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Team spirit

Working together, bacteria and other microbes can accomplish much more than they can alone. Now scientists hope to harness that ability by engineering their own microbial consortia.

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2:47pm, January 2, 2009
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Bacteria aren’t loners. In fact, they are quite social: These single-celled creatures band together to form sophisticated communities. They can even call out to each other to congregate, conspire and coordinate. Highly developed communication skills allow them to orchestrate small acts of cooperation and tackle big jobs as a unified force. For life’s tiniest players, living and working is a team sport.

Researchers now want to join in the game — and change the rules. Synthetic biologists are working to find ways to manipulate entire microbe communities to get them to do things they ordinarily wouldn’t — like tracking down cancer cells to deliver drugs, fighting antibiotic-resistant infections or manufacturing fuel. By tweaking the genes that direct bacterial communication, or introducing new genes into the microbes, scientists are creating microbial fantasy teams to perform jobs that natural populations simply cannot do.

To be sure, engineering bacteria isn’t new. Scientists have been putting genes into bacteria and other cells for decades. Genetic engineers already know how to hijack microbes’ biosynthetic machinery to produce single proteins, or to generate whole pathways of cellular reactions such as those used to make human insulin.

But now scientists want to program entire ecosystems — made up of multiple species — to carry out specific tasks. Such reprogrammed consortia of bacteria could be used in medicine, environmental cleanup and biocomputing.

“Many of the things we now dream about doing in synthetic biology — from making new sources of energy to curing diseases or to producing chemicals — require multiple steps or processes,” says biochemical engineer Frances Arnold of the California Institute of Technology in Pasadena. “It becomes complicated to engineer all these properties into a single organism.”

So it may take multiple organisms working together to achieve these goals. Microbial communities are ideal because their high level of cooperation allows them to divide labor, share resources and mount attacks on invading species.

Once they are rooted in a community, bacteria act less like a collection of single-celled individuals and more like a microbial “superorganism,” Arnold says. “In the future, if you have a really complex task, it might be interesting to consider engineering a whole set of different organisms that have to work together to solve it.”

Microbial communities are everywhere. Although microbiologists have long focused on free-floating bacteria grown in laboratory cultures, most bacteria in the natural world settle down into structured communities. Most of these take the form of a biofilm, in which large clumps of bacteria adhere to each other in a goo-like slime. Biofilms will latch on to most any surface. They glom on to the hulls of boats and the surfaces of ponds and clog the walls of drains and pipes. They form infection-inducing films on implanted medical devices and cause deadly lung infections in cystic fibrosis patients.

But biofilms can be beneficial, and their knack for breaking things down allows them to take on some of the toughest tasks. In the human body, biofilms help digest food, metabolize drugs and manufacture vitamins. In nature, they release nutrients from the soil, converting them into a form that plants can use. Other naturally occurring biofilms are used to degrade contaminants in wastewater or remove toxins such as jet fuel from sites where spills have occurred.

“If you look at the really complex and interesting things that microbes do in nature, it’s almost always in the form of multiple populations, or a consortium,” Arnold says.

Like human groups, these natural communities vary in size and complexity. Some exist as a single biofilm or a group of adjacent biofilms; others consist of clumps of cells connected by the pores in soil. Some contain only a single species of bacteria while other, more diverse communities comprise multiple bacterial species and perhaps include other organisms, such as fungi and algae.

Microbial communities are so complex that they have yet to be reproduced in their full splendor in the lab. Yet, by studying simplified communities, scientists are getting a glimpse of bacteria’s elaborate social lives and are learning how to intercede, says Katie Brenner, a microbiologist in Arnold’s Caltech lab. Brenner and Arnold outlined efforts to design such communities in the September Trends in Biotechnology.

Ideally, a synthetic bioengineer would be able to choose from a number of organisms to design a community capable of getting the job done. At the moment, most labs are focusing on ways to engineer communities of bacteria made up of a single species because these systems are better characterized and easier to manipulate than multispecies groups. And bacteria’s well-studied system for communicating provides a way for scientists to steer the conversations among congregating microbes by changing the way they talk to each other.

