The holy grail of cancer drug targets is akin to a unicorn horn: a marker that only cancer cells have, clearly distinguishing them from healthy cells. In reality, nearly all cancer drug targets are also found on many healthy cells, leading to serious off-tumor toxicity that — in extreme scenarios — can be fatal.
Synthetic biologist Kobi Benenson might have a way around that. Inside an engineered virus, he and his colleagues at ETH Zurich packaged a programmable genetic circuit that uses multiple targets to build a profile of a cancer cell. Detailed in a mouse study recently published in Science, it’s a nanoscopic biological computer that roams through the body, executing a program that seeks to recognize and kill cells matching that cancer profile, but spares healthy cells that don’t fit all the criteria.
“[Simple drugs] are like trying to catch a criminal by saying ‘everyone who wears baggy pants is a criminal’ or something like that,” Benenson explained. “With this broad criterion, we’ll catch like 99% innocent people. One really has to really be narrowed down by combining multiple pieces of information. So, it’s the same in the disease.”
The biological computer is a genetic circuit with engineered molecular switches that can make simple computations, similar to the way silicon transistors at the core of smartphones and laptops carry out calculations. Benenson’s circuit has two major components — an “AND” function and a “NOT” function — so that the computer looks for cells that have a profile of two molecules common in cancer cells, but not a third that’s common only in healthy cells. That makes the computer more likely to accurately distinguish cancer cells from healthy ones.
Liquid biopsies could help screen for countless cancers. But who should get them?
“So, we have this if A and B but not C type of decision,” Benenson said. “That ultimately translates into activation or lack thereof of a therapeutic that can kill the cancer cell.”
The “AND” function is made of two molecular switches on the computer’s genetic circuit that bind to designated cancer targets. For those targets, Benenson’s team used one protein common in liver cancer cells and another protein common in liver cells in general. If the first switch binds to its protein, it sends a molecular signal to the second switch. If the second switch also binds to its protein, then the circuit forces the cell to create a new protein called HSV-TK. This combines with another compound, which must be separately injected, to kill the cell.
But healthy cells also carry these targets, so, the team had a third molecular switch on the circuit recognize a compound known as let-7c, which is common in healthy cells but not cancerous ones. If this switch binds to let-7c, then it triggers a process that shuts down the computer’s kill command, saving the cell from execution.
Scientists have been working on biomolecular computers for years, said Wilson Wong, a biomedical engineer at Boston University who wasn’t involved with the research. He called Benenson’s …….