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Biomedicine

Teaching Bacteria to Behave

Single-celled organisms could be “trained” to deliver drugs.

A century after Pavlov’s dog first salivated at the sound of a bell, researchers are saying that single-celled organisms such as bacteria can be “trained” to react in a similar way. Rather than use complex networks of nerve cells, or neurons, bacteria can “learn” to associate one stimulus with another by employing molecular circuits, according to a multidisciplinary team from Germany, Holland, and the United Kingdom.

This raises the possibility that bioengineers could teach old bacteria new tricks by having them act as sentinels for the human body, ready to spot and respond to signs of danger, the team says in the October issue of Journal of the Royal Society Interface (DOI: 10.1098/rsif.2008.0344). The basis for the claim is that single-celled organisms are able to associate stimuli that are applied simultaneously, according to the theoretical model produced by Chrisantha Fernando at the U.K.’s National Institute for Medical Research, in London, and his collaborators.

Bright bug: Chrisantha Fernando of the U.K.’s National Institute for Medical Research, in London, says that bacteria such as this E. coli can be trained through associative learning.

As with Pavlov’s dog and all other examples of associative learning, the bacteria in the model learn to build stronger associations between the two stimuli the more they occur together. The Canadian neuropsychologist Donald Hebb established an underlying explanation back in 1945. Now called Hebbian learning, it’s often expressed as a situation in which “neurons that fire together wire together.” In the hungry dog’s case, nerve cells triggered by the smell of food started to make physical links with the nerve cells simultaneously triggered by the sound of a bell. According to Hebb’s theory, the more often the two stimuli are applied at the same time, the greater the link or “synaptic weight” between them.

Bacteria, of course, don’t have synapses or nerve cells. Nonetheless, there are indications that single-celled organisms can learn. In the 1970s, Todd Hennessey claimed that paramecia, the single-celled pond dweller, could be conditioned in the lab. He electrocuted them and associated this with a buzzer. Following the simultaneous exposure to the buzzer and to electric currents, he claimed that the paramecia swam away from the buzzer when they had not done so before. The finding was never properly reproduced, but it raised the intriguing possibility that some sort of associated learning was possible for single-cell life forms.

Now Fernando’s team has proposed a model for how bacteria might be trained. He has designed a cellular circuit that consists of several genes and their promoters, which produce proteins (transcription factors) that act to switch each other on and off like a digital electric circuit. The researchers’ theoretical circuit consists of three fictional genes. Two of these genes, A and B, produce proteins pA and pB, which react with other transcription factors, iA and iB, to switch on the third gene, C.

The gene products pA and pB would persist in the cell and therefore act as a memory that lasts for a long time once they have been produced. Their concentrations are the equivalents of the synaptic weights in the Pavlovian-dog model. Only in conjunction with these molecules can iA and iB (the analogs of the smell and the bell) have their effects. By the researchers pairing the iA and iB, the bacteria is able to respond to iB, whereas before it only responded to iA. This means that the bacterium has been “trained” to respond to iB, says Fernando.

Eva Jablonka, a theoretical biologist at Tel-Aviv University and a leading researcher in the field, agrees. “This is conceptually a bit difficult,” she says, “but if you look at the definition of learning–because of something happening, you have some kind of physical traces, and this changes the threshold of the response in the future–then this is what you have here.” She adds, “I think that it is a good and potentially very useful paper, and I think they do demonstrate associative learning.”

The model is based on the assumption that such a chemical-genetic circuit could be created and planted into a bacterium such as E. coli. “It seems to me quite possible at the theoretical level, and I don’t see great obvious hurdles for the construction of the suggested vectors,” says Jablonka, who published a paper on conditioning in single-celled organisms this month.

Significantly, Fernando estimates that the changes induced in the bacteria could easily persist for the 30-minute life cycle of an E. coli bacterium. This would make the changes, or “learning,” heritable. This is an especially important point when it comes to medical applications for trained bacterium. “After all, diseases or drug doses are going to last longer than 30 minutes,” notes Jablonka.

The trick would be to train bacteria to recognize chemical processes in the body that are associated with danger. This might be an adverse and dangerous reaction to a drug, or to the presence of tumor cells, indicating that a medicine in the system needs to be activated in certain tissues.

Research on genetically engineering remote-controlled bacteria to release drugs is already under way. In 2005, for example, a team from the National Institutes of Health proposed genetically engineering naturally occurring bacteria to release antiviral treatments for HIV. The realization that such bacteria might be trained to do this work more effectively could bring a whole new dimension to the field.

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