MRI: Development of a fully automated, 1,000-MicroChemostat microfluidic system for parallel, independent, long-duration, machine-guided experiments

An award is made to Vanderbilt University to develop Genesis, a fully automated microfluidic system containing 1,000 microchemostats for parallel, independent, long-duration, machine-guided experiments to study microbial cells. Microbes such as the baker’s and brewer’s yeast Saccharomyces cerevisiae are expected to play an ever-increasing role in the production of vaccines, cancer therapies and other pharmaceuticals, food protein, and feedstock for the chemical industry, and sequestration of carbon dioxide from the atmosphere, all areas of pressing societal need.

Genesis will use machine learning and artificial intelligence (AI) to serve as a “robot scientist” or “self-driving laboratory” to accelerate the development of mathematical models that describe microbial metabolism and growth. These will help us understand, and possibly optimize, for example, the interactions between the many different microbial species that comprise the human microbiome and contribute to both health and disease.

The ability of Genesis to create computational models of cellular signaling and metabolism on its own should advance medicine, biotechnology, and fundamental biological knowledge, since such models are required to optimize experiments and interpret data to reveal the rules that govern biological processes. The Genesis project will involve three established research and training programs at Vanderbilt, all of which are active in the recruitment and involvement of undergraduate and graduate students and postdoctoral trainees in their research projects.

Genesis offers a breadth of very attractive technical challenges and scientific and social opportunities ideal for interdisciplinary research training in AI, swarm robotics, machine learning, the exploration of signaling and metabolic pathways in microbes and suspended mammalian cells, and addressing how the complexity of biology could in fact be utilized to solve societal problems in nutrition, health, and medicine. Genesis will allow scientists and engineers and their trainees to address a number of important scientific, commercial, and societal problems by advancing our understanding of biology and disease and improving the efficiency of industrial production of biochemicals and pharmaceuticals.

Genesis also provides additional impact as a tool for classroom instruction, in that ultimately it will allow students to pose questions and ask Genesis to design and conduct the experiments needed to answer them. Genesis will be designed to be mass produced at low cost, so that small laboratories could afford a small-scale system.

In common use, yeast does its work in batches, where it grows and multiplies until it runs out of food or creates an environment where it can no longer thrive. A small batch of yeast grown in a research laboratory might require a milliliter of growth media in one well of a multi-well plate, whereas a yeast bioreactor at a pharmaceutical company could hold a few thousand liters, and one in a brewery a million liters.

As an alternative to batches, a continuous-flow bioreactor, termed a chemostat, provides a steady supply of food and continuously removes excess yeast or even suspended mammalian cells and their metabolites to maintain steady-state growth. There is a growing recognition that chemostats can provide reproducible, reliable, and biologically homogeneous datasets that are well suited for probing the metabolism and signaling of living cells.

However, the application of “self-driving” and machine-learning technologies to advancing biological knowledge will benefit from a thousand or more chemostats operating in parallel under computer control. Neither commercial production nor research chemostats have the correct combination of size, cost, and automated instrumentation. The Genesis system will address this need by using state-of-the-art, multi-channel microfluidic pumps and valves to control all of the microchemostats over a wide range of conditions with different strains of yeast, swarm robots to move 48 microchemostats at a time, and very high-throughput mass spectrometers to make a broad metabolic measurement every 10 or 15 seconds that will generate terabytes of data that exceed the ability of humans to control, process, and interpret.

The resulting computational models could have thousands of equations. Genesis will provide, for the first time, an efficient means to design and conduct the massive number of biological experiments needed to parameterize, validate, and utilize these models to probe and even control biological systems for specific applications. Projects that will be pursued as soon as Genesis is operational include basic research in cell signaling and metabolism, quantitative explorations of the metabolomic interactions of co-cultured bacterial species that together could produce protein for food and chemical feedstocks, tracking multiple, parallel evolutionary histories to determine which environmental and genetic factors are important for the evolution of microbial cooperation, and improved methods to use mammalian cells to produce therapeutic antibodies.

The parallel development of two Genesis instruments, one funded by NSF and the other by the Chalmers University of Technology in Gothenburg, Sweden, integrates Vanderbilt’s expertise in microfluidics and mass spectrometry with Chalmers’ expertise in AI, machine learning, and yeast to create a pair of robot scientists that will accelerate inquiries into the rules of life and the discovery of new solutions to some of society’s pressing problems.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.