How a Japanese scientist's curiosity about molds led to a life-saving medical breakthrough
Explore the StoryFor decades, cardiovascular disease has reigned as the leading cause of death globally. The fight against this modern plague took a dramatic turn in the 1970s, sparked not in a high-tech lab, but in the ancient world of fungi. This is the story of statins—a class of drugs born from moldy oranges and scientific perseverance that has revolutionized preventive medicine and saved millions of lives.
The journey begins with understanding cholesterol. This waxy substance is not inherently bad; it's a crucial component of animal cell membranes and a precursor for vital hormones 1 . However, the Framingham Heart Study in the 1960s definitively revealed a tight correlation between high levels of blood cholesterol, particularly the low-density lipoprotein (LDL) form, and the risk of developing cardiovascular disease 1 .
Helps remove LDL from arteries
Builds up in arteries, increasing CVD risk
Cholesterol management became a medical grail. Scientists discovered that the body controls cholesterol levels through a feedback system. A key enzyme, HMG-CoA reductase, acts as the pacemaker in the liver's cholesterol production line. This enzyme converts HMG-CoA to mevalonate, the immediate precursor to cholesterol, and is itself inhibited by cholesterol—a perfect natural feedback loop 1 . Researchers realized that inhibiting this enzyme could be the key to artificially lowering cholesterol, but a safe and effective inhibitor remained elusive.
The hero of our story is Akira Endo, a Japanese biochemist working for Sankyo Co. in Tokyo. Fascinated by fungi since childhood and inspired by Alexander Fleming's discovery of penicillin from mold, Endo spent years screening microbial strains for useful enzymes 1 2 .
After learning about the link between high cholesterol and heart disease during a research stint in New York, Endo had a brilliant hypothesis. He speculated that fungi might produce substances to inhibit HMG-CoA reductase as a defense mechanism against competing microorganisms that require sterols for growth 1 3 . If such a compound could be found, it might work as a drug in humans.
In 1971, Endo and his colleague Masao Kuroda embarked on a monumental task. They began screening thousands of microbial strains for their ability to inhibit cholesterol synthesis in rat-liver extracts 1 2 .
Fungal cultures painstakingly tested
First promising culture was too toxic
From Penicillium citrinum mold
The breakthrough came from a common mold: Penicillium citrinum, a relative of the fungus that puts the blue in blue cheese and grows on old oranges 1 . From a massive 2,900-liter batch of filtered mold culture, they isolated a potent inhibitor they called ML-236B—later known as mevastatin or compactin 1 . This molecule was a structural mimic of HMG-CoA, allowing it to dock onto HMG-CoA reductase and block its action, thus halting the production of cholesterol 2 .
The initial excitement was soon met with disappointment. When tested long-term in rats, mevastatin produced no consistent cholesterol-lowering effect. The entire project was on the brink of being abandoned 1 .
Facing failure, Endo received an unexpected offer from a colleague: a flock of egg-laying hens. Given the high cholesterol content of eggs, these birds seemed a perfect model for a last-ditch experiment 1 .
| Subject | Treatment | Duration | Effect on Blood Cholesterol | Notes |
|---|---|---|---|---|
| Egg-laying hens | Commercial feed + Mevastatin | Not specified | Decreased by up to 50% | Body weight, food intake, and egg production unaffected |
This single experiment proved that mevastatin could dramatically lower cholesterol in vivo without apparent short-term toxicity. It provided the critical evidence needed to continue development, saving the statin program from termination and paving the way for human trials 1 .
The path from mevastatin to today's statins was a global effort involving multiple pharmaceutical companies and researchers.
Akira Endo isolates mevastatin from Penicillium citrinum, the first statin 1 .
Researchers at Merck isolate mevinolin (lovastatin) from Aspergillus terreus 2 .
Lovastatin (Mevacor) becomes the first FDA-approved statin 2 .
Atorvastatin (Lipitor) and other synthetic statins are developed, offering greater potency 2 .
