When living cells grow, divide, or respond to drugs, they emit tiny amounts of heat that provide information about what the cells are doing. However, these thermal signals are so small that they disappear, so it has traditionally been impossible to measure them directly.
Researchers at Harvard’s John A. Paulson School of Engineering and Applied Sciences (SEAS) have developed a calorimeter (a device that measures heat transfer between a biological system and its environment) that can detect metabolic heat signals on the order of 100 picowatts, or trillionths of a watt, inside living cells. This device is the most sensitive of any comparable biocalorimeter to date. A new “picocorimeter” can track the metabolism of small bacterial populations in real time, as well as monitor how bacterial growth changes in response to different antibiotics.
The research is from the lab of Jost Vlasak, the Abbott and James Lawrence Professor of Materials Science, and was conducted by Harvard University Associate Professor Huangfang Zheng, a former postdoctoral fellow in Vlasak’s lab. This study Proceedings of the National Academy of Sciences.
Measure heat directly from cells
Biologists can often measure cellular metabolism only through indirect calorimetry, such as measuring oxygen consumption or chemical byproducts. In contrast, SEAS devices measure heat itself.
Heat is a direct measure of cellular metabolism. As the cells behave normally, depending on the media, you’ll see some really nice exponential growth. ”
Joost Vlassak, John A. Paulson School of Engineering and Applied Sciences, Harvard University
The sensor consists of three microscopic glass capillaries attached to a very thin microfabricated membrane. One capillary contains the biological sample in liquid growth medium, and the other two serve as references. As the cells in the sample grow and consume nutrients, heat is released, creating a small temperature difference between the sample capillary and the reference. A nearby thermopile, or heat-to-electricity converter, reads the temperature difference.
The capillary and sensor are housed in a vacuum chamber and are thermally isolated. This design increases sensitivity by an order of magnitude compared to the previous generation of picocalorimeters developed by Vlassak and co-workers. Previous versions consisted of droplets on a floating membrane. The new vacuum-sealed microfluidic design makes the new sensor easier to operate and more robust.
Demonstration of bacterial growth
To demonstrate the usefulness of the device, the team used a picocalorimeter to track E. coli growth starting with just 30 to 40 bacteria.
They also demonstrated the potential of the device as an antibiotic resistance probe by investigating the change in colorimetric signal that occurs when an antibiotic is added to a bacterial sample. This paper reports measurements of E. coli growth in the presence of three drugs with different mechanisms of action: chloramphenicol, rifampicin, and ampicillin.
The research team showed how antibiotics change metabolic activity by comparing heat signatures with and without different concentrations of antibiotics. Because all measurements are direct, changes can be detected long before standard culture-based methods.
Another use case they envision is sepsis, where there may be only a few dozen bacteria per milliliter in a sick patient’s blood, Vlasak said. Due to the high sensitivity of picocorimeters, in principle the metabolic activity and drug response of similarly small bacterial populations can be monitored in just a few hours, without having to wait days for large colonies to form.
“The most exciting thing is seeing people from different types of research institutions ask questions about our device,” Zheng said. “Measuring dynamic information from small living systems is extremely difficult. Using this platform, we can begin to monitor cell viability, growth rates, proliferation, and drug responses in real time. More broadly, we can get early functional readouts of what biological systems are doing, such as whether they are growing, undergoing stress, responding to treatments, or changing metabolic state.”
20 years of picocalorimetry research
The new device builds on nearly 20 years of research in micro- and pico-calorimetry from the Vlassak group. After joining the lab in 2016, Zheng initially developed a nanocalorimetry system to study phase transformations in thin film shape memory alloys and metallic glasses. Over time, she began working on ultrasensitive calorimetry methods for biological applications, such as measuring metabolic heat in large cells and developing embryos.
Harvard University’s Office of Technology Development has filed multiple patents for this device and its use in antimicrobial susceptibility testing. Zheng co-founded a company out of Vrasak’s lab to develop a picocorimetry-based tool. This tool turns thermal measurements into practical, real-time, label-free functional readouts of small biological samples, with potential applications in biological research, drug response assays, and antimicrobial susceptibility testing. She is also an Activate Fellow, part of a prestigious fellowship program that supports deep technology founders whose scientific breakthroughs have real-world impact. Efforts to advance technology are also supported by the Harvard GRID Accelerator.
sauce:
Harvard University John A. Paulson School of Engineering and Applied Sciences
Reference magazines:
Henn, J. others. (2026) Picocalorimeter for cellular metabolism and antimicrobial susceptibility testing. Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2603171123. https://www.pnas.org/doi/10.1073/pnas.2603171123.
