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Bacteria have been genetically engineered to enter and live inside mouse immune cells, where they released proteins that altered the behaviour of those cells. The work is a first step towards creating 鈥渁rtificial endosymbionts鈥� that could live inside some human body cells and do everything from guiding the regeneration of damaged tissues to treating cancer.

鈥淭hat鈥檚 the vision in the long run,鈥� says at Michigan State University.

Several other groups are also developing artificial endosymbionts, which they say could allow us to make crops and farm animals more productive, and could treat age-related conditions.

The idea of creating artificial endosymbionts used to be regarded as fanciful, says at the University of Western Ontario in Canada, but due to the huge advances in our ability to engineer organisms in recent years, it is starting to be seen as feasible.

鈥淭his is going to be one of the biggest things in the very near future,鈥� he says. 鈥淚鈥檝e seen huge interest in the last five years or so.鈥�

Most organisms depend on the microbes living on or in them 鈥� the microbiome 鈥� but sometimes the relationship is even more intimate. Some bacteria live inside the cells of plants or animals in a mutually beneficial relationship called endosymbiosis.

Endosymbionts can give organisms abilities vital for their survival. The energy-producing structures in all animal and plant cells evolved from endosymbiotic bacteria, as did the photosynthetic structures in all plant cells.

To create a new endosymbiont from scratch, Contag鈥檚 team started with a bacterium called Bacillus subtilis, found in our guts among other places. 鈥淚t鈥檚 a normal microbiome bacterium,鈥� says team member Cody Madsen, also at Michigan State University.

The researchers engineered it to produce mammalian proteins that alter the activity of genes and thus control what mammalian cells do.

To get the bacteria inside mouse cells, Contag and Madsen and their colleagues relied on the fact that some animal cells can engulf bacteria via a process called phagocytosis. Normally, engulfed bacteria remain trapped in membrane-bound sacs where they are digested. But the engineered B. subtilis strain secretes a protein that enables it to break out of these sacs.

The researchers added the engineered bacteria to mouse immune cells known as macrophages growing in a dish. They managed to get the bacteria into 99 per cent of cells. They also showed that the mammalian proteins the bacteria had been engineered to produce altered the behaviour of the macrophages.

What the team has yet to achieve is getting the bacteria to live in harmony with their new hosts. After two days, 10 per cent of the macrophages were killed by the bacteria inside them, which divided and reproduced too fast.

The next step, says Madsen, is to add a genetic circuit that will ensure the bacteria divide only when the host cell divides.

The team also plans to engineer the bacteria so they can be controlled once they are inside an animal, by making them respond to specific chemicals or magnetic fields. The advantage of using magnetism is that it would give localised control.

鈥淵ou could make the cells that have these endosymbionts into stem cells, and then flip another switch and turn that stem cell into another cell type,鈥� says Contag.

Such switches could also be used to kill off the bacteria if necessary, says Madsen.

It is amazing the team managed to get the bacteria into such a high proportion of cells, say Karas. But achieving this in the body, and in other cell types, will be much more difficult, he says, and getting long-term survival is obviously crucial.

鈥淚鈥檓 not convinced that engineered endosymbionts would necessarily offer advantages beyond less complex approaches,鈥� says , a stem cell expert at the University of Sydney. 鈥淭he regulatory hurdles and ethical challenges are probably even greater than the technical ones.鈥�

There are many other ways to control gene activity in mammalian cells, says at the Swinburne University of Technology in Australia. 鈥淭he most immediate application [of artificial endosymbionts] could be in agriculture,鈥� he says.

For instance, plants such as beans don鈥檛 need nitrogen fertilisers because they can capture nitrogen directly from the atmosphere with the help of bacteria growing on their roots. Karas鈥檚 team is trying to give other crops this ability by turning the nitrogen-fixing bacteria into endosymbionts.

This could have enormous benefits, as nitrogen fertilisers are a large source of greenhouse gases as well as a major pollutant of rivers and seas.

In principle, artificial endosymbionts could be used to give animals some extraordinary abilities. Sumer says his team had begun experiments to see if mammalian cells could be made to photosynthesise before the pandemic interrupted the work.

Reference: bioRxiv,聽