Library of Genetic Circuits Developed For Scientific Functions
August 3, 2012

Library Of Genetic Circuits Developed For Scientific Functions

April Flowers for - Your Universe Online

For about a dozen years, synthetic biologists have been working on designing genetic circuits to perform novel functions such as manufacturing new drugs, producing fuel or even programming the suicide of cancer cells.

Many factors have to be controlled for this dream to become a reality. Scientists have to gain control over complex genetic and cellular components, including genes and the regulatory proteins, called transcription factors, that turn them on and off.

So far, most researchers use bacterium transcription factors to design their synthetic circuits. These don't always translate well to nonbacterial cells and can be a challenge to scale. This makes it harder to create complex circuits.

Timothy Lu, assistant professor of Electrical Engineering and Computer Science at MIT, and a group of colleagues from Boston University and Massachusetts General Hospital have come up with a new method to design transcription factors for nonbacterial cells (in this case, yeast cells). To overcome the current bottleneck that has limited synthetic biology so far, they have designed an initial library of 19 new transcription factors.

Published in the August 2 issue of the journal Cell, the project is touted as being part of a larger, ongoing effort to create genetic "parts" that can then be assembled into circuits to achieve specific functions.

“If you look at a parts registry, a lot of these parts come from a hodgepodge of different organisms. You put them together into your organism of choice and hope that it works,” says Lu.

The team got a much-needed boost to build this new library of "parts" from recent advances in designer proteins that bind DNA.

Transcription factors have a section that latches onto specific DNA sequences, called a promoter. The protein then uses an enzyme called RNA polymerase to start copying the gene into messenger RNA, the molecule that carries genetic instructions to the rest of the cell.

The DNA binding section consists of proteins called zinc fingers, which target different DNA sequences depending on their structure. The research team based their new zinc fingers designs on the structure of naturally occurring zinc finger proteins by modifying specific amino acids to target new sequences of DNA. These new zinc fingers were attached to existing activar segments, allowing them to create new combinations with varying strengths and specificity. They also designed transcription factors that work together, so that a gene can only be turned on if the factors bind to each other.

These new transcription factors should make it easier for synthetic biologists to design circuits for tasks such as sensing a cell's environmental conditions.

The team built some simple circuits in yeast, so far, but they plan to develop more complex circuits in the future.

“We didn´t build a massive 10- or 15-transcription factor circuit, but that´s something that we´re definitely planning to do down the road,” Lu says. “We want to see how far we can scale the type of circuits we can build out of this framework.”

Synthetic biology circuits can be analog or digital, just like electrical circuits. Digital circuits include logic functions such as AND and OR gates, which allow cells to make decisions while analog circuits are useful for sensors that take continuous measurements within a cell. By combining digital and analog circuits, researchers can design truly complex systems. For example, a digital decision could be triggered only when an analog sensor reaches a certain threshold.

The team is also planning to try their new transcription factors in other species of yeast, and eventually in mammalian cells, including human.

“What we´re really hoping at the end of the day is that yeast are a good launching pad for designing those circuits,” Lu says. “Working on mammalian cells is slower and more tedious, so if we can build verified circuits and parts in yeast and them import them over, that would be the ideal situation. But we haven´t proven that we can do that yet.”