Sep 16 : A team of Harvard Medical School researchers has successfully synthesized a DNA-based memory loop in yeast cells.

After constructing genes from random bits of DNA, the scientists in the lab of Professor Pamela Silver, a faculty member in the school’s Department of Systems Biology, reconstructed the dynamics of memory, and created a mathematical model that predicted how such a memory “device” might work.

The researchers say that their findings mark a significant step in forwarding the emerging field of synthetic biology.

“Synthetic biology is an incredibly exciting field, with more possibilities than many of us can imagine. While this proof-of-concept experiment is simply one step forward, we’ve established a foundational technology that just might set the standard of what we should expect in subsequent work,” said Prof. Silver, lead author of the paper.

Some researchers see synthetic biology as a means to boost the production of biotech products, such as proteins for pharmaceutical uses or other kinds of molecules for, say, environmental clean-up. Others see it as a means to creating computer platforms that may bypass many of the onerous stages of clinical trials.

Prof. Silver’s team decided to demonstrate that not only could they construct circuits out of genetic material, but that they could also develop mathematical models whose predictive abilities matched those of any electrical engineering system.

“That’s the litmus test, namely, building a biological device that does precisely what you predicted it would do,” said David Drubin, a postdoctoral scientist in Prof. Silver’s team.

The components of this memory loop were simple: two genes that coded for proteins called transcription factors. The researchers placed two of these newly synthesized, transcription factor-coding genes into a yeast cell, and then exposed the cell to galactose (a kind of sugar). The first gene, which was designed to switch on when exposed to galactose, created a transcription factor that grabbed on to, and thus activated, the second gene.

The second gene also created a transcription factor. But this transcription factor, like a boomerang, swung back around and bound to that same gene from which it had originated, reactivating it. This caused the gene to once again create that very same transcription factor, which once again looped back and reactivated the gene.

In other words, the second gene continually switched itself on via the very transcription factor it created when it was switched on.

The researchers then eliminated the galactose, causing the first synthetic gene, the one that had initiated this whole process, to shut off. Even with this gene gone, the feedback loop continued.

“Essentially what happened is that the cell remembered that it had been exposed to galactose, and continued to pass this memory on to its descendents. So after many cell divisions, the feedback loop remained intact without galactose or any other sort of molecular trigger,” said Caroline Ajo-Franklin, a scientist in Prof. Silver’s team.

The researchers are now working to scale-up the memory device into a larger, more complex circuit, one that can, for example, respond to DNA damage in cells.

“One day we’d like to have a comprehensive library of these so-called black boxes. In the same way you take a component off the shelf and plug it into a circuit and get a predicted reaction, that’s what we’d one day like to do in cells,” said Drubin.

The study will appear in the September 15 issue of the journal Genes and Development. (ANI)