Scientists have long known that the human immune system has a method for detecting and destroying precancerous cells. But finding the cells behind this defense mechanism in order to study and perhaps even mimic them has proved quite the challenge. Since the malignant precancerous cells are eradicated before we even know they exist, identifying the cells that killed them seemed nearly impossible. Now European researchers have built a microfluidic biosensor that traps single immune cells together with single tumor cells, allowing the researchers to pick the most potent of these cancer killers out of a crowded field.
The project, called Cell On CHIp bioSEnsor (COCHISE), was initiated by microsystems engineer Roberto Guerrieri at the University of Bologna, Italy. Guerrieri noticed that immunologists had no way to identify and isolate those rare immune cells, or lymphocytes, with antitumor properties–only about one in every 1,000 immune cells has such properties.
Together with postdoctoral researcher Massimo Bocchi, Guerrieri created a microfluidics platform with an array of 1,536 microwells. In each well, electric fields force contact between a fluorescently labeled tumor cell and a labeled immune cell. An automated system then scans the array and detects wells in which the tumor cell’s color has disappeared, thereby identifying the lymphocytes that are likely most effective against the leukemia and lymphoma cancers they tested.
The researchers then collect the individual cells that have triumphed over the tumor cells andprovide them to immunologists for study and propagation. “Analyzing a cell we know is active is a large step for research, because you can correlate expression of cytokines or gene expression,” Bocchi says. “You can then identify genetic properties that are probably responsible for the cell being active against the tumor.” He notes that this could one day be used to find new drugs to fight the disease.
Guerrieri and his colleagues are also working to clone entire cell lines from these single, potent lymphocytes. They plan to see if the resulting daughter cells maintain the same anticancer properties. If so, such an approach could be useful for developing cancer vaccines based on a transplant of a patient’s own lymphocytes, the researchers say.
As far as the biosensor is concerned, “the design itself is not really new,” says Luke Lee, director of the Biomolecular Nanotechnology Center at the University of California at Berkeley. Others have developed similar designs, although Lee notes that none are as user-friendly as the COCHISE system. Unlike the other devices, Lee says, the biosensor devised by Guerrieri and Bocchi and their collaborators offers a way to cleanly deliver cells to the chip and manipulate them. “Most demonstrations aren’t as clean as this,” he says.
“It seems like an interesting technology,” says Yale University hematology-oncology specialist Madhav Dhodapkar. Despite the technology’s promise, however, he notes that problems can arise when tumor cells are removed from the environment that surrounds them inside the body. “We should not lose track of the complexity of cancer,” Dhodapkar says. “A tumor cell separated from its microenvironment does not have the same biology, so studying interactions by taking cells out of their microenvironment has caveats.”
Dhodapkar still believes the technology holds great promise for immunologists, cell biologists, and other researchers. “I think the biggest advantage of this technology may very well be that it will allow an opportunity to ask really detailed questions of cell-to-cell interactions that otherwise are much harder to do,” he says. “If it pans out, it could be a very useful tool. Not just for cancer but for many other platforms.”
That’s precisely what Bocchi is hoping. “When we completed the project, we observed that the tool wasn’t just for immunology but a more general platform that could run a large number of applications,” he says. Among other uses, he points to gene therapy and even the study of microalgae–one of the great biofuel hopes.
In 2006, just as COCHISE was getting off the ground, Bocchi started a company called MindSeeds to develop and commercialize the technology. Before it can go much further, the company still needs to find ways to scale up the technology–its automated platform currently examines only one cell at a time–and to standardize the technology so that every experiment can be repeated to yield the same results. “Because we’re not bound to a specific type of cell, we can potentially address several markets, and several fields,” Bocchi says.