachines capable of independent life. Cells are capable of many complex functions such as motility, cell-cell communication, synthesis of chemicals and macromolecules, and reproduction. All of these activities occur at scales far smaller than a human hair, from atomic to microscopic. From simple cells such as yeast or algae, to complex cells such as stem cells or neuronal cells, all rely on an orchestra of proteins, lipids, small molecules, DNA, RNA, and many other types of molecules, working in concert to sustain life at this small scale.

The cell membrane, or cell wall, is a fluid and dynamic structure that separates the inside of the cells from the surrounding environment. The cell wall is the barrier through which all drugs, chemicals, ions, and cellular signals must pass. It is the cell’s only interface to the environment, and the cell relies on this interface in order to survive. Many cellular processes, which allow the cell to respond to its environment and neighboring cells, take place at this surface. The complexity that exists in the cellular world is almost unimaginable, and many unresolved questions about the mechanisms behind single cell life remain.


Top | Introduction | Atomic Force Microscopy | Cell Motion | The AFM | Sonocytology

Atomic Force Microscopy

The Atomic Force Microscope (AFM) was invented in 1986 by Binnig, Quate and Gerber1, and has since become an incredibly useful tool in physics, surface science, biology, material chemistry, nanoscience and many other disciplines. The AFM is a relatively simple microscope, which uses tactile sensing to generate three-dimensional images of surfaces at very high resolution. It is not uncommon for the AFM to be used to visualize atoms2, molecules3, proteins4 and living cells5.

The AFM consists of a cantilever with a small tip at the end (fig. 1) that is mounted on a tube shaped piezoelectric crystal. This type of crystal will expand and contract proportionally to an applied voltage. Three sets of electrodes are attached on the tube to control the crystals motions in the X, Y and Z directions (fig. 2). When a voltage is applied to one of the electrodes, the crystal will contract or expand. Applied voltages on the X and Y electrodes will cause the piezoelectric crystal to move back and forth in the X-Y plane in a raster fashion, and in turn this will drag the AFM tip across the surface of the sample. Moving across the surface the tip will follow the topography of the sample, and this positional data is recorded with a laser (fig. 3). The laser is bounced off the back of the cantilever and deflects upward and downward, depending on the height map of the surface. This process can be described using the analogy of a record player needle moving over the bumps in the groove of a record. As the AFM tip scans the surface of a sample, its displacements are recorded and a three-dimensional map of the surface is built.

The AFM tip is extremely sensitive to small forces acting on it (as small as 1 pico-Newton or 0.000000000001 Newtons), and can be thought of as a tiny “nanoscale finger” which can literally "feel" the structure of the surface, and sense motion taking place at the surface.

Figure 1. a) An optical microscope image of a triangular AFM cantilever. At the apex of the triangle is a small tip that is barely visible and appears as a small block spot. A cartoon zoom of the side view of the cantilever shows the pyramidal shape of the tip that has an approximate radius of about 20 nanometers. In b) a schematic of the AFM cantilever is shown. The tip itself has a 35 degree half opening angle. c) A cartoon of the AFM setup. The AFM cantilever is mounted on the end of a tube piezoelectric crystal. As the crystal moves the tip over the surface, a laser monitors the tip displacement. The laser is bounced off the back of the cantilever into a position sensitive photodiode that records the cantilever motion. A computer assembles a three dimensional image based on this data.

Figure 2. A tube piezoelectric crystal has three sets of electrodes which control its motions in the X, Y and Z directions when voltages are applied to them. A voltage applied on the +X or –X electrode will cause the tube to bend in either direction. Using X and Y electrodes, the crystal can be manipulated in a raster fashion and scanned over a surface. Since the AFM cantilever is fixed to the crystal it will move over the surface and its path is shown in red. As the tip moves it will follow the topology of the surface and the computer will build a line-by-line three-dimensional image of the surface.

Figure 3. As the tip moves over the surface is will follow the topology as seen in the figure. The motion of the tip is recorded by optical deflection of a laser. Any motion of the tip will be recorded this way giving the user an image of the surface but also tactile information such as friction or chemical interactions between the tip and the surface.

The AFM can be used not only to record high-resolution images of living cells, but also to investigate the nanomechanical motion of the cell membrane/wall. A recent discovery has shown that information regarding the metabolic state of a living cell can be gained from observing them this way6.


Top | Introduction | Atomic Force Microscopy | Cell Motion | The AFM | Sonocytology

Cell Motion

Not only does the AFM tip move when dragged across a surface, but it also can sense motion while it rests in a still position. If the tip is held stationary over a surface that is vibrating or moving, the tip will bend and follow these motions. This fact opens up a door for a whole new set of experiments. The AFM can now be used not only as an imaging tool, but also as an ultra-sensitive, high-resolution motion detector.

Living cells are dynamic organisms and display plenty of small scale (nanometer to micrometer) motions at their cell membranes. For example, the AFM has been used in the past to measure the beating motion of heart cells5. A layer of heart cells can be grown onto a Petri dish, and the AFM tip will be placed over them. As the cell beats (expands and contracts) the tip will follow the motion. Thus the AFM provides a real time tool to monitor the beating rate of the cells.

But what about cells which are not known to display any sort of specific motion? Can we measure the “random” fluctuations of cell membranes or cell walls and extract useful information? Since cells are living organisms, there must be some type of motion taking place at the cell membrane, and it is enticing to try to measure that motion by “feeling” the cell. In order to carry out such an experiment, a highly sensitive AFM is needed.


