They’re the world’s smallest documentary makers. E. coli bacteria have had their DNA hacked so they can store memories of their cellular environment. And they do it in much the same way as an analogue tape recorder. Other more complicated cells should be capable of the feat too, which could pave the way for cellular biographers that can be inserted into our bodies for the inside scoop on our health.
E. coli may be one of the most widely used microbes in scientific research, but there are still aspects of its biology that are mysterious. “There are these DNA sequences called retrons that were discovered 30 years ago – but there’s still a lot of controversy over what they actually do,” says Timothy Lu at the Massachusetts Institute of Technology.
What we do know is that the retrons carry the genetic code for enzymes that generate new strands of DNA. These strands can then insert themselves into the cell’s genome. Lu and his MIT colleague Fahim Farzadfard realised that they could manipulate these retrons so that, when the E. coli is exposed to a particular chemical – or some other input like bright light – it inserts a new chunk of DNA into a specific site in the genome. That DNA chunk is then effectively a “memory” of the experience.
Each of the E. coli cells records a personal account of its experiences. That could be useful, but it’s when whole populations of cells record their experiences that the system becomes really powerful.
Lu and Farzadfard engineered the retrons to be only partially efficient, so that when a population of E. coli is exposed to an input, like a light signal, only a few cells will instantly record a memory of the event.
As time goes by, more of the cells will respond to the input and record the memory. By calculating at a certain point how many of the cells carry the memory, it’s possible to work out either the input’s strength, or the length of exposure.
“Imagine having 1000 humans all exposed to sunlight,” says Lu. “Some proportion will develop a mole on skin from over-exposure. With more exposure, an increasing number of people will develop the mole. So by counting the number of people with moles you can back-calculate how intense or how long the exposure was.”
Play back memories
“That’s the crux of it,” says Cameron Myhrvold at Harvard University’s Wyss Institute for Biologically Inspired Engineering, who was not involved in the research. “You can encode extra information because it’s a signal that accumulates over time rather than an all-or-nothing switch.” In other words, its analogue rather than digital.
“We think this is going to be very useful in monitoring applications,” says Lu. The retrons are known to function in animal cells, he says, so if some of our cells were engineered to record the conditions they are exposed to, they could later be extracted and their DNA sequenced to play back the memories.
That kind of cellular monitoring is already possible with some microscopy techniques, but Lu says that these techniques require researchers to keep a constant eye on the cells. With his method, cellular environments could be seeded with cells to remotely record events in much the same way that forests are wired up with camera traps to remotely track wildlife.
For example, modified gut cells could be used to track the progress of conditions like irritable bowel syndrome, or modified brain cells could help establish the nature of individual cellular connections within neural networks, says Lu.
In principle, the cellular system could be used to monitor the spread of disease, such as the growth and spread of cancers, perhaps by responding to the cellular signals generated by cancer cells, although Lu says additional development will be needed before that can be demonstrated.
Although an analogue system allows you to record more nuanced information, Myhrvold says that this is also a potential weakness. It means it works best when there is a large population of cellular recorders, so might not work so well for monitoring environments that contain relatively small numbers of cells to begin with, he says. That’s an important point, agrees Lu, and one he’s working on.
Myhrvold also says that retrons might mutate and malfunction in some more challenging cellular environments, which could compromise their ability to record cellular events. This is a problem that his Harvard colleague, Pamela Silver, addressed earlier this year by inserting a responsive genetic switch into E. coli that is so resistant to mutation that it is stable even in the hostile environment of the mammalian gut.