Bilirubin, as a natural product of heme metabolism, has long played an important role in the field of medicine and biomaterials.
The traditional extraction method relies on animal bile, which has some problems such as low purity, high cost and ethical controversy.
In recent years, the rise of synthetic biology has provided a disruptive solution for bilirubin production.
Technological synthesis route: from “animal extraction” to “cell factory”
1. Bottleneck of traditional technology
Bilirubin is traditionally extracted from the bile of animals such as cattle and pigs, which requires complex separation and purification steps and is limited by the unstable supply of raw materials and large batch differences.
Animal-derived ingredients may carry pathogens and are difficult to meet the high purity requirements of pharmaceutical grade.
2. Breakthrough pathways in synthetic biology
Designing microbial “cell factories” to directly synthesize bilirubin from cheap carbon sources such as glucose has become a mainstream research direction.
The core technology is to reconstruct the metabolism pathway of heme and optimize the production strains:
Key enzyme transformation:
Heme metabolism involves multi-step enzymatic reactions (e.g., heme oxygenase HO-1, biliverdin reductase) that require gene editing (CRISPR/Cas9) to enhance enzyme activity and reduce byproducts.
Case in point: In 2023, a Chinese Academy of Sciences team overexpressed HO-1 and UGT1A1 in E. coli, resulting in a three-fold increase in bilirubin production (source: Metabolic Engineering).
Dynamic control strategy:
Metabolic sensors (such as oxygen concentration response elements) are used to dynamically control the synthesis and decomposition pathways of heme to avoid the cytotoxicity caused by the accumulation of intermediate products.
Innovation: The light-controlled gene circuitry developed by the MIT team enables spatio-temporal separation of bilirubin synthesis from bacterial growth (Nature Biotechnology, 2022).
Cofactor engineering:
The synthesis of bilirubin depends on NADPH and other cofactors, and the conversion efficiency can be significantly improved by introducing exogenous coenzyme regeneration system (such as pentose phosphate pathway enhancement).
Recent research progress: game between efficiency and cost
1. Iteration of high yield strains
Application of non-model microorganisms:
In addition to Escherichia coli and yeast, corynebacterium glutamicum has become a new host due to its natural high heme yield.
The Korean research team achieved a bilirubin titer of 8.2 g/L through genome streamlining and pathway modularization (2024 preprint data).
Ai-assisted design:
Prediction of optimal enzyme combinations and fermentation conditions based on deep learning.
For example, the algorithm developed by DeepSynth reduced metabolic flux analysis time by 90%, accelerating the strain optimization process.
2. Green process upgrading
Cell-free synthesis system:
In vitro reconstruction of enzyme catalytic system to avoid the complexity of live cell culture.
A microfluidic reactor developed at the University of California, Berkeley, enables continuous production of bilirubin with a purity of up to 99.5%.
Waste recycling:
The hydrolysate of agricultural waste (such as corn stalk) is used as a carbon source to reduce production costs.
The EU “BioBil” project has achieved pilot scale verification.
Market analysis: opportunities and challenges of ten billion Blue Ocean
1. Application scenarios drive demand growth
Medical field:
The antioxidant and anti-inflammatory properties of bilirubin have great potential in the treatment of neonatal jaundice, neurodegenerative diseases (such as Alzheimer’s disease) and anti-cancer drug adjuvants.
The global pharmaceutical grade bilirubin market is expected to reach $1.2 billion (8.7% CAGR) by 2028.
High-end cosmetics:
As a “natural antioxidant”, anti-aging serum with bilirubin is priced at a premium of up to 300%.
Estee Lauder and other giants have laid out relevant patents.
Biological materials:
Bilirubin derivatives are used to prepare biodegradable medical scaffolds and antibacterial coatings, which is in line with the upgrading trend of medical consumables.
2. Competitive landscape and player dynamics
Traditional enterprise transformation:
Bile extraction companies such as Germany’s Diapharm have accelerated acquisitions of synthetic biology start-ups in response to the raw material shortage crisis.
The rise of new powers:
SynthBil: The first FDA-approved supplier of synthetic bilirubin with a production capacity of 10 tons/year.
China blue Crystal Microorganism: Collaborating with Wuxi Apptec to develop a low-cost process with a target price of 60% lower than traditional methods.
Policy and risk tips
Regulatory barriers:
Pharmaceutical grade products must comply with cGMP, EP/ USP standards, and the impurity spectrum analysis of the synthetic path is the key to approval.
Technical bottleneck:
Microbial methods still face challenges of product inhibition (toxicity of bilirubin to host cells) and high downstream separation costs.
Marketing Education:
Consumer acceptance of “synthetic biology-derived” products needs to be nurtured over time, especially in the field of health products.
Future Outlook: “last mile” from laboratory to industry
Synthetic biology is pushing bilirubin production from “relying on nature” to “designing nature”.
With the deep integration of CRISPR gene editing, automated fermentation platform and AI metabolic modeling, the next 3-5 years or will usher in the outbreak of industrialization.
Interdisciplinary collaboration (bioengineers + clinical experts + policy makers) remains central to bridging technology chains and value chains.
