Akira Endo
(November 14, 1933 - )
Born in Japan
Year of Discovery: 1972
Discovered a Drug That Lowers the Risk of Heart Attacks

Akira Endo is the medical research scientist who discovered the first statin drug-compactin. The drugs used before this discovery to lower cholesterol did so by increasing the removal of cholesterol from the body or by inhibiting its absorption from food. These methods were not very effective and produced severe side effects. Statins are a class of drugs with remarkable cholesterol-lowering properties. They lower the part of cholesterol known as “bad cholesterol,” technically known as low density lipoprotein or LDL cholesterol.  They work by limiting cholesterol synthesis within the liver and have proven to be a much safer and effective alternative. In fact, these drugs have created a revolution in the prevention and treatment of coronary heart disease since they became available in the late 1980s.

 Coronary heart disease (CHD) is the most common form of heart disease.  It affects about 18 million people in the United States, killing 365,000 in 2017. This disease emerges when a combination of fatty material, calcium, and scar tissue builds up in the arteries that supply the heart with the oxygen and other nutrients it needs to function properly. The blood flow begins to decrease as this plaque builds up on the artery walls. This can lead to chest pain, angina and, when the flow becomes completely blocked, heart attacks.  

After studying in the U.S., Endo came to realize the connection between cholesterol and coronary heart disease. Cholesterol is necessary for our body to function, but too much of it can cause coronary heart diseaese.  Cholesterol is supplied to the body either through the intake of food or through synthesis by the body, mainly by the liver. When the food supply is unable to meet the required amount, the liver  compensates and makes it. However, when the supply is adequately met by food, synthesis of cholesterol by the liver is suppressed. In this way, the body has a way to prevent cholesterol levels from becoming excessive. Diets high in saturated fat interfere with this mechanism causing many people to develop heart disease. Armed with this knowledge, Endo decided to search for a substance that would inhibit this synthesis and thereby battle the CHD epidemic. He realized that such a substance would have to be taken the rest of a person's life, so he chose to search in fungi.  He reasoned that fungi had been proven safe for antibiotic drugs such as penicillin. As well, he knew how popular mushrooms (a fungi) were as a food in Japan, so knew that most were safe.  After two and a half years and examining 6,392 fungi, he discovered a compound that lowered cholesterol - compactin. This was the beginning of the statin revolution.  Major drug companies in the U.S. read his academic papers and asked for samples.  Statins provided doctors with the first weapon to truly fight heart disease. 

Statins have now been out for more than 30 years and many longterm studies have been completed.  A most remarkable occurance has been the number of studies that have been stopped early.  In those, statins were so successful, having so many fewer of those on statins dieing than those in the placebo control group,  that continuing the studiy and keeping statins from the control group was determined to be unethical. Meta-analysis of numerous large studies indicate that use of statins lower LDL-C cholesterol levels from 20%-40% and reduce coronary heart disease mortality 23%.  Statins have also been found to reduce strokes (another leading cause of death) by 30%. Akira Endo's statin drugs have revolutionized cardiovascular medicine.  This might best be stated by two Nobel Prize winning scientists for their work on cholesterol. Michael Brown and Joseph Goldstein say:
"The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo and his search through fungal extracts at the Sankyo Co."

Endo's Popular Drug
In 2005, out of 10,000 drugs sold in the world, the best-selling drug was a statin -- Lipitor with $8.4 billion in sales.  Worldwide sales of statin drugs have far surpassed $100 billion.

You Know Someone Helped By Endo's Drug
Currently 10 percent of the adult population in the US takes a statin. Moreover, 27 percent of those older than 65 swallow the precious pills every day. While that calculates out to around 20 million individuals, it is estimated that twice as many should be on statins.

With that said, there was no guarantee that I would be able to discover an HMGCR inhibitor, so I decided to study a few thousand strains of fungi over a two-year period. It was going to be a research like a bet...and if I was unable to discover the substance I set out to find, I would then terminate my research.

My team and I shouted with joy and toasted our success when we discovered the dramatic effect of compactin!

We received no response from Merck and had a feeling of dread that maybe they were contriving a plot of some sort.
                         - Merck asked for and received a sample of Endo's statin drug, but never licensed or paid for it

The discovery of the medicine was a continuation of difficulty which was like a seesaw. However, when I pass the difficulty, there is the pleasant feeling like after I exercise.... The discovery and development of statins were a huge gamble for me in achieving my dream. Thanks to my success with statins, the dream from my boyhood was realized and I received appreciation from a large number of people from all over the world. This is a source of immeasurable joy for me.

Reflecting on Life
Since I was born as a human in this world, I want to leave my mark before I die. I want to die after I do at least one thing useful for the world.