Statins become one of the most prescribed drug classes worldwide.
| Statin | Origin | Type | FDA Approval Year | Note |
|---|---|---|---|---|
| Lovastatin (Mevacor) | Aspergillus terreus | Natural | 1987 | First commercial statin |
| Pravastatin (Pravachol) | Microbial transformation | Semi-synthetic | 1991 | Derived from mevastatin |
| Simvastatin (Zocor) | Chemical modification | Semi-synthetic | 1991 | More potent than lovastatin |
| Atorvastatin (Lipitor) | Fully synthetic | Synthetic | 1996 | Became one of the best-selling drugs ever |
| Rosuvastatin (Crestor) | Fully synthetic | Synthetic | 2003 | High potency |
Statins' primary mechanism is elegantly simple: they competitively inhibit HMG-CoA reductase, reducing the liver's production of cholesterol 2 . This triggers a cascade of beneficial effects:
The liver's internal cholesterol synthesis is slowed.
Additional receptors scavenge harmful LDL cholesterol from the bloodstream.
Interestingly, while statins decrease overall cholesterol production, they often lead to a slight increase in the "good" HDL cholesterol, making them even more cardioprotective—a beneficial effect that scientists are still working to fully explain 1 .
Research has revealed that statins do more than just lower cholesterol. By blocking the mevalonate pathway, they also affect the production of other important molecules, leading to "pleiotropic effects" 4 . These include:
| Reagent | Function | Role in Research & Diagnostics |
|---|---|---|
| Cholesterol Oxidase (EC 1.1.3.6) | Catalyzes the oxidation of cholesterol to produce hydrogen peroxide 5 . | Used in enzymatic assays to quantify total cholesterol levels in blood samples 5 6 . |
| Cholesterol Esterase (EC 3.1.1.13) | Hydrolyzes cholesterol esters into free cholesterol and fatty acids 5 . | Works with cholesterol oxidase to measure both free and esterified cholesterol in diagnostic kits 6 7 . |
| Peroxidase (EC 1.11.1.7) | Uses the hydrogen peroxide produced by cholesterol oxidase to generate a measurable color change 5 6 . | Acts as the indicator enzyme in the coupled reaction, allowing for photometric determination of cholesterol concentration. |
| HMG-CoA Reductase | The target enzyme of statins; catalyzes the rate-limiting step in cholesterol biosynthesis. | Used in in vitro assays to screen for and characterize potential new inhibitory compounds, just as Endo did. |
Clinical trials and real-world evidence have consistently demonstrated the powerful impact of statins on cardiovascular outcomes.
Data from a large evidence review by the UK's National Institute for Health and Care Excellence (NICE) 8 .
| Population | Intervention | Key Outcome | Effect (Risk Ratio) |
|---|---|---|---|
| Adults without established CVD (Primary Prevention) | Statin vs. Placebo | Major Adverse Cardiovascular Events | 0.72 (i.e., a 28% reduction in risk) |
| Adults with established CVD (Secondary Prevention) | High- vs. Low-Intensity Statin | Major Adverse Cardiovascular Events | 0.80 (i.e., a 20% further reduction in risk) |
| Example: Myocardial Infarction | Statin vs. Placebo | Fatal and Non-fatal Events | 0.68 (i.e., a 32% reduction) |
The statin story is far from over. Research continues into new cholesterol-lowering agents, such as PCSK9 inhibitors, which use novel DNA-based techniques to achieve dramatic reductions in LDL cholesterol without the side effects associated with statins 9 . Furthermore, scientists are actively exploring the repurposing of statins for conditions like cancer, thanks to their newly discovered effects on kinase signaling and epigenetic regulation 4 .
From a mold on a rice culture to a cornerstone of global public health, the journey of statins is a powerful testament to curiosity-driven research. Akira Endo's fusion of mycology and biochemistry, his persistence through years of screening, and his clever use of a chicken model, ultimately gifted the world one of its most important families of medicines. It stands as a brilliant example of how solving a fundamental chemical puzzle can profoundly improve human health.