In the cafeteria at the Japanese University Tohoku, a bell rang every evening at about eight o’clock, and whoever came running quickly enough received the day’s leftovers. Many poor students lived on these free evening meals during their study years. Among them was a future biochemist Akira Endo, who like the others often waited for the cafeteria bell and ran to get some of the free food. Even though he later spent many years conducting research at Sankyo, a pharmaceutical company, working hard to discover one of the most profitable medicines in the entire pharmaceutical industry, he received no additional compensation for his success beyond his usual pay and pension.
After concluding his studies, Endo got a job at Sankyo where his initial research work consisted of isolating certain constituent parts or products of yeast organisms that would prove commercially viable. During that time in Japan, every student had to complete at least five years’ work as a researcher in a relevant industry before they could obtain their doctorate. By the time he submitted his dissertation, Endo had already written no less than 15 research papers. His hard work and findings, which proved extremely lucrative for the company, brought Endo the chance to do post-doctoral training in the US in 1966. While in New York, he decided to switch his area of research to the biochemistry of lipids, commonly known as fat and cholesterol.
Good and bad cholesterol
Cholesterol is one of the key components of cellular membranes with important functions in the digestion of fat and the formation of hormones including estrogen and testosterone. 93% of all body cholesterol is stored in our cells, with only 7% in the blood, and is ingested with food or produced by the liver.
Cholesterol is carried around with help from two sorts of molecule called lipoproteins. LDL (low density lipoproteins) carry cholesterol from the liver to other parts of the body, while HDL (high density lipoproteins) return any surplus of cholesterol from the arteries, where it can cause a number of problems, back to the liver. Of course, both types of lipoprotein are essential for maintaining normal bodily functions, yet in today’s vocabulary of heightened nutritional awareness, the HDL type has been labelled “good cholesterol” for its vein-cleansing properties, whereas LDL has been branded as “bad cholesterol”. If our blood contains an increased amount of LDL particles, they begin sticking to the walls of the arteries and cause problems by forming plaque, which in the worst-case scenarios cause our veins to clog, raising the likelihood of a heart attack or stroke.
Searching for a magical substance among thousands of samples
After returning to Japan, Akira Endo set his mind to finding a substance that would prevent the formation of new cholesterol in the body. It had been known since the 1960s that the enzyme HMGCR (HMG-CoA-reductase) was responsible for cholesterol regulation. Endo needed to find a substance that would inhibit this enzyme, which plays a central role in the production of cholesterol in the liver. But where should he look? A few decades earlier, a number of effective antibiotics were discovered among microbes. Endo was certain that he would find a cholesterol-regulating medicine by thoroughly researching the world of microorganisms.
He embarked on a colossal project, studying thousands of samples of different soils, fungi and other organisms that might provide the right medicinal properties. He worked out a procedure for combining rat liver extract with a radioactive marker that enabled him to measure the amount of cholesterol produced by a correlated increase in radioactivity. He was soon able to confirm the existence of certain substances that inhibited cholesterol production, but it proved difficult to isolate them and rule out unwanted side effects.
At the beginning of the 1970s, after looking at thousands of samples, Endo and his team discovered four potential candidates among the substances that decreased cholesterol levels in the blood, two of which appeared especially promising. One of the samples was isolated from a parasite found on rice and cucumbers, called Citrinin, but unfortunately proved to be toxic. The other originated from microorganisms found on rice bought in the 1950s in Kyoto.
After two and a half years, the team tested 6392 samples, of which they found only one was suitable for animal testing. They named it Compactin. Unfortunately, rat tests showed no long-term effect in lowering cholesterol levels, even though it inhibited the functions of the HMGCR hormone responsible for the synthesis of cholesterol. It appeared that the mechanism regulating cholesterol levels in the rats’ blood was so powerful that it reacted to the reduction of HMGCR by triggering additional mechanisms which brought cholesterol levels back up.
It already seemed that further research on Compactin would be abandoned when in January 1976 Endo met an old colleague in the cafeteria who had just finished experimenting on chickens. Since the chickens were headed for the slaughterhouse anyway, Endo decided to test his new drug on them. This time the results were very encouraging. Cholesterol levels in the test group dropped by half and no harmful side effects were observed.
Endo’s first patient
In 1977 Endo was contacted by a doctor treating a girl with a severe case of hypercholesterolemia who had already suffered great problems from excessive cholesterol accumulation. Since the company couldn’t officially allow the medicine to be administered to the patient, Endo endured a long moral struggle before finally travelling to Osaka with a dose containing fifty grams of Compactin and handing it to the doctor.
The eighteen-year-old girl became the first patient to be treated with one of the cholesterol-lowering drugs now known as statins. Her level of cholesterol soon dropped by 20%, but three weeks into her treatment she developed severe muscle pain. The doctors adjusted her dosage and lowered the medication eight other patients were receiving. Cholesterol levels dropped by an average of 30% in the test group, a result that was good enough to put the medication through to the first phase of full clinical trials.
Endo then decided to leave Sankyo and accepted a teaching position at Tokyo University. This change of employment was unheard of at the time in Japan’s conservative corporate culture, but Endo hoped he would be treated with understanding given his contributions to the company. He was wrong. After twenty-one years and eight months of dedicated work, he had to clear his office, pack his things and leave without any help from his colleagues.
Pharmaceutical companies and their astronomical profits
The Sankyo company itself was very naïve in consenting to share all its results with researchers from Merck, the firm that offered to help develop the final product. In the end, Merck cheated Sankyo out of the deal and patented the winning version of the statin themselves.
While doing research at the university, Endo discovered a new form of statin in another variety of rice and proceeded to file a patent. The Merck researchers contacted him immediately and asked for a sample. Endo reluctantly obliged. Even though Endo was the first to patent the substance, Merck insisted that they had invented it a few months earlier but circumstances had prevented them from filing a patent. Merck managed to convince the US Patent Office they indeed were first and in 1987 they launched exactly this substance under the brand name Lovastatin.
Akira Endo, today in his eighties, lives in Tokyo and still enjoys hiking with his friends in the neighboring hills. A few years ago he said in an interview that his personal physician found his cholesterol levels slightly increased and told him: “Don’t worry. I know a very good drug.”