Training cells to perform Boolean functions? It's logical

May 30, 2012

Johns Hopkins scientists have engineered cells that behave like AND and OR Boolean logic gates, producing an output based on one or more unique inputs. This feat, published in the May issue of Nature Chemical Biology, could eventually help researchers create computers that use cells as tiny circuits.

Study leader Takanari Inoue, Ph.D., an assistant professor in the Department of Cell Biology and member of the Institute of Basic Biomedical Sciences' Center for Cell Dynamics at the Johns Hopkins University School of Medicine, explains that many researchers are striving to mimic devices in everyday use by engineering new qualities into biological materials, including biomolecules and cells. Several of those engaged in this relatively new field, known as synthetic biology, have tried to create biological computers.

At the heart of both the biological and the more everyday silicon-based variety of computers are Boolean logic gates, which produce responses that vary depending on what type and how many inputs they receive. For example, AND gates need two unique inputs to generate an output. In contrast, OR gates generate an output based on whether they receive one input, or another, or both.

Inoue says that previous research has shown some success in generating logic gates based on biomolecules in test tubes or petri dishes. However, he adds, developing logic gates using whole cells has proven significantly trickier. Most previous efforts have taken advantage of cells' transcriptional machinery -- the cellular processes that read genes to create proteins -- to generate an output signal. But transcription can be a slow process, taking from minutes to days to produce the desired response.

"People like to have speedy computation," Inoue says. "We were hoping to achieve computation in cells on the order of seconds, which is significantly faster than what people have achieved thus far."

To accomplish their goal, the researchers used a technique called chemically inducible dimerization, or CID. This tool takes advantage of natural biological mechanisms that bring together two proteins into a complex in the presence of a chemical.

Since AND and OR gates generate a response based on two different inputs, either together or separately, the researchers needed two different CID systems that didn't compete or overlap with each other. They relied on one system that's been studied for years, which brings two proteins, called FRB and FKBP, together in the presence of a drug called rapamycin. Rapamycin comes from bacteria, and FRB and FKBP come from animals.

In addition, they used a second CID system that brings together two other proteins, known as GID1 and GAI, in the presence of a plant hormone called gibberellin. Since this system is native to plants, the gibberellin-based system doesn't compete with the rapamycin-based one, Inoue explains.

The researchers engineered mammalian cells that produce all four of the requisite proteins, as well as a response when the right two proteins came together. When either FRB and FKBP or GID1 and GAI linked up, the cell's membrane developed ruffles easily visible under a microscope.

To create the OR gate, FRB and GAI were bound together at the cell membrane, while FKBP and GID1 were bound together floating freely in the cell. Adding either rapamycin, gibberellin, or both to cells brought the freely floating complex to the one at the cellular membrane, linking up the matching proteins and triggering the output signal.

To create the AND gate, the researchers placed just GAI at the cell membrane, with just FRB and complexes of FKBP and GID1 free-floating in the cell. This system required all four proteins to link up to produce membrane ruffling, which wouldn't occur without both input chemicals.

Tests showed that each of the engineered cellular logic gates produced the desired response reliably, in a matter of seconds. Additionally, as a second proof of principle, the researchers generated similar logic gates that used fluorescence as an output, which worked just as well and quickly.

Eventually, Inoue notes, researchers might use similar cellular logic gates to build larger, more complex circuits that could form the basis for computers that use cells as basic units. In the meantime, these individual cellular circuits could be engineered to produce specific outputs in the presence of chemicals, making them useful detectors or diagnostic agents. He adds that researchers might also use synthetic logic gate systems like this one to study how cells naturally produce outputs to keep bodily functions running smoothly.
-end-
This study was supported in part by the National Institute of Health (NIH) GM092930, DK090868, NS072241, the National Science Foundation IOS-0641548 and MCB-0923723, and the National Center for Research Resources of the NIH and NIH Roadmap for Medical Research UL1 RR 025005.

Other researchers who participated in this study include Takafumi Miyamoto, Robert DeRose, Allison Suarez, Tasuku Ueno, Melinda Chen, Mi

For more information, go to:
http://www.hopkinsmedicine.org/pharmacology_molecular_sciences/faculty/bios/inoue.html
www.jhu.edu/inouelab
http://www.nature.com/nchembio/index.html

Johns Hopkins Medicine
Media Relations and Public Affairs
Media Contacts: Audrey Huang; 410-614-5105; audrey@jhmi.edu
Vanessa McMains; 410-502-9410; vmcmain1@jhmi.edu

Johns Hopkins Medicine

Related Proteins Articles from Brightsurf:

New understanding of how proteins operate
A ground-breaking discovery by Centenary Institute scientists has provided new understanding as to the nature of proteins and how they exist and operate in the human body.

Finding a handle to bag the right proteins
A method that lights up tags attached to selected proteins can help to purify the proteins from a mixed protein pool.

Designing vaccines from artificial proteins
EPFL scientists have developed a new computational approach to create artificial proteins, which showed promising results in vivo as functional vaccines.

New method to monitor Alzheimer's proteins
IBS-CINAP research team has reported a new method to identify the aggregation state of amyloid beta (Aβ) proteins in solution.

Composing new proteins with artificial intelligence
Scientists have long studied how to improve proteins or design new ones.

Hero proteins are here to save other proteins
Researchers at the University of Tokyo have discovered a new group of proteins, remarkable for their unusual shape and abilities to protect against protein clumps associated with neurodegenerative diseases in lab experiments.

Designer proteins
David Baker, Professor of Biochemistry at the University of Washington to speak at the AAAS 2020 session, 'Synthetic Biology: Digital Design of Living Systems.' Prof.

Gone fishin' -- for proteins
Casting lines into human cells to snag proteins, a team of Montreal researchers has solved a 20-year-old mystery of cell biology.

Coupled proteins
Researchers from Heidelberg University and Sendai University in Japan used new biotechnological methods to study how human cells react to and further process external signals.

Understanding the power of honey through its proteins
Honey is a culinary staple that can be found in kitchens around the world.

Read More: Proteins News and Proteins Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.