How a pioneering scientist is reprogramming microorganisms to build a sustainable bio-based economy
In an era of climate change and dwindling fossil fuels, the quest for sustainable alternatives has become one of humanity's most pressing challenges.
While renewable energy often captures headlines, a quieter revolution is brewing in laboratories worldwide—the transformation of microscopic organisms into tiny factories capable of producing everything from fuels to pharmaceuticals. At the forefront of this revolution stands Sang Yup Lee, a visionary scientist whose work in metabolic engineering is reshaping our relationship with biological systems.
Recently awarded the prestigious 2025 Gregory N. Stephanopoulos Award for Metabolic Engineering 3 4 , Lee's three decades of research demonstrate how we can harness nature's complexity without depleting its resources. His journey offers a fascinating glimpse into how biotechnology might ultimately wean society off its fossil fuel dependence and usher in a truly bio-based economy.
At its core, metabolic engineering is the practice of optimizing the genetic and regulatory processes within cells to produce valuable substances. The International Metabolic Engineering Society defines it as "the manipulation of metabolic pathways in microorganisms or cells to produce useful substances (such as pharmaceuticals, biofuels, and chemical products)" 3 .
Think of it as cellular reprogramming—taking the natural metabolic pathways that organisms use to grow and reproduce and redirecting those biochemical resources toward manufacturing specific compounds we need.
High temperatures, pressures, and hazardous materials required
Room temperature processes using renewable biological resources
Unlike traditional chemical manufacturing, which often requires high temperatures, pressures, and hazardous materials, metabolic engineering harnesses the power of biological systems that operate at room temperature using renewable resources. These microbial workhorses can transform simple sugars into complex chemicals with precision that often surpasses synthetic chemistry approaches.
The field represents a remarkable convergence of biology, engineering, and computational science—a fusion that Sang Yup Lee has mastered like few others.
Throughout his 31-year tenure at KAIST, Lee has pioneered what he terms "systems metabolic engineering"—a holistic approach that integrates systems biology, synthetic biology, and evolutionary engineering with traditional metabolic engineering 1 9 . This multidisciplinary framework allows researchers to approach cellular reprogramming with unprecedented sophistication.
"Systems metabolic engineering allows for the development of more competitive, high-performance microbial strains for the industrial production of chemicals, fuels and materials from renewable resources." — Sang Yup Lee 9
His approach isn't merely about making incremental tweaks to existing organisms but rather about fundamentally reimagining what microorganisms can do.
Perhaps most remarkably, Lee's team achieved what many thought impossible—developing a one-step fermentation process for producing polylactic acid (a biodegradable plastic) directly inside microorganisms 1 . This breakthrough exemplifies how metabolic engineering can simplify manufacturing processes that traditionally required multiple chemical steps.
A recent landmark study from Lee's laboratory, published in Nature Communications, demonstrates the power of his systematic approach 5 7 . The research team set out to solve a fundamental challenge in metabolic engineering: selecting the optimal microbial host for producing specific chemicals.
Lee's team conducted a comprehensive in silico analysis (using computer simulations) of five representative industrial microorganisms: Escherichia coli, Saccharomyces cerevisiae, Bacillus subtilis, Corynebacterium glutamicum, and Pseudomonas putida . They evaluated these microorganisms' capabilities for producing 235 different bio-based chemicals using genome-scale metabolic models (GEMs).
GEMs are mathematical representations of the metabolic networks within an organism based on its entire genome information. These models allow researchers to simulate and analyze metabolic fluxes—the flow of nutrients through biochemical pathways—that would be incredibly time-consuming and expensive to study through experimentation alone 5 .
The findings provided unprecedented clarity on which microorganisms excel at producing specific chemicals. The researchers discovered that for most chemicals, fewer than five heterologous reactions (reactions borrowed from other organisms) were needed to create functional biosynthetic pathways in host strains . This suggests that engineering microorganisms for chemical production may be more straightforward than previously assumed.
| Chemical | Primary Microbial Host | Yield (mol/mol glucose) | Key Application |
|---|---|---|---|
| L-lysine | S. cerevisiae | 0.8571 | Animal feed, nutrition |
| L-glutamate | C. glutamicum | 0.8182 | Food additive, neuroscience |
| Mevalonic acid | E. coli (engineered) | 1.2530 | Precursor to pharmaceuticals |
| Putrescine | S. cerevisiae | 0.7018 | Engineering plastics |
| Propanol | E. coli (engineered) | 0.6842 | Solvent, biofuel |
The study also revealed that yield decreases slightly with longer biosynthetic pathways (Spearman correlation: -0.3005 for Yₜ and -0.3032 for Yₐ), emphasizing the importance of pathway efficiency rather than just length .
