Traditional Chinese Medicine (TCM) is a traditional medical system originating in China with a history of thousands of years. It is not only a crystallization of wisdom accumulated by ancient Chinese people in their long-term struggle against diseases, but also has become a unique and important part of the world's medical treasure trove. Different from Western medicine, TCM features unique diagnostic methods such as pulse diagnosis, as well as special treatment approaches including Chinese herbal medicine, acupuncture and tuina (Chinese therapeutic massage). For thousands of years, TCM has always accompanied the health and well-being of the Chinese people. From addressing daily ailments to preventing and controlling large-scale diseases, it has continuously accumulated experience and improved itself, forming a set of diagnostic and therapeutic logic that conforms to human body laws and the natural environment. To this day, it still plays an important role in safeguarding people's health.
In the diagnostic and therapeutic logic of TCM, "syndrome differentiation and treatment" is the core concept. The essence of "syndrome differentiation and treatment" lies in "treating diseases based on each individual's specific condition". During the diagnosis and treatment process, TCM practitioners usually judge the root cause of the disease and uncover the internal factors behind the superficial symptoms based on the information obtained from inquiry (interviewing the patient about symptoms, medical history, etc.) and pulse diagnosis. In this way, they can truly achieve "treating each person differently and formulating a personalized prescription for each patient", rather than using a uniform plan to deal with all similar symptoms.
Pulse diagnosis is a crucial way for TCM to "read" the health signals of the human body, and it is a prerequisite for "syndrome differentiation and treatment". TCM holds that the pulse of the human body is closely related to the functions of internal organs and the circulation of qi and blood, serving as a built-in "health signal device" of the body. When conducting pulse diagnosis, the practitioner first asks the patient to relax their arm and place it flat with the palm facing up. Then, the practitioner gently presses the artery on the inner side of the patient's wrist, near the thumb, with the index finger, middle finger and ring finger. During the pressing process, the practitioner adjusts the pressure of their fingers to carefully perceive the details of the pulse, focusing on three core dimensions: the "depth" (how deep the pulse can be felt under the skin), "speed" (heart rate) and "strength" (force of the pulse beat) of the pulse. Based on the obtained pulse information, TCM practitioners judge a person's physical condition and then carry out diagnosis and treatment.
Just as humans fall ill due to wind-cold invasion or internal accumulation of dampness-heat, microorganisms—such as the yeast we study—also face plights like scorching high temperatures, hyperosmotic shock, and oxidative damage in industrial environments, falling into a state of metabolic disorder and functional imbalance. Yet this "imbalance" never leaves no traces: it manifests as unique "vital signals" of yeast cells—possibly rhythmic fluctuations in the expression of key proteins, or ups and downs in the concentration of metabolites. These dynamic traces hidden in the microscopic world are the "pulse" of microorganisms.
Following this line of thinking, an interesting idea naturally emerges: Can we build an exclusive "cellular pulse" system for yeast, allowing us to decipher its "status code" just as Traditional Chinese Medicine (TCM) practitioners diagnose human pulses?
The core of "diagnosing microbes’ pulses" lies in truly treating microorganisms as "living individuals": It doesn’t need to "speak"—we only need to capture its "pulse" (those subtle physiological signals) to accurately tell if it’s in a comfortable state or under stress; we no longer have to adjust culture conditions through "blind trial and error"—we just follow the clues from the "pulse" to optimize the environment in a targeted way, enabling yeast to efficiently complete production tasks while reducing stress-induced damage. More importantly, this idea essentially extends the ancient TCM wisdom of "respecting life and dynamically balancing" to the microscopic world of microorganisms—it transforms the "cooperation" between humans and microorganisms from the cold dynamic of "controlling and being controlled" to a gentler one of "perceiving and adapting," ultimately achieving the dual goal of efficiency and care for life.
It is because yeast cell factories and the biomanufacturing they represent hold vast prospects and can generate enormous economic benefits.
Biomanufacturing refers to the use of biological systems comprising enzymes or living cells to convert renewable resources into chemicals, pesticides, nutraceuticals, pharmaceuticals, fuels, or other high-value-added products. Recognized by the OECD as the most promising technology for sustainable industrial development due to its low-carbon, recyclable, green, and safe characteristics, the biomanufacturing industry has already reached a significant scale and boasts a bright future. The bio-based chemicals market was valued at approximately $74.85 billion in 2024 and is projected to grow to around $165.41 billion by 2032, reaching an astounding $30 trillion in economic value by the end of the century. Within this grand landscape, Saccharomyces cerevisiae, a microorganism used by humans for over 6,000 years, has evolved into a large-scale sustainable production platform combining scalability, sustainability, cost-effectiveness, and high-yield potential, aided by synthetic biology tools.
In the diagnostic and therapeutic logic of TCM, "syndrome differentiation and treatment" is the core concept. The essence of "syndrome differentiation and treatment" lies in "treating diseases based on each individual's specific condition". During the diagnosis and treatment process, TCM practitioners usually judge the root cause of the disease and uncover the internal factors behind the superficial symptoms based on the information obtained from inquiry (interviewing the patient about symptoms, medical history, etc.) and pulse diagnosis. In this way, they can truly achieve "treating each person differently and formulating a personalized prescription for each patient", rather than using a uniform plan to deal with all similar symptoms.
