Yeast cells that can “talk” to one another using a dexterous plant hormone called auxin have been engineered by scientists at the University of Washington. These primitive fungal cells, called Saccharomyces cerevisiae, typically do their jobs, like making bread rise or converting sugar into alcohol, without having to communicate or work together.
Researchers described a novel cell-to-cell communication system, which enables one yeast cell to regulate the expression of genes and influence the behavior of an entirely separate yeast cell.
It’s a basic step in understanding the communication and cooperative processes that might lead to synthetic stem cells that could grow into artificial organs or organisms that require different types of cells to work together.
Senior author Eric Klavins, an associate professor of electrical engineering and of bioengineering at University of Washington, says:
“Until you can actually build a multicellular organism that starts from a single cell, you don’t really understand it. And until we can do that, it’s going to be hard to do things like regrow a kidney for someone who needs it.”
It might also enable engineered yeast to perform complicated behaviors that coordinated multicellular systems such as our immune system can pull off, like recognizing an invading pathogen and mounting a response. If so, one might program those cells to collaboratively diagnose the flu or malaria: just add saliva to a packet of yeast and see if it changes color.
For now, though, the team simply wanted to see if it could induce one yeast cell to send a signal that sets off a cascade of changes in another cell.
In the initial experiment, they used the plant hormone auxin—which yeast cells don’t normally recognize or respond to—to “turn off” a target gene in another cell. In this case, the gene that was switched off was an inserted jellyfish gene that turned the yeast fluorescent green.
“This project was to find out whether we could use auxin to make the cells talk to each other in a really simple way,” says Klavins. “We’re not sending complicated messages yet. One cell is saying ‘hello?’ and the other cell says ‘I can hear you.’ Eventually they’ll say ‘I’m this kind of cell. What are you? Let’s work together.’ But for now it’s pretty much ‘hi.’”
Synthetic biologists, who assemble genetic parts in new ways with the goal of popping them into an organism to produce reliable behaviors, have struggled to build modules that enable cell-to-cell communication in organisms that don’t naturally do it.
The team overcame this hurdle by engineering a suite of novel transcription factors—proteins that control whether a specific gene inside a cell’s DNA is expressed or not—with varying sensitivities to auxin. That “tunability” offers important control in regulating cell behavior.
With coauthor and associate biology professor Jennifer Nemhauser, the team figured out how to make a “sender” yeast cell produce auxin, a versatile hormone that controls everything from where a plant’s roots develop to how effectively they fight off pathogens. Through trial and error, the team learned an enzyme borrowed from a soil bacterium can induce yeast to convert a commonly available chemical into auxin.
In the “receiver” yeast cells, the researchers inserted the new transcription factor—which was assembled from so many different genetic parts that they call it the “Frankenfactor”—and engineered it to activate the jellyfish gene that turned the cell green.
When the sender cell released auxin, additional proteins that the researchers introduced in the receiver cell were able to degrade the Frankenfactor and switch off the gene that turned the receiver cell green.
That type of simple communication forms the bedrock of multicellular organisms in which different types of cells collaborate to carry out complicated tasks. As a next step, the team plans to test whether auxin can induce more complex behaviors in yeast cells, such as forming patterns or cooperatively computing basic functions.
Since auxin is a plant hormone, mammalian cells also ignore it, making auxin a potentially useful tool in designing gene therapies or other applications without adverse reactions in humans. This new method, which uses a “guide RNA” to target the gene of interest, could be adapted to produce a number of genetic or behavior changes.
“If you ask someone in computer science what they can do with a programming language, they’ll laugh and say they can do anything with it,” Klavins says. “If we can figure out the programming language of life, we can do anything that life does—except in a more controllable, reliable way.”
Cell–Cell Communication in Yeast Using Auxin Biosynthesis and Auxin Responsive CRISPR Transcription Factors
Arjun Khakhar, Nicholas J. Bolten, Jennifer Nemhauser, and Eric Klavins
ACS Synthetic Biology Article ASAP DOI: 10.1021/acssynbio.5b00064
Illustration: U. Washington