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Research aligns with foundation goal to sharpen ‘scientific understanding of the physical principles and mechanisms that distinguish living systems from inanimate matter’

Meredith Betterton, a �Ǹ�Թ� professor of physics and molecular, cellular and developmental biology, has been awarded a grant from the program.

The two-year, $594,487 grant will support Betterton’s ongoing research on microtubules, the small, long tubes inside cells that serve several functions and that Betterton’s research suggests may be less fixed and static than previously thought.

The Sloan Matter-to-Life program aims “to sharpen our scientific understanding of the physical principles and mechanisms that distinguish living systems from inanimate matter, and to explore the conditions under which physical principles and mechanisms guide the complexification of matter towards life.”

CU �Ǹ�Թ� scientist Meredith Betterton has been awarded a two-year, $594,487 grant from the Alfred P. Sloan Foundation Matter-to-Life program.��

Betterton and her research colleagues study microtubules in cells, which help maintain cell structure similar to how beams support a building and also act like highways that move traffic along, she explains.��

“Because (microtubules) have this important role as highways that things stick to and then move along, people have thought about them as being kind of fixed,” she says. “You build a microtubule, it’s there to be a highway and then it’s pretty static.

“The thought has been that once they’re there (in the cell), they sit there. Our project has to do with the idea that there might be subtle changes within the (microtubule) structure that act as a signal that sends information—so they act in some ways not as a highway, but like a telephone wire that’s sending signals.”

Building with bricks

Microtubules are built of subunits, called tubulin, that can be compared to bricks, Betterton explains. These tubulin “bricks” are known to make small internal changes to their shape and size; what hasn’t been known is what happens to the rest of the tubulin in the microtubule if one changes. “Imagine packing a lot of bricks together in a wall,” she says. “If you change the shape of one, what happens to the others nearby?”

Several years ago, Betterton and her research group, in collaboration with another team of research colleagues including Radhika Subramanian and Sithara S. Wijeratne at Harvard Medical School, along microtubules, which is done by motor proteins. These proteins take “steps” along the microtubule. They also can pile up and cause traffic jams, so Betterton and her colleagues were studying those jams to better understand the motors.��

The researchers discovered this phenomenon because the math wasn’t working. “In my group we were working on mathematical modeling of this, and we couldn’t get the model to work,” she says. “We put in measurements, and the equations gave us predictions that were really different from what experiments showed. We found the only way we could get the model to make sense was if something was happening where the motors could talk to each other over really long distances.”

While this action happens on a nanometer scale, “if you scaled it up it would be as if, when you’re driving a car, you could know there’s another car two miles away and how fast it’s driving,” she says. “That really was the initial discovery—this weird, long-range effect that we didn’t know where it was coming from.”

Other research had explored the conformational transitions, or structural shifts in tubulin, and how motor proteins can stick to microtubules and change their state if they bind in large numbers. Betterton and her research group are exploring whether a change of state can happen when motor proteins bind in small numbers and send signals over long distances.

How cells process information

A key aspect of this research, Betterton says, is it explores a different paradigm for how to think about these particular molecules in cells and aims for broader understanding of the way cells process information.

For example, she says, much is known about how neurons in the brain send electrical signals—a vital process for information transmission in the brain—but that process “can only happen in that one type of cell, whereas microtubules are in every cell,” Betterton says. “They could be sensing something happening in one part of the cell, so we’re studying this new way that cells could be responding.”

She adds that there are various potential applications for this avenue of research, including developing more targeted chemotherapy drugs: “There’s one (tubulin) that seems to be resistant to this subtle expansion and contraction. Recent work shows that makes them not as responsive to chemotherapy drugs. Because microtubules are involved in cell division, some first-line chemotherapy drugs for cancer act against microtubules.

“What has been discovered is that some cancers can resist these chemotherapy drugs by switching to this other type of tubulin that doesn’t change shape as well,” she says, adding that understanding more about tubulin expansion and contraction could possibly lead to more effective drugs.

There also could be potential applications in the physics of materials and using microtubules and motor proteins to make new types of materials that are more tunable to specific functions.

“The Sloan program is interested in this research because this specific program is called Matter-to-Life,” Betterton says. “What that’s trying to say of matter is that it’s some collections of molecules, but what about it becomes different between something that’s inert versus something that could be more alive? That’s a really exciting question.”��

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