Photo by Bo Jungmayer / Fred Hutch News Service
From before we are born — in fact, from the time we are no more than microscopic embryos — each one of our cells is already adept at sensing and responding to its neighbors. To survive as a whole, each cell of a multicellular being (such as a human) must be exquisitely tuned to its environment, using signals from outside itself to drive important cellular milestones such as when or whether to divide, whether and where to migrate, and even when to end their own lives.
Even single-celled creatures — bacteria, yeast, algae — need to perceive and react to outside signals to survive.
In other words, no cell is an island.
Getting those environmental messages across is no simple feat, however. To parse and react to any signal coming from the outside world, a cell must translate external signals into a new molecular language inside its borders. That internal message is then transmitted in a step-wise fashion, from protein to protein, across the approximately 1/10,000 of an inch between the cell’s surface and its decision-making center, the nucleus.
Now, a new study, which was published Thursday in the journal Cell Systems and which was led by Fred Hutchinson Cancer Research Center molecular biologist Dr. Roger Brent and computational biologist Dr. Steven Andrews, addresses the molecular chain of events that occurs when cells receive external information. Through computational modeling of that tiny information bucket brigade, the biologists uncovered hints pointing to the mechanism cells may use to transmit a certain type of signal faithfully from cell surface to its nucleus, where all the cell's genetic information is stored.
To their surprise, the mechanism the cells choose — or that which evolution chose for them — is not the obvious way a human would engineer such a system, Brent said.
The mechanism they found, known as push-pull control, is a way of “transmitting an accurate symbol through bags of goo [i.e., cells], instead of a nice wire or something that a human would use,” he said.
And as illogical as it may seem, the existence of push-pull control in these types of signaling pathways could explain why certain cancer drugs work as they do, the researchers said.
A 'seemingly ramshackle' system
Brent, Andrews and their colleagues study a certain type of information cascade — one in which the cell needs to communicate to its DNA not only what is happening on its surface, but the magnitude of that external event.
There are many such situations in our cells and in simpler beings where a cell needs to respond in different ways to different amounts of an environmental cue. For example: insulin-sensing fat cells in our bodies scale their conversion of sugar to fat storage in response to increasing levels of the insulin hormone. Or, in the case of the type of cells that Brent, Andrews and their colleagues study, single-celled yeast looking for a mate respond to the highest level of mating pheromone in their surroundings by growing in that direction, an environmental response that requires precise changes in approximately 200 of the yeast’s genes.
Cells are tiny, and yeast cells especially so, but that fraction of an inch distance between cell surface and its genes is immense when you consider that any information transmitted relies on the chance collision of molecules as they float through the cell’s soupy interior.
“It’s seemingly ramshackle; it’s seemingly chaotic,” Brent said. “No human designer would ever design such a system.”
Given the randomness inherent in cellular information transmission, it’s perhaps not too surprising that cells don’t use the same technique a human engineer would. But in a previous study published in the journal Nature in 2008, Brent and his colleagues found some evidence for a logical technique.
To design an information transmission system that accurately conveys both what a signal is as well as its magnitude, humans would typically use something known as closed-loop feedback control, Brent said. In closed-loop control, the output of the system figuratively loops back to influence the activity of the system itself.
Think the heating system in your house, Brent said. When the temperature of the room drops below a certain threshold, the furnace kicks on and produces heat. When the room is warm enough, the thermostat tells the furnace to turn off.
In yeast, when information is transmitted through the pheromone-response cascade, each protein involved activates its downstream partner — starting with a protein that sits on the cell surface and recognizes pheromone molecules in the environment, and ending with proteins that change the activity of the genes involved in mating. In their 2008 study, the researchers had found that one piece of this pathway exhibited what looked like the same type of negative feedback control as the furnace and thermostat.
“We had found an example of negative feedback in the system and were so excited that we figured this must be the key to the universe,” Brent said.
So Andrews set out to model the entire system to more precisely pin down the mechanism. And that’s when their closed-loop feedback theory fell apart.
The activity of so-called ‘inactive’ molecules
To get at the mechanism, Andrews developed a computer program that broadly mimics the yeast pheromone-response system. He asked which type of signaling cascade produced the same sort of alignment between input and output as live cells exhibit. Based on their past study, one of the first models they tried was the sort of negative feedback for which they’d seen evidence.
“That was surprising — it was supposed to work, but it didn’t,” Andrews said.
Getting to the answer from that point took many years and a lot of computational power, he said. Rather than addressing the relatively simple question, “Can this model do that? The answer’s yes or no,” Andrews said, they had to ask what mechanism, chosen from an infinite number of possible choices, matched the experimental data. “So it was an enormous problem,” he said.
Racking their brains for different mechanisms, models and parameters, the researchers tested 30 different types of mechanisms and millions of different models.
“All of them failed. Except for one,” Andrews said.
The winning mechanism is known as push-pull control, and it’s a bit unusual. In push-pull, the “inactive” forms of the proteins in the information cascade actively keep the steps ahead of them shut off, while the active forms turn those steps on. Their finding raises the question of whether it’s accurate to call these proteins inactive in the first place, Andrews said.
“Active stuff does something, an inactive thing doesn’t do much, that’s the assumption,” he said. “There’s sort of a big shift here. We’re saying, wait a moment, we think the inactive form is actually much more important than we give it credit for.”
There are hints that push-pull control exists in nature. There’s evidence of it in plants, and the Fred Hutch researchers’ collaborators from the Institute of Physiology, Molecular Biology and Neuroscience in Buenos Aires, Argentina, have confirmed these computational results in living yeast, Brent said.
And their results have a biological tie to human cancer, too. The yeast pheromone-sensing pathway is closely related to a human-signaling system known as the epidermal growth factor receptor, or EGFR, pathway. Mutations in the EGFR protein are commonly found in certain cancers, including non-small cell lung cancer, glioblastoma and head and neck cancers — these mutations ramp the system into overdrive, causing cells to grow and divide out of control and eventually become tumors.
Certain cancer drugs block intermediate steps in the EGFR pathway — drugs such as trametinib, sorafenib and vemurafenib. And these drugs wouldn't work the way they do if closed-loop feedback was taking place in the EGFR pathway. Since the cancer-causing mutations lead to overactivity in the EGFR protein, closed-loop feedback control in the pathway would override the action of drugs blocking steps downstream of EGFR. But the drugs work, meaning it's possible push-pull control could be ruling this human system as well, Brent said.
It's just a speculation, he said, but based on their findings in yeast, “it is a strong one.”
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.
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