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U-M launches ambitious exploration of inner space

A path-breaking collaborative effort of U-M researchers will attempt to capture never-before-seen views of the chemical activity inside living cells in real time and 3-D.

A U-M research team is using nanoprobes studded with molecules that bind to ions like zinc, calcium or potassium to reveal the patterns of ion exchange that make the cell function. The probes are injected into a cell and computer models are used to interpret the signals probes emit when they have captured a target ion. In this artist’s conception, the sensors are targeting ions on the surface of mitochondria. (Illustration by Christopher Burke)

The three-year project brings together public health, engineering, chemistry, biology, physics and statistics with support from a $1.5 million grant from the W.M. Keck Foundation in Los Angeles. The University has committed an additional $500,000 to the project.

The U-M team will use synthetic nanoprobes small enough to fit inside a cell without interrupting its normal functions to measure the activity of crucial metal ions like zinc and copper as the cell works. Sophisticated statistical modeling programs will be used to interpret data that looks something like a swarm of fast-moving fruit flies zinging around a bowl of fruit.

Trafficking metal ions in and out of the cell is crucial to basic functions such as muscle contraction and the nervous system. But science has been unable to measure this dynamic process in real time.

"We're creating a seamless connection between analytical chemistry, experimental cell biology and these mathematical models," says project co-leader Martin Philbert, associate professor of toxicology in the School of Public Health. "For the first time, we have a real shot at looking at the function of these low-abundance metal ions which we know are so critical for cell function."

The study will look for patterns in the motion of ions to determine when and how individual molecules in the swarm might trigger the cell to act in a certain way at a particular time. Biochemists in the group will provide proteins that bind specifically to zinc and copper ions to help the nanoprobes do their work.

"In this project, the biochemists are the device guys and we engineers are the hypothesis-testers," says Ann Marie Sastry, the project co-leader, and associate professor of mechanical and biomedical engineering. "It's usually the other way around."

"The key is to model the experiment beforehand to design a probe that won't be too aggressive about capturing ions, or too passive," Sastry says. "The simulations are also used to figure how and where to deliver the probes to the cell. A supercomputer crunches through millions of different scenarios to help the scientists later determine which actions were random, and which had meaning."

The nanoprobes that will help make these measurements were developed by Philbert and Raoul Kopelman, the Kasimir Fajans Collegiate Professor of Chemistry, Physics and Applied Physics. They can be made from a variety of synthetic materials, including plastics, and tailored for a variety of uses, including exploding on cue as a smart-bomb against individual cancer cells. Kopelman and Philbert call them PEBBLEs, or Probes Encapsulated By Biologically Localized Embedding.

To get some sense of how small these probes are, if the cell were the size of a football stadium, the PEBBLE would be about the size of an offensive lineman. So it and thousands of its colleagues are able to move around without disturbing the cell too much.

In a test of the modeling software, Sastry's group simulated zinc binding with parameters provided by U-M biochemist Carol Fierke, professor of chemistry and a charter faculty member of the Life Sciences Institute, and found that significant noise results from rapid binding and unbinding of zinc ions within the cell. "We showed that the intracellular zinc concentrations are probably higher than previously thought, by analyzing this 'noise'," Sastry says, "but we need to track the actions of individual atoms to be certain."

Zinc ions are among the targets of this study because they are known to be important players in many neurological diseases and conditions, including Alzheimer's and brain injuries, but they are notoriously difficult to measure. Fierke estimates that the understanding of zinc signals is about 20 years behind what we know about calcium signals. "In the zinc field, we are just beginning to learn how to think about the complexity of ion exchange," Fierke says.

Dennis Thiele, professor of biological chemistry, also will provide the project with a complete catalog of the proteins he has discovered that bind copper.

Each of the technologies being applied to this project has developed a pretty good track record on its own. But by bringing them together in a new way, this approach to cell-by-cell diagnostics should be able to see healthy and diseased cells in action and determine how they operate differently from one another.

"The applications for this kind of technology are going to be as wild as the imagination of the people we are training in our labs," Philbert says.

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