It is precisely this immense scale and potential that highlights the urgent necessity to "take the pulse" of yeast. Currently, while we can design sophisticated yeast cell factories, we lack a real-time window into their physiological state under industrial stress. Therefore, it is imperative to translate the philosophy of TCM pulse diagnosis into an engineering paradigm. By continuously monitoring the cellular "pulse," we can shift from indirect inference to directly interpreting the cells' "vital signals." This precision approach, akin to TCM's "syndrome differentiation and treatment," ensures the cells remain in a harmonious and efficient state, thereby maximizing yield, ensuring stability, and reducing waste.
There’re still many problems to solve. Among them, some physical constraints, such as high temperature and high osmotic pressure, have been strongly influencing bioproduction at scale. Large-scale bioreactors can exacerbate expression stochasticity due to the improper physical conditions and the cellular deleterious states caused by them, like oxidative stress. They may lead to suboptimal production and potentially harmful mutations.
Given the above challenges, maintaining optimal operating conditions is crucial in yeast cell factory to maximize product yield and ensure process stability. This typically demands advanced monitoring systems and energy-intensive control infrastructure with a considerable expenditure. Against the backdrop of ongoing climate change and sustainable development initiatives, biomanufacturing engineering must also strive to achieve reduced energy consumption, a lower carbon footprint, and minimized environmental pollution.
The implementation of engineered stress-tolerant yeast strains offers substantial economic benefits by mitigating operational risks and reducing control costs. These strains help avoid economic losses by minimizing process failures such as viability loss which typically incur losses of 10%-30% of annual cost.
Furthermore, the expanded operating windows allow for the use of simpler and more cost-effective control systems. Calculations indicate that for every 5°C increase in the fermentation culture temperature, water consumption is reduced by 15%. Based on the fundamental thermodynamic principle that the energy required for media sterilization is directly proportional to the temperature difference between the initial media and the sterilization temperature（121℃ for instance), raising the fermentation temperature from 30°C to 35°C reduces the required ΔT from 91°C to 86°C. This 5.5% reduction in the thermal load translates directly to a 5.5% saving in steam consumption. When it comes to electricity, it is supposed that every 5°C increase can reduce electricity consumption for cooling by 1.728 million kWh in an enterprise with an annual output of 10,000 tons of fermentation products.
Taking Ningxia Yipin Bio as an example—an annual producer of 2,500 tons of yeast products—expanding the operational temperature window by 5°C leads to substantial resource conservation, resulting in yearly savings of 423,000 kWh of electricity (a 5.32% reduction) , 1,485 tons(a 5.5% reduction) of steam and 37,594 cubic meters of freshwater (a 15% reduction). Based on industrial utility rates in Ningxia, where electricity costs ¥0.65 per kWh, steam ¥190 per ton, and freshwater ¥2 per cubic meter, these reductions yield significant economic benefits. The total annual cost savings amount to ¥632,288. This improvement highlights how operational flexibility, supported by regional energy policies, can enhance both economic and environmental performance in industrial bioprocessing.
Given the above challenges, maintaining optimal operating conditions is crucial in yeast cell factory to maximize product yield and ensure process stability. This typically demands advanced monitoring systems and energy-intensive control infrastructure with a considerable expenditure. Against the backdrop of ongoing climate change and sustainable development initiatives, biomanufacturing engineering must also strive to achieve reduced energy consumption, a lower carbon footprint, and minimized environmental pollution.
The implementation of engineered stress-tolerant yeast strains offers substantial economic benefits by mitigating operational risks and reducing control costs. These strains help avoid economic losses by minimizing process failures such as viability loss which typically incur losses of 10%-30% of annual cost.
Furthermore, the expanded operating windows allow for the use of simpler and more cost-effective control systems. Calculations indicate that for every 5°C increase in the fermentation culture temperature, water consumption is reduced by 15%. Based on the fundamental thermodynamic principle that the energy required for media sterilization is directly proportional to the temperature difference between the initial media and the sterilization temperature（121℃ for instance), raising the fermentation temperature from 30°C to 35°C reduces the required ΔT from 91°C to 86°C. This 5.5% reduction in the thermal load translates directly to a 5.5% saving in steam consumption. When it comes to electricity, it is supposed that every 5°C increase can reduce electricity consumption for cooling by 1.728 million kWh in an enterprise with an annual output of 10,000 tons of fermentation products.
Taking Ningxia Yipin Bio as an example—an annual producer of 2,500 tons of yeast products—expanding the operational temperature window by 5°C leads to substantial resource conservation, resulting in yearly savings of 423,000 kWh of electricity (a 5.32% reduction) , 1,485 tons(a 5.5% reduction) of steam and 37,594 cubic meters of freshwater (a 15% reduction). Based on industrial utility rates in Ningxia, where electricity costs ¥0.65 per kWh, steam ¥190 per ton, and freshwater ¥2 per cubic meter, these reductions yield significant economic benefits. The total annual cost savings amount to ¥632,288. This improvement highlights how operational flexibility, supported by regional energy policies, can enhance both economic and environmental performance in industrial bioprocessing.
Drawing extensively on TCM theory, we coupled a classic ternary oscillator with three regulatory genes that counter different types of stress, thereby creating a yeast-based ternary oscillator scheme for stress resistance.
The core of this scheme is to enable yeasts to possess "monitorable" stress resistance. Specifically, by leveraging the ternary oscillator, we maintain the steady state among the protein concentrations in yeast cells, aligning with the TCM principle of ‘balance’.
Second, every single engineered yeast of ours can achieve simultaneous resistance to three stressors with lower energy consumption and faster response, reflecting the TCM concept of ‘pattern-based treatment (bianzheng shizhi)’.
Last but not least, the yeasts’ output stress-resistance state can be used to characterize its ‘pulse’, enabling better adjustment of the environment and thereby supporting their growth and production.
