by Katie Galloway
Long before Samuel Morse put his telegraphic code to work, neurons and other cells were processing extracellular dash- and dot-type signals into instructions for cellular decisions. Researchers in Germany recently reported on how the cell reads and responds to these directions.1
Signals from outside the cell control many intracellular programs, even directing how cells develop into organs and whole organisms. Among other outcomes, these signals lead to bone growth, wound healing, and programmed cell death. In fact, nearly every type of cell utilizes extracellular instructions.
Receptor proteins on the cell surface comprise the first layer in signal-relays that control whether a cell grows, divides, specializes, or dies. When a receptor binds to its target molecule, it initiates an internal cascade of protein messengers that directs the cell to activate a genetic program. For example, when a growth factor like the epidermal growth factor (EGF) binds to a growth receptor, the signal induces the cell to grow and divide via the genetic growth program. If instead a neuronal growth factor (NGF) is added to the extracellular environment, a cell differentiates (transforms) into a neuron.
This seems like a straightforward system, but scientists were surprised to find that the internal signals for growth (triggered by EGF) and differentiation (triggered by NGF) are sent to the nucleus via the same exact proteins, known as ERKs. To biologists, this is like going to a busy restaurant and ordering a hamburger without giving the server your name or describing what you want on the burger. How could the server get the order right or expect to get it back to the correct customer? The same kinds of questions could be asked of cellular signaling systems. There simply isn’t enough information communicated—or so it seems. Despite the potential for scrambled instructions, biological systems get it right. But how do cellular signals produce the correct genetic “order”?
By studying the activation of the internal signaling proteins over time, German researchers at European Molecular Biology Laboratory noticed emerging patterns. When they hit (bio-slang for “dosed”) rat brain cells with EGF, the ERK protein spiked in activation and then dropped back to pre-stimulated levels within fifteen minutes (equivalent to a dot in Morse code), causing the cells to grow and divide.2 When NGF was used instead, ERK spiked and remained elevated for nearly an hour (similar to a dash), causing the cells to differentiate. It turns out the signal types (ERK profiles) produced by each growth factor send different messages to the cell, thus, prompting different activities. Somehow the cells use this telegraph-like signaling to communicate information.
To confirm their theory that the signal types control cell behavior, the research team molecularly cross-wired the systems so that each growth factor would produce the opposite ERK profile. Would cell responses be decided by the growth factor or by the signal type? Somewhat surprisingly, the researchers found that the signal type was the deciding factor. Even if hit with NGF, cells wired for a spike and quick recovery grew and divided; whereas when wired for a sustained signal, cells hit with EGF transformed into neurons.
Just like a telegraph system, these cells demonstrate that the intensity of the signal over time, not the initiator type, conveys the critical information. (See here3 for the technical review on this work). The advent of molecular systems biology has just begun to uncover this new level of elegance in biological systems. As this field of study develops, researchers are likely to uncover even more examples of sophisticated natural gene circuits.
The ability of cells to make accurate decisions via complex signal-processing strategies demonstrates that biological systems possess design. Further, experiments such as those conducted by the German research team lend insight into potential therapeutic strategies for reregulating diseased cells. Over one third of human cancers and many other diseases are known to result from improper activation of cellular programs via the described ERK pathway.
Understanding how cells make decisions gives researchers the tools they need to appropriately design therapies for intervention in improper responses like cancer. As our knowledge of biological strategies improves, the more we see how nature reveals intricate designs and further builds the case for a merciful Creator.
- Silvia D. M. Santos, Peter J. Verveer, and Philippe I. H. Bastiaens, “Growth Factor-Induced MAPK Network Topology Shapes Erk Response Determining PC-12 Cell Fate,” Nature Cell Biology 9, no. 3 (March 2007): 324–30.
- Boris N. Kholodenko, “Untangling the Signalling Wires,” Nature Cell Biology 9, no. 3 (March 2007): 247–49.