DNA Mutation Can Have An Impact On Whether Or Not A Cell Starts Dividing Out Of Control

Cells permanently change their behavior in response to temporary changes to the environment, a kind of biological memory that controls processes as important and complex as how stem cells differentiate into specific tissues or how the immune system “remembers” dangerous pathogens. As many of the most interesting books on this topic point out, at its simplest, cellular memory is achieved with a positive feedback loop–once activated by some external signal, the feedback loop will continually activate itself, even as the cell divides and the signal is taken away. In synthetic biology we can recreate such simple feedback loops, genetic circuits built of parts that activate in response to signals and keep turning themselves on, remembering past chemical events. A few years ago a couple of scientists made such a synthetic genetic apparatus in yeast that recalls if the cells have been grown in media containing the sugar galactose.

They connected genetic elements that turn on when the cells taste galactose to a protein that fluoresces red and to a protein that activates the synthetic positive feedback loop. The positive feedback cycle in turn is made of a protein that fluoresces yellow and the protein that activates the loop, starting a permanent cycle of feedback. Through various videos on the web, as well as this list of interesting books on this matter, you can readily see the red protein turn on and then off again as the galactose is removed, but the yellow protein stays on in the population, even as the cells divide and grow. We don’t usually need to know whether or not cells have tasted galactose, but the parts of the synthetic circuit are modular, they can be swapped out and activated with different triggers to create larger networks of interconnected feedback loops to create more complicated behaviors, or to ask questions about cell biology.

In galactose each and every cell responded and galvanized the feedback loop, but in more natural conditions, for example in tissues in the body or in mixed populations of microorganisms in the situation, cellular reactions to signals are rarely uniform. When radiation or carcinogens damage cells’ DNA in a tissue, some cells may have more mutations and more strongly activate the cellular stress response to fix their DNA. (It’s this point that makes for the sole contention of various interesting books on this subject.) These different reactions to DNA impairment between varying cells show up even in populations of single-celled organisms and can have implications for how we understand cancer progression, where a cell’s response to DNA mutation can have an impact on whether or not that cell starts dividing out of control. Another researcher wanted to use synthetic memory to be able to track yeast cells that “remembered” having experienced significant DNA damage, to study how they are different from their neighbors that escaped with minimal mutations. She swapped out the genetic part that tastes galactose in the old yeast memory circuit to one that turns on when the cell’s DNA is mutated by radiation or chemical carcinogens, cutely and somewhat strangely named HUG1. When she poisoned the yeast cells that had the synthetic memory in place with EMS, a chemical that causes DNA mutations, she saw something very similar to the previous memory circuit. The red fluorescent protein (RFP) stayed on for a short time after the carcinogen was washed off of the cells, but the yellow protein (YFP) stayed on for several days after that, identifying cells that remembered the DNA damage and their offspring. This is already pretty cool, but the really interesting part of the story started when she started to study how the cells that remembered the damage were different from the ones that didn’t.