Bac talk

Bacteria sense their neighbors and respond to the presence of others in the colony by exchanging small molecules and bits of proteins called peptides — a process known as quorum sensing. Through this exchange, bacteria send and receive chemical cues that turn genes off or on. This process enables many types of bacteria not only to communicate with their neighbors, but also to collaborate in intricate ways to divide labor and perform tasks requiring multiple steps. At first, quorum sensing, discovered in marine bacteria, seemed a special ability, but in the time since its discovery, scientists have racked up quite a list of chatty microbe species. In fact, some scientists believe that nearly all bacteria communicate in one form or another.

More important, quorum sensing offers an open channel that scientists can tap to steer bacteria’s small talk. In 2006, researchers at the University of California, Berkeley used quorum sensing to engineer a single population of bacteria capable of seeking out and treating cancer cells. When the bacteria entered an environment low on oxygen — such as within a tumor — they would start to release a toxic protein to kill the cancer cells, the researchers reported in the Journal of Molecular Biology.

The problem is that low-oxygen environments occur in other places in the human body where you wouldn’t want toxins, Brenner says. By creating a consortium made up of two or more populations, scientists may be able to better target the release of such substances, reducing the risk of harming healthy tissue. “Hypothetically, neither cell would be toxic alone, but somehow when they came together they would communicate and produce a toxic response,” she says.

In 2007, Brenner and Arnold developed the first consortium to use a two-way engineered communication system. While most bacteria use a class of small signaling molecules called acylated homoserine lactones, or AHLs, to “talk,” E. coli don’t. The team found a way to hijack the genes that control this chatter in other bacteria and put them into two distinct populations of E. coli grown together in a biofilm.

Each of the populations synthesized a communication molecule. One population manufactured one type of AHL molecule; the other population made a different AHL molecule. By detecting each other’s molecules, the two E. coli groups were able to yak back and forth, Brenner and colleagues reported in 2007 in the Proceedings of the National Academy of Sciences.

“It’s just like a conversation between two people,” Brenner says. “My voice is different from yours, so you can tell that I’m talking to you, and I can recognize your voice and know that it’s not me talking to myself, but it’s you talking to me.”

The forced conversation had consequences not known to follow from human dialog. When it received a communication from its partner, one E. coli population turned fluorescent green. When the other population picked up on the message, it fluoresced red. The experiment illustrated, in bright detail, the scientists’ ability to manipulate microbes’ communication and behavior within a biofilm.

This stripped-down version of a natural system could serve as a mock-up for more complicated systems and help scientists navigate the obstacles posed by genetically engineering closely linked networks of bacterial populations.

“There’s a real challenge associated with making stable genetic changes to bacteria, or to any microorganism, let alone a community,” Brenner says. “Even though we can put some changes in, we don’t know exactly how that will affect the dynamics of growth and reproduction in a microbial community.”

Synthetic communities may be fabricated in a lab, but there’s nothing unnatural about their inhabitants. These single-celled colonists are living organisms with their own quirks.

“When we build a synthetic system, we think we know what the major interactions are, because we build them in. But these are growing, complex organisms, and they’re responding to their environment,” Arnold says. “They’re growing and doubling and doing what they want to do at the same time as they’re doing what we force them to do.”

One thing microbes apparently don’t want to do is bend to the will of outsiders. Colonies of E. coli, for example, can, over time, “mutate out” the genetic changes introduced by scientist-saboteurs, presumably because those changes create an extra metabolic load.

“Bacteria don’t like to do what you tell them to do,” Brenner says. “It slows them down and gets in the way of their very efficient lifestyle.”

One way to reduce this metabolic burden is to find a way to divide the labor between two or more species, so that neither one is slowed down, says DukeUniversity bioengineer Lingchong You. In nature, microbes use this strategy to keep moving at warp speed, but it’s not yet possible to mimic in the lab. To do so, scientists must better understand the back-and-forth nature of talking and sharing that occurs in natural populations.

Culture conflict

Given that quorum sensing allows microbes to talk to one another, it’s not surprising that some organisms just can’t get along. In nature, strains vying for nutrients or other resources can reposition themselves to work alongside neighboring species without getting so close that competition becomes a problem. But when mixtures of species are stirred in a lab culture, they have to slug it out. In such cases, one species will often outcompete the others.