Beyond simply selecting natural champions, the team proposed innovative strategies to enhance microbial capabilities:
Adding metabolic reactions from other organisms to expand biosynthetic capabilities
Swapping molecular helpers in metabolic reactions to improve efficiency
Identifying which enzyme reactions to up-regulate or down-regulate to maximize production
| Chemical | Base Yield | With Heterologous Reactions | With Cofactor Exchange | Combined Improvement |
|---|---|---|---|---|
| Mevalonic acid | 0.892 | 1.134 (+27.1%) | 1.253 (+40.5%) | +40.5% |
| Fatty acids | 0.308 | 0.379 (+23.1%) | 0.411 (+33.4%) | +33.4% |
| Isoprenoids | 0.225 | 0.291 (+29.3%) | 0.317 (+40.9%) | +40.9% |
This systematic approach dramatically reduces the time and cost required to develop efficient microbial cell factories—what once took years can now be accelerated through computational prediction and precision engineering.
Metabolic engineering relies on a sophisticated array of tools and technologies. Here are some key components of Sang Yup Lee's research toolkit:
| Tool/Technology | Function | Application in Lee's Research |
|---|---|---|
| Genome-scale metabolic models (GEMs) | Mathematical representations of metabolic networks | Predicting metabolic fluxes and identifying engineering targets 5 |
| CRISPR-Cas9 systems | Precision genome editing | Modifying microbial genomes to optimize metabolic pathways |
| Synthetic small RNA | Fine-tuning gene expression | Genome-wide metabolic engineering without modifying DNA 1 |
| Serine recombinase-assisted genome engineering (SAGE) | Rapid DNA insertion and deletion | Engineering non-model organisms |
| High-throughput screening | Testing thousands of variants simultaneously | Identifying optimal microbial strains 5 |
| Cofactor engineering | Optimizing energy and redox balance | Enhancing yield of target chemicals |
For Lee, scientific discovery is only valuable when it translates into real-world applications. His research philosophy embraces both fundamental understanding and practical implementation:
"Metabolic engineering is a discipline that leads the current and future of biotechnology. It is a tremendous honor to receive this meaningful award at a time when the transition to a bio-based economy is accelerating" 3 .
This translation from lab to market is evidenced by his staggering 860 patents and numerous technology transfers to industry 3 4 . Unlike many academics who focus solely on publication, Lee has actively founded companies commercializing discoveries in advanced biofuels, wound healing, and cosmetic products 4 .
His impact extends beyond business ventures to global scientific leadership. Lee serves as Co-Chair of the Global Future Council on Biotechnology at the World Economic Forum and is a member of the Presidential Advisory Council on Science and Technology of Korea 1 . His work has been recognized with numerous honors, including the National Science Medal, Ho-Am Prize, POSCO TJ Park Prize, and Italy's Eni Award (often called the Nobel Prize in energy) 1 9 .
"I still consider myself a chemical engineer. Chemical engineering is a discipline where one converts low value raw materials to higher value products needed by society... I thought that the use of biology in the context of chemical engineering was exciting and could lead to discoveries that would improve the state of the world." 9
"In Asia, teachers and students have a different relationship compared to that in the Western world. My success will be best judged by the successes of my students... As a scientist, my motivation would be to contribute to developing technologies that could create a better world." 9
"Metabolic engineering not only boosts the production of bio-based products but also facilitates the creation of novel chemicals that are beneficial to both humans and the environment. My enthusiasm for metabolic engineering stems from its profound enabling potential, which promotes the development of cell factories or the use of cellular components to manufacture useful products in a sustainable and environmentally friendly way." 4
"Working with industry is not only good for commercializing technologies developed in the lab, but also great for training students. Students will have good opportunities to learn how companies plan projects, perform tasks and make decisions." 9
"Technologies, including biotechnology, are advancing very rapidly... Therefore, the urgent problems in biotechnology or other fields do not lie with the technology itself, but rather, how we will more smartly and more inclusively use those technologies." 9
Sang Yup Lee's work exemplifies how interdisciplinary science can address pressing global challenges.
His systems metabolic engineering approach has transformed not only what we can produce biologically but how we think about biological production itself. By combining computational modeling with sophisticated genetic engineering, Lee and his team have dramatically accelerated the design-build-test cycle that once bottlenecked metabolic engineering progress.
As climate change accelerates and fossil resources diminish, the importance of sustainable bioproduction only grows more urgent. Lee's research offers a roadmap toward a future where chemicals, materials, and fuels come not from oil wells but from responsibly managed renewable resources processed by engineered biological systems.
Perhaps most inspiring is Lee's vision that extends beyond individual discoveries to ecosystem building—training the next generation of scientists, bridging academia and industry, and advising governments on science policy. His career demonstrates that the most impactful science doesn't just advance knowledge but creates platforms upon which others can build.
"We have developed several important technologies, but we will continue to work hard" 9 .
For a pioneer who has already given so much to his field, this continued commitment to progress might be his most valuable contribution yet.