CLICK HERE: Pamela Silver explains how her lab constructed their synthetic memory loop. The yeast cell culture is on the left. The red dye indicates the synthesis of the first transcription factor; the green dye indicates the second. Image: COURTESY OF PAMELA SILVER LAB
A genetic feedback loop installed in a yeast cell, the first of these circuits to be built in a eukaryotic cell—one with membrane-bound structures, such as a nucleus—may allow scientists to construct cells that can remember when they've been exposed to certain signals, a development that could one day halt the spread of cancer and better assess environmental damage.
Such a project—involving new gene construction, a predictive behavioral model, and the synthesis of their desired functions—is a major step forward for the fledgling field of synthetic biology, which seeks to better understand and co-opt the machinery of cells.
"Synthetic biology is a new area that's really exciting to young scientists—to have things begin to work in this way is a sort of validation of the field," says Pamela Silver, a professor of systems biology at Harvard University Medical School and co-author of a study demonstrating one of the first synthetic restructurings of a eukaryotic cell that is described in the journal Genes & Development. "Even though these are sort of demonstration experiments" (indicating that the technology is feasible), "they can be carried over into applications."
Among the possible applications, says Silver, would be tinkering with cells so that they can be used to assess the severity of an environmental incident, such as an oil spill, when they activate synthesized genes that respond to the presence of certain chemical. They could also be jerry-rigged to recognize and quantify the amount of DNA damage they have sustained—a development that would be helpful in preventing and combating diseases such as cancer.
Silver and her team constructed two new genes that would code for two artificial proteins designed to behave as transcription factors (proteins that control the amount of other proteins that a particular gene can make.) The genes for each transcription factor were made from different bits of DNA that code for the functional parts of proteins, such as a domain that can bind to DNA and another that provides the protein with access to the cell's nucleus.
In a nutshell, the researchers set up a system in which the yeast cell would activate the first of the implanted genes and its corresponding transcription factor (tasked with switching on the second gene) when exposed to the sugar galactose. The second gene would then manufacture its corresponding transcription factor, which was designed to bind to and ratchet up the activity of the same gene that created it.
This created a closed loop that did little to affect the normal life of the cell. Because of the looping effect that the second transcription factor had on its own gene, the second transcription factor continued to be manufactured even when galactose was eliminated from the cells' environment (thus shutting off the activity of the first gene). Silver says that this effectively sustains the memory of galactose exposure.
"Think of it as you expose the cells to something and then you take it away, but they remember that they saw it," she says. "Imagine going forward [that] you might want to build a cell that not only told you it was exposed to something but it could tell you how much or when." Silver says her lab will try to build such a cell that they can then implant into mammals to detect and report on the extent of harm caused by UV radiation, which damages DNA and is a risk factor in the development of cancer.