Tweaking Mother Nature, biologists aim for better cancer-fighting cells

The field called synthetic biology is all about improving on Mother Nature, creating components of living things that evolution hasn’t. In two studies published in Cell on Thursday, scientists reported doing just that: They synthesized new forms of a molecule that stretches from the inside of a cell to the outside. In so doing, they took a step toward improving on a new cancer therapy that is shaking up oncology.

More than any potential use in cancer treatment, however, the studies suggest that it’s possible to engineer a customized switch into a cell — able to recognize any molecule in the body and turn on any genes in response.

Cells might be able to sense molecules associated with injury and turn on genes that stimulate repair, for instance. Or they might sense molecules that scream “cancer” and activate genes that let the immune system kill tumor cells. Or they might even sense proteins that make up tiny, man-made scaffolds and fill them with bladder or liver or other specialized cells to create replacement organs.

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“It sounds like magic,” said Wendell Lim of the University of California, San Francisco, who led both studies. “But we think we can program cells to sense anything [in the body] and respond by activating any gene we choose.”

Lim and his team made new versions of the inside-to-outside protein molecule, they reported. Called Notch, it lets cells sense who their neighbors are and what the neighborhood is like. Each Notch molecule is a nano-version of a member of a bucket brigade, standing in a doorway with one arm stretching outside, grabbing buckets, and the other reaching inside, passing the buckets along. Notch (a “receptor,” in bio-speak) basically grabs onto molecules outside the cell and then reaches into the cell’s nucleus to turn particular genes on or off. That results in, for example, the formation of blood vessels and brain neurons.

Nature has made only four Notch molecules. Lim and his colleagues found that quite unimaginative.

They therefore created new Notches, with new outside-sensing parts and new gene-activating parts, in mouse cells. Some of the newly Notched cells sensed a molecule commonly found on the immune system’s B cells and glowed emerald like the brilliant green fluorescence in some ocean creatures. Other mouse cells with man-made Notch proteins sensed the same molecule but turned on genes that caused the cells to become muscle cells.

“We can engineer Notch to sense whatever [molecular] signal we want and hook it up to almost any gene we want to turn on,” said Lim. To repair damaged tissue, for instance, “you could engineer Notch to sense proteins released by the body as a result of injury and turn on genes in stem cells that cause them to differentiate into any cells you want,” perhaps those of damaged heart muscle or torn ligaments.

In principle, Lim said, scientists could engineer Notch to sense man-made molecules, including those in the scaffolds that researchers are using to build organs. “There are so many possibilities,” he said.

Scientists not involved in the new studies were impressed. Dr. Stephen Blacklow, a Notch expert and cancer biologist at Harvard Medical School, called the research “elegantly executed.” It shows that Notch “readily lends itself to molecular engineering as a synthetic detection and response system” and is a “conceptual advance over prior work” such as a 2015 paper from his own lab.

“No question the implications of the work are exciting,” Blacklow said, especially if lab-made Notches are as versatile as Lim hopes.

In the second study, the UCSF scientists created synthetic Notches for T cells, the immune system’s engulf-and-devour troops that are being used to destroy cancer cells, as this video shows. These cells have been somewhat successful against leukemia: Biologists have genetically engineered T cells to produce a molecule on their surface that recognizes and clutches targets on these cancerous cells.

Trouble is, some of those tumor targets are also on healthy cells, so the engineered T cells (called CAR Ts, for “chimeric antigen receptor” T cells) ravage healthy cells, too. In addition, scientists haven’t managed to make CAR T cells that devour solid tumors.

The UCSF scientists created T cells with both lab-made Notch and CAR receptors that sense molecules on cancer cells. Notch both recognizes a tumor-cell molecule and turns on genes that let the T cell recognize a second, different tumor-cell molecule. When they turned these engineered cells loose on tumors in mice, the scientists found that the cells devoured the tumors while sparing similar but healthy tissue.

Harnessing that finding to produce a cancer therapy is years away, but if even one of the uses for lab-made Notch pans out, it will show that synthetic biology really can improve on nature.

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