NUS's Pioneering Work in Synthetic Biology for Brain Health

Singapore's National University of Singapore (NUS) continues to lead in biomedical innovation through its Synthetic Biology for Clinical and Technological Innovation (SynCTI) initiative. Researchers have developed a groundbreaking therapy using engineered gut bacteria to address hepatic encephalopathy (HE), a debilitating brain dysfunction stemming from advanced liver failure. This advancement highlights NUS's commitment to translating synthetic biology into practical clinical solutions, positioning the university as a hub for microbiome-based therapies in Southeast Asia.

Hepatic encephalopathy occurs when the liver can no longer filter toxins like ammonia from the blood, allowing them to reach the brain and cause cognitive impairments, confusion, anxiety, and in severe cases, coma. In Singapore, where chronic hepatitis B (CHB) affects about 3.6 percent of the population, liver cirrhosis—a precursor to HE—is a significant health concern. This NUS discovery offers hope for better management of such conditions prevalent in the region.

Understanding the Burden of Liver-Related Brain Dysfunction in Singapore

Liver cirrhosis remains a major public health issue in Singapore, driven primarily by viral hepatitis, non-alcoholic fatty liver disease, and alcohol-related damage. Studies indicate that complications like HE affect up to 14 percent of cirrhosis patients during their clinical course, making it a leading cause of hospital readmissions. With Singapore's aging population and rising metabolic diseases, the demand for effective HE treatments is growing, underscoring the relevance of university-led research from institutions like NUS.

NUS Yong Loo Lin School of Medicine researchers emphasize that current therapies fall short. Lactulose, a laxative, reduces ammonia by promoting its excretion, while rifaximin, an antibiotic, targets toxin-producing gut bacteria. However, these provide only symptomatic relief, with recurrence rates as high as 40 percent, straining healthcare resources.

The Innovative Engineering of Gut Bacteria at NUS

At the heart of this NUS breakthrough is the reprogramming of Lactobacillus plantarum WCFS1, a safe, naturally occurring probiotic bacterium found in the human gut. SynCTI scientists created two complementary strains: one dubbed the 'ammonia eater' that captures excess ammonia and converts it into essential branched-chain amino acids (BCAAs)—valine, leucine, and isoleucine—which are often depleted in HE patients. The second strain targets L-glutamine, a precursor to ammonia production, breaking it down to halt toxin generation at the source.

This dual-action approach represents a paradigm shift. Administered orally as a powder or capsule, the bacteria cocktail acts precisely within the gut, modulating the gut-liver-brain axis without disrupting the overall microbiome.

Step-by-Step: How NUS's Engineered Bacteria Combat Toxins

1. Gut Colonization: The bacteria safely colonize the intestines, leveraging their natural probiotic properties.
2. Ammonia Detoxification: The first strain absorbs free ammonia, transforming it into BCAAs via engineered metabolic pathways, replenishing vital nutrients.
3. Glutamine Breakdown: The second strain enzymatically degrades L-glutamine, preventing bacterial conversion to ammonia.
4. Systemic Effects: Reduced gut-derived toxins lower blood ammonia levels by up to tenfold, restoring brain homeostasis, neuronal signaling, and reducing inflammation.
5. Clearance: Bacteria are naturally cleared within 72 hours, minimizing risks.

This step-by-step precision differentiates it from broad-spectrum antibiotics.

Impressive Results from Rigorous Mouse Model Studies

In preclinical mouse models simulating liver failure-induced HE, the bacterial cocktail dramatically outperformed controls. Blood ammonia dropped to healthy levels, BCAA levels normalized, and brain glutamine excesses were corrected. Behavioral tests showed marked improvements in short-term memory and reduced anxiety-like symptoms—superior to rifaximin. Neuroimaging revealed normalized brain activity and lessened inflammation, with no adverse effects observed.

Crucially, gut microbiome diversity remained intact, unlike antibiotic treatments that deplete beneficial microbes. These findings, detailed in a recent high-impact publication, pave the way for human trials.

Meet the NUS Research Powerhouse Behind the Discovery

The project was spearheaded by Associate Professor Jonathan Lee from NUS SynCTI and Yong Loo Lin School of Medicine, alongside Professor Matthew Chang, SynCTI director and Yong Loo Lin faculty, and Dr. Nikhil Aggarwal, a senior research fellow at SynCTI. Their interdisciplinary collaboration exemplifies NUS's strength in merging synthetic biology with clinical medicine.

"This directly addresses a major limitation of current treatments," noted Prof. Chang, highlighting the therapy's multi-target efficacy. Over eight years of development, this team has filed a patent, signaling rapid translation potential.

SynCTI: NUS's Flagship for Singapore's Biotech Future

NUS SynCTI, launched to harness synthetic biology for health challenges, embodies Singapore's Smart Nation vision. By engineering microbes as 'living medicines,' SynCTI addresses unmet needs in metabolic disorders. This HE project builds on prior successes in microbiome therapeutics, attracting global partnerships and talent to NUS.

In Singapore's competitive higher education landscape, NUS's focus on translational research draws top students and faculty, fostering innovations that benefit national health priorities like combating non-communicable diseases.

Advantages Over Traditional HE Treatments

This comparison underscores the therapy's potential to redefine HE management.

Implications for Singapore's University-Led Health Research

This NUS achievement bolsters Singapore's biomedical ecosystem, where universities like NUS and NTU drive R&D. With government backing via A*STAR and NRF grants, such projects enhance Singapore's global standing in biotech. For higher education, it attracts PhD candidates and postdocs, offering hands-on experience in cutting-edge synthetic biology.

Duke-NUS Medical School complements with fatty liver research, creating synergies across Singapore institutions.

Path to Clinical Trials and Beyond

Next steps include long-term safety studies and human trials, with patent protection accelerating commercialization. Prof. Chang envisions expanding to urea cycle disorders and other hyperammonemia conditions. For NUS students, this opens doors in microbiome engineering, aligning with Singapore's life sciences push.

As Singapore grapples with rising liver diseases amid urbanization and diet shifts, university innovations like this promise reduced healthcare burdens and improved patient outcomes.

NUS's Role in Shaping Singapore's Biomedical Talent Pipeline

NUS programs in biomedical engineering and microbiology equip students for such breakthroughs. Collaborations with industry ensure graduates transition to roles in biotech firms, supporting Singapore's goal of 20,000 life sciences jobs by 2030. This research exemplifies how NUS fosters interdisciplinary talent, from undergrad labs to PhD theses on microbial therapeutics.

• Training in CRISPR gene editing for bacteria.
• Hands-on microbiome culturing techniques.
• Ethical considerations in synthetic biology.

Prospective students can explore these via NUS's Yong Loo Lin admissions.

Photo by Sean Seah on Unsplash