Replacing a red lightbulb with a green one is to manipulating the underlying wiring // Turning one gene completely off is to creating dimmer switches for a number of genes // Creating a modified E. coli is to creating an E. coli that can count to three.
Ever since 1973, when a research team in California—led by Stanley Cohen at Stanford and Herbert Boyer at the University of California, San Francisco—introduced foreign DNA into a bacterium, thus creating the first genetically altered organism, scientists have been devising remarkable techniques in what came to be known as genetic engineering. From that beginning, an entire industry—biotechnology—has sprung, as has the promise, and often the reality, of lifesaving, paradigm-shifting therapies. But the work of genetic engineers, long at the forefront of biomedicine, has come to seem almost plodding to some scientists.
Genetic engineers typically work with just one gene, proceeding by trial and error in a process that’s as much art as science. And they use tools that haven’t changed much since the early days, when they learned how to snip a piece of DNA from one organism, such as a mouse, insert it into a virus or other “vector,” which delivers it into another organism—a worm, say—and then observe what happens. Or they alter a gene from a mouse to study that gene’s function—extrapolating by observing what occurs when the gene isn’t working. That capability alone has spawned generations of “knockout” animals (a gene’s function is “knocked out”) that are used to better understand the role of genes in disease and to test treatments.
But now, says James Collins, a bioengineer at Boston University, “many engineers don’t consider genetic engineering to be engineering. They view it more as, say, replacing a red lightbulb with a green lightbulb.”
Collins prefers to manipulate the underlying wiring, operating in the realm of synthetic biology, where researchers may add entire “circuits” of genes, often taken from several species, into a single organism. The genes in the circuit interact; one gene may turn another on or off, depending on the environment, and the second gene may then affect the third and so on. Or each gene may produce a protein needed to achieve a desired outcome—making a complex drug, for example. These gene circuits are often added to yeast or to the bacterium E. coli (which provides the energy and raw materials) to make those microorganisms perform complicated, prescribed functions—in a sense, as microscopic factories.
Almost 10 years ago, Collins wondered whether a simple cell could become a primitive computer. Computer code is based on the binary system, with every piece of information reduced to a series of zeros and ones. Attempting to create a similar on/off mode for E. coli, Collins came up with a kind of toggle switch, a pairing of genes, each of which produced a protein that turned the other gene off; they couldn’t both be on or off at the same time.
“The toggle switch is just a simple form of memory,” says Collins, who in 2004 reported that he had programmed E. coli cells using a similar toggle switch to “remember” events, such as DNA damage to the cells, using the toggle switch’s on/off positions, which work like a computer’s binary code. When radiation, for instance, strikes the DNA, the switch turns on one of the bacterium’s genes, and that causes the other gene to turn off permanently, thus committing the event to a cell’s binary memory even if there’s no more DNA damage for the life of the cell. What’s more, because the second gene Collins used also represses the action of a gene he added that produces green fluorescing protein, turning off the first gene enables GFP to turn on—and its green glow serves as a visual clue that the cell’s DNA has been harmed.
This sort of work could be useful for making bacteria respond to a change in their environment. For example, Collins linked the toggle switch to a gene that triggers the formation of a biofilm, a complex grouping of bacteria that protect the E. coli cells against further damage from the destructive agent that attacked their DNA. Other researchers are using synthetic biology to create cheap fuel from microbes, to eliminate the growing resistance of bacteria to antibiotics, and to build drug factories inside yeast cells, so they can replicate natural processes but at a fraction of the cost of typical drug production.