To see how man-made microbial populations keep each other in check, You and his colleagues from Caltech and StanfordUniversity rewrote the software of E. coli to form a mutually dependent system of predators and prey. In this case, the bacterial predators don’t actually eat the prey. Instead, the bacteria use quorum sensing to keep each other’s populations in check, turning each other’s suicide rates up or down, the team reported in the April 15 Molecular Systems Biology.

While his system is not an exact representation of real predator-prey relationships, You says it can serve as a tool to learn how genetic modifications play out to influence population changes. “This system is much like the natural world, where one species suffers from the growth of another species,” You says.

Crowding or space constraints can also be a source of conflict. Bacterial communities are not just a smear of slime: They are a complex structure of columns and channels designed to support community activities. In biofilms, water moves through channels to deliver nutrients and remove waste. Other communities, such as those found in soil and marine sediments, organize themselves by the distribution of species. Such structures enable the microbes to work as a group.

Finding ways to control a colony’s spatial structure is essential for culturing communities of microbes in the laboratory, says James Boedicker of the University of Chicago, who studies biological structures. “This helps both in terms of stabilizing the community and allowing the microbes to have interactions similar to those in natural settings.”

Recently, Boedicker and his colleagues showed how the spatial structure of a microbial community works to dictate the flow of nutrients, environmental signals and communications among its members. The study, published in the Nov. 25 Proceedings of the National Academy of Sciences, found that a stable community requires a particular variety of structures.

“Space influences all interactions between the microbes, both beneficial interactions … and harmful interactions such as toxin production and depletion of local nutrients,” Boedicker says. “Not just any spatial structure will be right for a given community.”

Biofilm versus biofilm

Studies of the highly organized interactions and structures within microbial communities may help scientists better understand how cells within a consortium act in concert. Such an understanding could spark new ideas about how to develop everything from medical materials to ship coatings that resist the buildup of harmful microbes, Brenner says.

Bacterial communities can be especially problematic in the human body. Biofilms stick to the surfaces of artificial hips, pacemakers and other medical devices, creating the potential for dangerous infections. Pseudomonas aeruginosa, another species that builds biofilms, causes respiratory tract infections that can be life threatening in people who have cystic fibrosis.

“Imagine engineering a biofilm that would essentially outcompete or smother the toxic biofilm that forms on the inside of the lung of cystic fibrosis patients,” Brenner says. “There are many ways you might go about trying to remove that biofilm, but using a consortium is a very realistic approach.”

Another potential application is to target the biofilms that cause life-threatening staph infections, such as the methicillin-resistant Staphylococcus aureus, or MRSA, a sometimes fatal strain immune to multiple antibiotics. The engineered biofilm would include bacteria capable of battling MRSA.

“There are bacteria in nature that can kill MRSA,” Brenner says. “Though these bacteria are usually toxic to humans, you could essentially commandeer the MRSA-fighting proteins out of the bacteria and install them under control of a circuit with checks and balances.”

Of course, the real world is never so simple. Most biofilm systems comprise multiple species of bacteria, including many organisms that are toxic to people. And applications such as new medical materials are years away. Still, Brenner says, the studies underway are a critical first step in re-creating and reprogramming the complex interactions in microbial communities. Understanding the chemical cues and signals within microbial communities may aid in developing planned communities that could settle down where needed and tell harmful bacteria to get lost. Very quietly.

Susan Gaidos is a science writer in Maine.

Citations


Brenner, K., et al. 2008. Engineering microbial consortia. Trends in Biotechnology 26(September):483-489.


Brenner, K.., et al. 2007. Engineered bidirectional communication mediates a consensus in a microbial biofilm consortium. Proceedings of the National Academy of Sciences 104(Oct. 30):17300–17304.


Balagadde, F.K. . . . and L. You. 2008. A synthetic Escherichia coli predator–prey ecosystem.” Molecular Systems Biology 4:187.


Kim, H.J., J.Q. Boedicker, et al. 2008. Defined spatial structure stabilizes a synthetic multispecies bacterial community. Proceedings of the National Academy of Sciences 105(Nov. 25):18188–18193.


Anderson, J.C., et al. 2006. Environmentally controlled invasion of cancer cells by engineered bacteria. Journal of Molecular Biology 355(Jan. 27):619–627.

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