The world of microbiology just got a whole lot hotter! Researchers at Harvard have developed a groundbreaking pico-calorimeter that can directly measure the heat traces of living cells, offering a new and incredibly sensitive way to detect antibiotic resistance. This device, which can track the metabolism of small populations of bacteria in real-time, is a game-changer for the field of biology and medicine.
A New Way to Measure Cellular Metabolism
For decades, biologists have relied on indirect methods to measure cellular metabolism, such as measuring oxygen consumption or chemical byproducts. But the Harvard team has taken a bold step forward by directly measuring heat, which is a more direct and sensitive indicator of cellular activity.
"Heat is a direct measure for cellular metabolism," says Joost Vlassak, the Abbott and James Lawrence Professor of Materials Engineering. "As the cells are going about their business, we see very nice exponential growth, depending on the media."
The device consists of three microscopic glass capillaries mounted on an extremely thin micromachined membrane. One capillary contains the biological sample in liquid growth medium, while the other two serve as references. As cells in the sample grow and consume nutrients, they release heat, creating minute temperature differences between the sample capillary and the references. A nearby thermopile, or heat-to-electricity converter, reads out the temperature differentials.
A Vacuum-Sealed, Microfluidic Design
The capillaries and sensors are housed inside a vacuum chamber to keep them thermally isolated. This design boosts sensitivity by an order of magnitude compared with earlier generations of the pico-calorimeter. The new vacuum-sealed, microfluidic design makes the sensors easier to operate and more robust.
Demonstrating the Device's Potential
To demonstrate the utility of the device, the team used the pico-calorimeter to track the growth of E. coli bacteria, starting with only 30-40 individual bacteria. They also demonstrated the potential of their device as an antibiotic resistance probe by exploring calorimetric signal changes that occur when antibiotics are added to a sample of bacteria.
A Tool for Sepsis Research
Another use case they envision is for sepsis, where sick patients might have only tens of bacteria per milliliter in their blood. Because of its high sensitivity, the pico-calorimeter could, in principle, monitor metabolic activity and drug response of similarly small bacterial populations in just a few hours, instead of waiting days for large colonies to form.
A New Era of Microcalorimetry
The new device builds on roughly two decades of work on micro- and pico-calorimetry in the Vlassak group. After joining the lab in 2016, Juanjuan Zheng initially developed nano-calorimetry systems for studying phase transformations in thin-film shape memory alloys and metallic glasses. Over time, she began to work on ultra-sensitive calorimetry methods for biological applications, including measurements of metabolic heat in large cells and developing embryos.
The Harvard Office of Technology Development has filed multiple patent applications on the device and its use in antimicrobial susceptibility testing. Zheng has co-founded a company out of the Vlassak lab to develop picocalorimetry-based tools that turn heat measurement into a practical, real-time, label-free functional readout for small biological samples, with potential applications in biological research, drug-response assays, and antimicrobial susceptibility testing.
This groundbreaking technology is a testament to the power of innovation and collaboration in science. It opens up a whole new world of possibilities for understanding and treating bacterial infections, and it's an exciting development for the field of microbiology.
