Digital technologies have changed how we live. Smart phones, computers and broadband Internet let us transmit and receive astoundingly complex information. The key is multiplexing: the ability to send many different signals through a single conduit.
However, while digital signaling is a great human achievement, it may not be an original idea. Research by UC Davis assistant professor John Albeck and others has shown that cells have been using similar mechanisms for eons. As happens so often, nature may have beaten us to the punch.
Uncovering a secret code
Cell signaling is essential to life. Using complex protein networks, cells communicate with each other and respond to changes in their surrounding microenvironments. These responses can govern hundreds of fateful decisions, some of which can lead to cancer and other diseases.
One of the most important signaling pathways revolves around the epidermal growth factor receptor (EGFR). When functioning normally, EGFR helps drive cell proliferation, survival, migration and other functions. When mutated, EGFR can go into overdrive, fueling cancer.
“EGFR controls many different processes in the cell,” says Albeck, “but how does it know which ones to turn on?”
Albeck wanted to understand how EGFR and other cellular switches pull off this multitasking. Scientists had thought that signaling was a one-to-one relationship: a protein, lipid or other ligand attached to a receptor and a single pathway was activated. But cell behavior was just too complicated. For example, genetically identical cells were responding differently in similar environments. There had to be more going on.
“There seemed to be a code that could allow a single signaling pathway to control different outputs independently,” says Wolf-Dietrich Heyer, professor and chair of microbiology and molecular genetics. “Different signals could turn on one protein, or a different protein or an entire set of proteins.”
In other words: multiplexing.
Recognizing that cell signaling was more complex than previously thought was just a start. Albeck and colleagues wanted to know why. While working at Harvard, he helped customize a technology to illuminate these networks. Fluorescence resonance energy transfer (FRET) allows researchers to observe energy conduction between molecules, a handy tool when measuring protein-protein interactions, the basis for cell signaling.
The Albeck lab has combined FRET, which narrowly focuses on individual cellular components, with automated microscopy, which can observe many cells at once. These complementary technologies allow them to record cell behavior in real time.
“We wanted to be able to look at a cell and then come back five minutes later and see what’s changed,” says Albeck. “Now we can observe an individual cell and understand what happened yesterday that is making it proliferate or go into apoptosis today.”
These observations have produced some amazing results.
“We used to think the amount of activity inside the cell would reflect the amount of EGF binding to the receptor,” says Albeck. “But the pathway is converting EGF into a series of digital blinks that are controlling activity in the cell. The frequency encodes information.”
This insight helps explain how cells respond to an ever-changing microenvironment. Proportional or analog signals don’t have the horsepower to transmit all this data. But a digital code, in which different sequences generate varied responses, could give cells the information they need to make the right choices.
Albeck’s EGFR research could have big implications for clinical care, as EGFR mutations are known to drive lung cancer, neurodevelopmental disorders and other conditions. Understanding how these receptors communicate could change how we approach them.
“Dr. Albeck’s basic research ties in nicely with the translational side,” says Heyer. “It’s helping us understand how cell signaling influences cancer, which may ultimately help us find better ways to treat it.”
For example, EGFR inhibitors have been used for years to treat lung cancer, but are these important drugs being delivered effectively?
“We’ve been using cancer drugs like antibiotics,” says Albeck. “We just apply the largest and longest dose the patient can tolerate. But cancer is a very different condition. Linear doses may not be the best approach because of the toxicity and the way cancer cells learn to respond.”
Albeck and others believe that EGFR inhibitors, and perhaps other anticancer drugs, could be delivered in pulses. This approach could maximize drug effectiveness while minimizing both toxicity and a tumor’s ability to develop resistance.
“We’re learning that it may be better to deliver these drugs during defined windows and give the cells a break,” says Albeck. “We just need to figure out what those windows are.”
Translating basic discoveries
While Albeck has been with UC Davis for only a year, he is already finding collaborators working to improve lung cancer therapies. Associate professor Philip Mack has been investigating new drug combinations for more than 15 years. Now, he is using advanced genomics to identify mutations in individual tumors and match treatments that target those mutations. He also has a keen interest in EGFR.
“A small subset of tumors are particularly dependent on EGFR for growth and survival,” says Mack. “Blocking that signaling will cause the tumor to stop growing and die.”
While this strategy often works in patients — for a time — cancer evolves mutations to escape the inhibitors. Mack hopes that the added insights into EGFR signaling might help clinicians and patients avoid this pitfall.
“We want to translate these laboratory strategies into improved patient care,” says Mack. “The better we understand these events at the molecular level, the more likely we’ll be able to use drugs in the right combinations, schedules and concentrations to make the tumor respond. We can also use these tools, in real time, to evaluate how a patient is responding to a particular therapy.”
The wider landscape
EGFR is an important signaling pathway, but it’s one of many. For example, signals conducted by the enzyme AMPK also may have a digital signature, a finding that could enhance our understanding of diabetes and other metabolic conditions.
“We don’t think this behavior is confined to the EGF pathway,” says Albeck. “It just happens to be the first one we looked at.”