[extropy-chat] switching gene expressions old article from 2000
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Tue Feb 3 02:30:21 UTC 2004
First Genetic Toggle Switch Engineered At Boston University
20 Jan 2000
On/Off switch holds promise for biotechnology, biocomputing, and gene therapy
(Boston, Mass.) - The first-ever "genetic toggle switch," designed to control the activity of genes, was recently engineered by scientists at Boston University's Center for BioDynamics (CBD) and Department of Biomedical Engineering. Working with the bacteria Escherichia coli, the researchers were able to successfully switch the expression of genes between stable on and off states by applying a brief chemical or temperature stimulus. The work is reported in the January 20 issue of Nature.
"Regulatory circuits that are stable in both the on and off positions exist naturally in some very specialized genetic systems," says James J. Collins, director of CBD and co-author, "but this is the first time anyone has been able to create a synthetic bistable on/off switch to control the expression of a gene - a switch that can be generalized to a variety of genes in many different organisms, including human cells."
The toggle also represents the core technology for additional genetic control devices. "Minor modifications to the toggle can be made to produce a genetic sensor with an adjustable threshold - a system in which genes are activated or repressed when a specific threshold is reached," notes Timothy S. Gardner, a Ph.D. candidate in biomedical engineering and lead author of the study. "This type of sensor would be useful in controlling diabetes, for example, by automatically activating the synthesis of insulin when blood glucose reaches a particular level." Such a system also has potential applications in the detection of biological warfare agents - turning the body's own cells into sensors that alert the individual to the presence of dangerous substances, and even triggering the production of an antidote.
Moreover, the toggle switch itself can function as an artificial cellular memory unit, the basis of cell-based computing. "Since Richard Feynman's visionary suggestion, in 1959, of engineering submicroscopic devices, the concept of nanoscale robotics has sparked researchers' imaginations," says Gardner. "In recent years, this possibility has frequently been identified with microelectromechanical devices. We suggest that nanoscale robotics may take on a 'wetter' form, namely, a living cell. Ultimately, we envision the combination of genetic toggles, genetic sensors, sequential expression networks, and other devices into a 'Genetic Applet' - a self-contained and fully programmable genetic network for the control of cell function."
Week of 28 January 2000
Vol. III, No. 21
BU scientists design on-off switch for genes
By Hope Green
A team of scientists at Boston University's Center for BioDynamics (CBD) and ENG's department of biomedical engineering have created the world's first "genetic toggle switch," a mechanism designed to control gene activity.
Timothy Gardner (ENG'00), a doctoral candidate in biomedical engineering and lead author of the study, demonstrated the procedure in a BU laboratory using genetic material from a common bacterium, Escherichia coli. With its ability to regulate the timing of gene expression -- the process in which genes manufacture proteins and RNA -- the technology has potential applications for treating a variety of diseases. The switch ultimately could function as an artificial cellular memory unit, turning living cells into microscopic computers.
"This is the first time anyone has been able to create a synthetic bistable on/off switch to control the expression of a gene -- a switch that can be generalized to a variety of genes in many different organisms, including humans," says James Collins, University Professor, ENG professor of biomedical engineering, and codirector of CBD. Collins is a coauthor of the study, which was reported in the January 20 issue of Nature.
Current gene-therapy technologies involve a therapeutic gene placed in a cell in a nonexpressive, or off, state. To flip the gene on and keep it on, a drug must be administered in a constant flow. "It would be as if you had to keep pressing your finger on a light switch in order to keep the light on," Collins explains. The problem with such therapies is that a continuous stream of drugs can have side effects for the patient. "What we did with our system is essentially construct the equivalent of the type of light switch we have in our offices," he says. "With just a brief delivery of a drug, you can flip the gene on. Likewise, you can deliver another chemical burst to switch it off."
Gardner built the toggle switch by stacking two repressor and two promoter genes from the bacterium in a unique setup that allowed only one of the promoter genes to be active at a given moment. He inserted a jellyfish gene that glowed fluorescent green to signal when the switch was turned on by the application of a synthetic chemical. "We have these two promoter genes linked together, each trying to shut the other off," Collins explains. "The system is bistable: we set it up so that one gene always wins." Techniques from the toggle experiment could become the foundation of more complex genetic-control devices. These include a genetic sensor that could, in a diabetes patient, enable a cell to detect when blood glucose reaches a critical threshold and automatically activate the production of insulin. For now, however, the team is developing a sensor that could respond to high blood glucose by changing a patch of skin a different color, warning the patient to take an insulin shot.
Such a system also has potential applications in the detection of biological warfare agents, turning the cells into sensors that alert the individual to the presence of dangerous substances, and even triggering the production of an antidote.
Ultimately, Gardner and Collins envision the combination of genetic toggles, genetic sensors, and other devices into a "genetic applet," a genetic network implanted in a patient that could be programmed to control cell function.
Gardner, who received his bachelor's degree in mechanical engineering from Princeton, has been collaborating on the research project for 14 months with Collins and Charles Cantor, ENG professor of biomedical engineering and director of BU's Center for Advanced Biotechnology.
After completing his Ph.D. requirements this spring, Gardner hopes to work in a postdoctoral position on the West Coast. In any case, he plans to maintain his connection with BU. The research team is applying for patents on the toggle-switch technology, and is mulling the prospect of launching a company.
"Tim is going to be a real academic superstar," Collins predicts. "My group was fortunate to get him."
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