Like Lucy Ricardo and Ethel Mertz scrambling to wrap the chocolates that roll relentlessly down the candy factory's conveyor belt, a cell's protein-folding team can only do so much with limited resources. And an unfolded protein that slips by unfolded can spark far more trouble for an organism than a stern factory supervisor.

Cells have an elaborate system in place to ensure their protein-folding resources are always prepared to meet demand. That system is so influential that it can make life-or-death decisions for cells, and its impact on cell survival has been implicated in a variety of human diseases. Teasing out the precise effects of each component of this regulatory system is a daunting task, but could help researchers find new ways to intervene in disease. So, with a new Collaborative Innovation Award from HHMI, a team of scientists led by HHMI investigator Peter Walter is taking on the challenge.

It's an opportunity to do science the way it should be done but rarely is. This initiative offers a huge opportunity to do science in a different way, in which each person's success drives the whole project.

Peter Walter

Cells rely on a continuous supply of signaling proteins to monitor their environment and communicate with other cells. They manufacture these proteins by first stringing together linear chains of building blocks called amino acids, then sending the chains to the endoplasmic reticulum, a processing center where enzymes and molecular chaperones mold each new protein into its characteristic shape. When the demand for new proteins increases and the cell's protein factories churn out too many amino acid chains, these workers can struggle to keep up, leaving many proteins folded sloppily or not at all.

Fortunately, unlike Lucy and Ethel, the protein-folding team has help. When a cell senses that unfolded or misfolded proteins are accumulating, it ramps up production of protein-folding equipment to meet the increased demand. At the same time, it slows the production of new proteins. It even employs Lucy's strategy—gobbling up some of the misfolded proteins to reduce strain on the system.

This coordinated effort to guard against the chaos that can be caused by misshapen proteins is called the unfolded protein response. The goal of the response is to protect not just cells, but the entire organism—so when its initial tactics fail to restore order, it tells the cell to kill itself to protect its neighbors. The system influences cell survival so strongly that it has been implicated in a variety of disorders, including diabetes, cancer, neurodegeneration, some forms of blindness, and viral infection.

Howard Hughes Medical Institute investigator Peter Walter discovered the unfolded protein response in yeast in 1994. He suspects that by manipulating the response—which comprises three intersecting signaling pathways—researchers may be able to intervene in disease. “But,” he says, “this is an evolutionarily ancient signaling pathway, so if we mess around with it, there could be all sorts of unanticipated consequences. At this time, we need proof of principle that we can manipulate the unfolded protein response, and show that it doesn't harm organisms if we tweak it this way or that. So we need to develop ways and tools by which to do that.”

Walter, who has received a Collaborative Innovation Award from HHMI, will team with Frank McCormick, HHMI investigator Kevan Shokat, Marc Shuman, and James Wells, all at the University of California, San Francisco, and Sebastián Bernales, who is at the Fundación Ciencia para la Vida in Santiago, Chile, to develop those tools. The group will work together to amass a collection of drug-like molecules that they and other researchers can use to enhance or dampen each branch of the unfolded protein response in predictable ways. Then they plan to use those tools to test whether the unfolded protein response can be exploited to kill cancer cells.

They plan to approach the problem using both a broad, unbiased screen of small molecules, as well as a more targeted search of molecules that, due to their structure, are expected to interfere with specific signaling proteins. They expect these strategies will turn up new ways to alter the system's abilities to sense unfolded proteins, to promote cell survival, and to trigger cell death. “We will screen for small molecules that affect all three branches, and then we will sort out how specific their effects are,” Walter explains. “Each branch of the unfolded protein response uses mechanisms that are unique in the cell, and this is wonderful for developing small molecules. If we can find something that exploits that uniqueness, it may not bind to other things,” thereby reducing the risks of unintended consequences.

“We now know the machines that transmit the signals of the unfolded protein response, and we're collaborating with a fantastic chemist, Kevan Shokat, to develop specific small molecules that fit into the nooks and crannies in those machines,” Walter says. Shokat has already created an extensive collection of molecules expected to alter the activity of IRE1, an enzyme that promotes cellular survival as unfolded proteins begin to accumulate. Correlating those molecules' effects on IRE1 to their chemical structures will help the team understand exactly what is needed to manipulate that branch of the response. Bernales, a former member of the Walter lab, will lead the efforts to screen existing and newly synthesized molecules from his lab in Chile. New structural data on IRE1 from the Walter lab will help guide this aspect of the study.

“Our other approach, with Jim Wells, is completely unbiased,” Walter says. Wells directs the Small Molecule Discovery Center at UCSF, and is an expert in developing and executing high-throughput assays to identify molecules that modulate cellular processes. Drawing on the Walter lab's understanding of the intricacies of the unfolded protein response, Wells will design and carry out assays to test a vast library of small molecules for their effects on each of the three signaling pathways. “It's an unbiased screen of a couple hundred thousand compounds,” Walter says. “We'll see what we get.”

To ensure that the team focuses its efforts toward potential clinical benefits, they have recruited Shuman, a physician-scientist who is fluent in both the medical and research languages and cultures. Shuman, an oncologist, will coordinate the project's basic research with its translational components, which will focus initially on multiple myeloma, a blood cancer caused by the accumulation of abnormal plasma cells.

When plasma cells turn cancerous, the unfolded protein response is thought to play a key role in allowing the cells to survive in the face of an elevated level of misshapen proteins. “They require the unfolded protein response for their survival, so if we block it, we may be able to take away their growth advantage,” says Walter. McCormick, who is the director of the UCSF Comprehensive Cancer Center, has considerable experience and success in transitioning basic research findings into the development of new cancer drugs, and will lead the group in designing experiments to test how effectively their drug-like molecules thwart the growth of cancer cells and deciphering the genetic abnormalities that drive those tumor cells.

“There's a lot of potential, but all of it is a pipe dream until we can actually test it,” Walter says. “The idea is to bring this research to the stage where it looks so believable that companies become convinced that it's a validated drug target.” He says that he and his collaborators have meddled in components of the project already, but the Collaborative Innovation Award from HHMI has given the team “wonderful momentum.”

Monthly videoconferences will ensure the continued exchange of ideas between the collaborators in San Francisco and Chile, and Walter is optimistic that a close and energetic collaboration over the next four years will allow the team to accomplish its goals.

“It's an opportunity to do science the way it should be done but rarely is,” Walter says. “A lot of success in science is measured by individual progress and the contributions of individuals, and it tends to make people think in their own little silo. This initiative offers a huge opportunity to do science in a different way, in which each person's success drives the whole project.”

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