Imagine if you could take an ant and make it as big as an elephant. You would see every detail of its body, every nuance, every movement. Now, bring this idea to the microscopic world. A team of scientists has managed to do something similar with bacteria: they magnified a thousand times. It's not magic, but an ingenious technique that combines advanced microscopy and polymer chemistry. The result? An unprecedented view of the bacterial world, capable of revealing hidden secrets about their behavior, their resistance to antibiotics and their survival strategies. Prepare yourself for an incredible journey into the kingdom of "giant" bacteria (it would be better to say magnified, but so it is) where the infinitely small finally becomes visible.
The challenge of seeing the invisible
How do bacteria, those tiny organisms that inhabit and surround us, coordinate their activities? How do they interact with each other and with their environment? These are fundamental questions for understanding both beneficial and harmful bacteria, responsible for infectious diseases. A recent study, published in the prestigious journal Science (I link it here), has opened new perspectives in this field, thanks to a technique that allows bacteria to be visualized in a completely new way.
Jeffrey Moffitt, PhD, and his colleagues at Program in Cellular and Molecular Medicine (PCMM) al Boston Children's Hospital, they used a molecular imaging technique called MERFISH, developed in part by Moffitt himself. This technique allows the analysis of messenger RNA (mRNA) within thousands of individual bacteria simultaneously. A true genetic census on a microscopic scale, which allows to map gene expression in a massive way and to reveal how spatial factors influence the activation of bacterial genes. A result never achieved before.
“Giant” Bacteria: Overcoming the Limits of Traditional Microscopy
There was one obstacle to overcome on the way to this mega-magnification: bacterial RNA, or bacterial transcriptome, is incredibly dense and compressed inside tiny cells. Think of it as a tangled ball of yarn in a shoebox. Visualizing it with traditional microscopes was nearly impossible. “It was a complete disaster, we couldn’t see anything,” he says. Moffitt.
The solution came by borrowing a technique developed in the laboratory of Ed Boyden, PhD, at MIT: the expansion microscopy. The researchers embedded the bacterial samples in a special hydrogel, anchoring the RNA to this gel-like structure. Then, they changed the chemical buffer in the gel, triggering an expansion process. The result? The sample swelled, increasing its volume by 50-1000 times. “All the bacterial RNA became individually resolvable,” he explains. Moffitt. As if the tangled ball of yarn had magically unraveled, revealing each individual thread.
What bacterial gene expression reveals
Until now, scientists could only study bacterial behavior “on average,” analyzing entire populations of bacteria. But this new ability to determine which genes are turned on in single bacteria opens up new perspectives. We can finally understand bacterial interactions at the individual level, reveal the mechanisms of virulence, study responses to stress, understand how bacteria develop resistance to antibiotics and how they form biofilms, those complex bacterial communities that form, for example, on catheters.
“We now have the tools to answer fascinating questions about host-microbe and microbe-microbe interactions,” he enthuses. Moffitt. “We can explore how bacteria communicate and compete for spatial niches, define the structure of microbial communities and study how pathogenic bacteria modify their gene expression when they infect mammalian cells.”
MERFISH bacterial microscopy also allows us to study bacteria that are difficult to grow in the laboratory. “Now we no longer have to grow them, we can simply image them in their natural environment,” he emphasizes. Moffitt. A huge advantage, considering that most existing bacteria cannot be cultivated with traditional techniques.
Survival Strategies Revealed by “Giant Bacteria”
To demonstrate the potential of the technique, the team of Moffitt conducted several experiments. For example, they managed to demonstrate that the individual bacteria E. coli, when deprived of glucose, try to use alternative food sources one after another, modifying their gene expression in a specific sequence. By analyzing a series of genomic “snapshots” over time, researchers were able to reconstruct this survival strategy. It’s a bit like watching an engine switch from one fuel to another to keep running.
The team also gained insight into how bacteria organize their RNA inside cells, which could be crucial in regulating gene expression. Finally, they showed that gut bacteria activate different genes depending on their physical location in the colon. A real genetic “postal code”, which varies depending on the micro-environment in which the bacteria are found.
A new era for bacterial research
“The same bacteria can do very different things in a space of tens of microns,” he concludes. Moffitt. “They see different environments and respond differently to them. It was very difficult to deal with that variation before, but now we can answer the kinds of questions that people dreamed of being able to ask.”
Thanks to expansive microscopy, a new era for bacterial research is opening up. Not only will we be able to study these microorganisms in unprecedented detail, but we will also be able to address fundamental questions about life, health, and the environment, with new weapons and new perspectives. A microscopic future, but with gigantic implications.
