Hijacking how neurons of nematode worms are wired is the first step in an approach that could revolutionise our understanding of brains and consciousness

Now with extra connections (Image: Heiti Paves/Alamy)

CALL it the first brain hack. The humble nematode worm has had its neural connections hot-wired, changing the way it responds to salt and smells.

As well as offering a way to create souped-up organisms, changing neural connectivity could one day allow us to treat brain damage in people by rerouting signals around damaged neurons. What’s more, it offers a different approach to probing brain mysteries such as how consciousness arises from wiring patterns – much like exploring the function of an electronic circuit by plugging and unplugging cables.

In our attempts to understand the brain, a lot of attention is given to neurons. A technique known as optogenetics, for example, lets researchers study the function of individual neurons by genetically altering them so they can be turned on and off by a light switch. But looking at the brain’s connections is as important as watching the activity of neurons.


Higher cognitive functions, such as an awareness of our place in the world, do not spring from a specific area, says Fani Deligianni at University College London. Deligianni and her colleagues are developing imaging techniques to map the brain’s connections, as are other groups around the world (see “Start with a worm…“). “From this we can begin to answer some of the big questions about the workings of the brain and consciousness which seem to depend on connectivity,” she says.

Tracing how the brain is wired is a great first step but to find out how this linking pattern produces a particular behaviour we need to be able to see how changing these links affects brain function. This is what a team led by William Schafer at the MRC Laboratory of Molecular Biology in Cambridge, UK, is attempting.

In both vertebrate and invertebrate nervous systems, neurons are connected to each other by chemical or electrical synapses. Chemical synapses are formed from hundreds of different types of protein, but electrical synapses are far simpler. They are gap junctions – channels between neighbouring neurons made by just one kind of protein. If two adjacent neurons produce that protein, they join up, forming a synapse through which electrical signals can flow.

Schafer’s team injected DNA that codes for their protein into the gonads of Caenorhabditis elegans nematode worms. When the next generation hatched, some worms expressed the new genes, giving rise to extra neural connections (see “A connection is made”). To ensure the introduced protein didn’t interact with other parts of the neuron, the team used the mouse version of the gene rather than the nematode’s usual invertebrate version.

To test their technique, the team inserted a connection between two unconnected neurons involved in the worms’ response to salt. In normal worms, salt increases the electrical activity in one neuron and decreases it in the other. But connecting them up synchronised the responses. “If one went up, the other did too,” says team member Ithai Rabinowitch at the Fred Hutchinson Cancer Research Centre in Seattle. As a result, rewired worms were far less sensitive to changes in salt concentration.

End of odours

Next, the team added an electrical synapse between two neurons normally joined by a chemical link. Rather than inserting a new connection, this was now editing an existing one. This second pair of neurons helps to control a worm’s sense of smell. Adding an extra electrical connection reversed the chemical signal. “It completely abolished the ability of the worm to track the odours,” says Rabinowitch (Nature Communications, doi.org/ts2.)

Mark Cunningham at Newcastle University, UK, is excited by the work. “It could have tremendous impact for our understanding of electrical synapses in the central nervous system,” he says.

The approach complements other brain-probing techniques, like optogenetics, says Schafer. Eventually, he says, it might be possible to extend optogenetics to synapses and use light to open and close connections, giving precise control over timing as well as location. “That would be a very powerful tool,” says Schafer.

So far the team has only added connections to C. elegans nematodes, which have just a few hundred neurons spread through the length of their body, rather than a centralised brain. In theory, though, the approach could be adapted for more complex organisms. There is evidence in frogs that gap junctions can be created in vertebrates using invertebrate proteins.

For now, though, we can learn a lot about ourselves from even the simplest brains. The cellular machinery underlying connections is strikingly similar, says Rabinowitch. The C. elegans circuit for smell that the team looked at, for example, shares features with brain circuits for eyes in more complex animals. “There are some incredible parallels,” he says.

Studying synapses in this way could bring crucial insights, says Cunningham. He thinks that over-powered electrical synapses may have a role in conditions like epilepsy. Tinkering with the brain’s connectivity in a mouse model, say, could help identify what the problem is. “We could play around with introducing new gap junctions into the system and see if it induces an epileptic state,” says Cunningham.

Rabinowitch thinks the work could ultimately open up new ways to treat brain damage, by creating neural bypasses that miss out the damaged neurons. Other researchers are looking at ways to do this by implanting electrodes, but a genetic approach would allow brain cells to grow their own alternative route. “You can envisage a time when someone who has had a stroke goes to a clinic and is given a pill to reconnect damaged parts of their brain,” he says. “It’s science fiction but you’ve got to start thinking about it.”

You can envisage someone who has had a stroke being given a pill to reconnect the damaged brain areas

One day, editing synaptic connections may even let us add to an organism’s capabilities, says Rabinowitch. Instead of training animals, we might grow them with specially designed brain circuits. For example, it might be possible to create C. elegans worms that protect fields of crops from disease by seeking out harmful bacteria.

“I view C. elegans as a kind of live prototyping tool,” says Rabinowitch. New connections for desired behaviour can be computer simulated and then tested.

Start with a worm… What can we learn from a worm? There are huge differences between the simple nervous system of the Caenorhabditis elegans nematode worm – with its 302 neurons and 7000 neural connections – and the network of 85 billion neurons and 100 trillion connections in a human brain. But at a basic cellular level, signals are sent and received in strikingly similar ways. C. elegans is well understood. Its connectome – the trace of its nervous system – was first mapped in 1986 and more comprehensive versions have been published since. Such blueprints allowed researchers to introduce extra brain connections in the worm (see main story). The nematode isn’t the only organism getting laid bare. The recently published Allen Mouse Brain Connectivity Atlas traces connectivity between 500,000 tiny cubes of brain tissue each containing up to 500 neurons. The Mouse Connectome Project aims to go a step further and build a 3D atlas of the mouse’s 75 million individual neurons. And people are, of course, studying the human brain. In 2011, Martijn van den Heuvel of the University Medical Center in Utrecht, the Netherlands, and his colleagues unveiled a map of the connections between different brain regions. They found that 12 areas of the brain had significantly busier pathways within and between them than all the others. The Human Connectome Project is also creating a map of our neural networks, again focusing on pathways between brain regions. The maps will get ever more detailed as imaging technology progresses. But we don’t have to wait for a complete blueprint to make medical leaps. In complex brains, neurons seem to act together. To see a noticeable effect, it might be possible to just modify a busy pathway of neurons rather than an individual connection.

This article appeared in print under the headline “The great brain hack”