Top | Introduction | Atomic Force Microscopy | Cell Motion | The AFM | Sonocytology


The AFM is mounted on top of a Nikon inverted optical microscope rests on a vibration-isolation table, which is inside an acoustic, thermal and electrical isolation chamber. This chamber is kept inside an acoustically isolated room, and all the computers controlling the AFM are kept in a separate room. With all these precautions in place, the noise level of the AFM (vibrations of the tip due to random motions) remains below 0.06 nanometers, less than the size of one atom.

Figure 4. The AFM is mounted on top of an inverted optical Nikon Microscope (A). In B, a close up of the AFM is shown; the piezoelectric crystal is housed inside a metal tube (arrow).

While the tip rests on top of some types of cells, we observe an oscillatory motion with amplitudes less than 5 nm. By Fourier transforming the oscillatory signal we find that the signal has a frequency in the kHz range. Exposing the cells to cytotoxic drugs will stop the motion and no frequencies are seen in the Fourier transform. In some cells, the motion is quite random and not oscillatory at all with no specific frequency components at all.


Top | Introduction | Atomic Force Microscopy | Cell Motion | The AFM | Sonocytology


Human hearing ranges from about 20 Hz to about 20,000 Hz. The frequencies observed in the study described above are well within the range of human hearing. Inspired by this finding, we have developed a way to convert the motion data into sound, allowing us to listen to the cells. From basic physics we know that any oscillating object creates sound. Sound is a disturbance, or wave, which moves through air, liquid and metals. As a vibrating object moves back and forth, it creates “pressure waves” or “density waves” in the surrounding air. The prongs of a vibrating tuning fork for example will move outwards, pushing the nearby air molecules together in a “high density”, or increased pressure region, and as the prong moves inwards, the pressure is decreased (fig. 9). These traveling regions of air molecules with high and low densities are the source of sound. As these molecules travel through space they will eventually come to your ear, and begin to crash against your eardrum. If the number of crashes per second against the eardrum is between 20 and 20,000, a sound can be heard.

Theoretically, if the yeast cell were in the air, they would create pressure waves with the appropriate number of “crashes per second”. However, there are other factors to consider before we press our ears close to a jar of yeast to hear a sound. First, the yeast cell wall is moving with such small amplitude that the pressure waves would not have enough energy to create a big enough impact on our eardrum to be heard, because the amplitude of a vibration is related to the volume of a sound. Also, the pressure waves would not have enough energy to travel far enough to reach our ears. Secondly, the yeast cell is in a fluid, and the waves it creates in fluid would not have enough energy to escape and make it to our eardrum in the first place.

Figure 9. As the tuning fork vibrates, its prongs push the surrounding air molecules into traveling regions of high and low pressure or density. As these pressure/density waves travel through space they will eventually come to our ear and we will hear sounds as they crash against our ear drum.

In fluid, where the cell is alive, the surrounding fluid molecules are much harder to move which hinders the creation of pressure or density waves. The cell is simply oscillating at too small of an amplitude. If the amplitude was much larger we would be able to hear it. However, due to the dampening nature of the fluid, the pressure/density wave will never have enough energy to travel outwards. Even though the yeast cell would not be able to create sound in air that is possible for us to hear, it is possible to use a computer to amplify the vibration of the cell to make it audible. This intensifies the volume of the yeast cell, but does not change the pitch or character of the sound itself.

The process of listening to cell sounds is analogues to sound processing in the digital realm: sound is converted into an electronic signal, amplified and projected utilizing speaker. Examining the data collected from oscillating cells we see that it is also an electronic signal (from the AFM) which is oscillating. This provides a perfect situation to convert the yeast cell data from graphical format into a digital sound file.

Using commercially available software (Awave Audio) the oscillating signal of the cells can be amplified and converted into an audio format. With these files in hand we can directly listen to the cell, without altering the cell or the frequencies in any way. The process of “feeling” a cell with the AFM and interpreting its motion as sound is the basis of Sonocytology. Observing the motion of cells in different situations, i.e. cells under stress, generates different sounds. In fact the state of a cell, if it is healthy or cancerous, can be distinguished by listening to its sound. Sonocytology is a diagnostic tool similar to listening to a beating heart. A doctor can diagnose heart conditions by listening to a person’s heart and comparing its sound with the sound of a healthy heart.

However, not all cells display motions that are oscillatory. We have found that cancer cells display a very noisy motion with no particular oscillations. In turn, the resulting sounds are also quite noisy. In the future we hope to bring our research in sonocytology to the point at which it can be integrated into medical disciplines such as cancer research. “Listening to cells” would allow a fast diagnosis of cancer without the use of drugs and/or surgery. Sonocytology might also make cancer detection possible before a tumor forms, and for this detection only one single cell would be needed.



1. G. Binnig, C. F. Quate, Ch. Gerber. Phys. Rev. Lett. 56, 930 (1986).
2. R. Erlandsson, L. Olsson, P. Mårtensson. Phys. Rev. B. 54, R8309 (1996).
3. S. Kasas et al. Biochemistry. 36, 461 (1997).
4. D. J. Muller, W. Baumeister, A. Engel. Proc. Natl. Acad. Sci. USA. 96, 13170 (1999).
5. J. Domke, W. J. Parak, M. George, H. E. Gaub, M. Radamacher. Eur. Biophys. J. 28, 179 (1999).
6. A. E. Pelling, S. Sehati, E. B. Gralla, J. S. Velentine, J. K. Gimzewski. Submitted.
7. This term was coined by James K. Gimzewski in an April 2003 LA Weekly article written by Margret Wertheim, “Bucky Balls and Screaming Cells”.