I did not start the research to make money or become a big man. Since I was born as a human in this world, I wanted to leave my mark before I die. I want to die after I do at least one thing useful for the world. I could start the research because I had such a thought....Therefore, we cannot measure the contribution, which statin did for the precious lives. Maybe we should not simply convert ‘to be useful for the world' into money. It is something we cannot convert.

Nowadays, it is said that money is important. However, we can find the pleasure of life and the value, when we do something for the world with a sense of mission. What I have done was rather for the world than a Japanese company or Japan. It was needed all over the world, so I challenged for it. Especially now, it is called the time of globalization, and borders are not clear. Humans made borders originally, so they exist, but they seem not to exist. I want to tell young people the message that the philosophy and sense of value of doing something for the world are more important than making money. That is the work left for me from now on.

Quotes about Endo and Statin Drugs
I think there is no doubt that the discovery of compactin (the first statin) by Dr. Endo was one of the great discoveries in the history of modern medicine.
                                                                                   - Scott M. Grundy, MD, PhD University of Texas

Statins are to cardiovascular disease what penicillin was to infectious disease.  They are one of the most important, if not the most important, advances in cardiovascular medicine.                                                                                      - Professor Leon Simons

The millions of people whose lives will be extended through statin therapy owe it all to Akira Endo and his search through fungal extracts at the Sankyo Co.
                                 - Michael Brown and Joseph Goldstein, Nobel Prize winners for their work on LDL receptors

How About a Suit Instead?
In high school Endo loved chemistry and his principal encouraged him to take the entrance exams to Tohoku University. His parents, knowing that if he passed the tests they could not afford to send him to college, sent his older brother to talk Akira out of dreaming so big. Their scheme was based on his clothing. Endo's dress could not be called stylish since he had only one pair of socks and had to wash them every night and let them dry by the fire. Tomiko, his brother's wife, recalls the trip. "His parents asked us to tell him that it was ‘not only you, you have brothers and sisters, so you cannot go to a university.' They gave us 20,000 yen (about $55) and said to us, ‘tell Akira if he does not go to the university, we will buy him a suit. Trick him.'"

When they arrived and attempted the bribe, Akira retorted, "I don't need any clothes, let me go to the university. Cut me off from your money." "Cut me off" was a serious phrase, meaning "disown me," so they knew Akira had made up his mind. Fortunately it never came to that - Endo's principal helped him get a scholarship.

The Fruity Fungus
Endo's first project for Sankyo led to the discovery of a fungus that produced pectinase, an enzyme that decomposes pectin. Pectin is a type of fiber produced in fruits such as apples and grapes, which causes their juices to be cloudy. Two years later Endo commercialized a process to make great quantities of pectinase. It was exactly the kind of applied science Sankyo wanted its researchers to do, and pectinase became very profitable to the company as a clarifying agent. They rewarded him by providing him education opportunities in America for two years.

Endo's Impressions of the U.S.
When Endo went to the U.S. to study in 1966 he laughed when he saw so many people looking like big sumo wrestlers. In restaurants Endo watched with amazement as people ordered steak "the size of a sandal." It was unheard of in Japan.

Japanese Ostracism
Endo says, "It was my dream for some time to move to a university once the development of compactin had reached a certain stage, and to conduct research together with young researchers."

When statins proved successful, he did move to Tokyo University of Agriculture. When word of Endo's retirement reached the top brass at Sankyo, they vented their unhappiness. At that time, Japanese corporate culture was very conservative. Many corporations viewed anyone who halfway resigned (the Japanese term for retiring by one's own choosing before the traditional retirement age of 55) as disloyal. Endo says, "I had wished that I would not receive the cold shoulder from my company because of the significant contribution I had made in the development of statin. However, I was treated exactly in the same way as my fellow workers who had resigned before me. My company's prohibiting my fellow workers from helping me clear my belongings from the office was just one example of this ostracism."

Key Insight
At the time Endo worked on limiting blood cholesterol two methods had been attempted. The first was to try to keep the body from absorbing cholesterol from food. This worked poorly. The second idea was to change the liver's ability to synthesize cholesterol by inhibiting HMGCR, the crucial enzyme in the cholesterol synthesis pathway. This had not been successful either, but Endo chose the liver synthesis path because he had a new insight. His brilliant hypothesis was where he might find a substance that would target the enzyme.

Endo knew a lot about microbes and the role evolution plays in the cutthroat world of microbes. He predicted that there were microbes that make a cholesterol synthesis inhibitor. There were sound reasons to postulate that such a microbe might exist. Plants and fungi produce cholesterol, although in much smaller quantities than do animals. Mevalonic acid, which the HMGCR enzyme helps to produce as a step in cholesterol synthesis, is also a precursor to other biological molecules. Endo thought it possible that some fungi had evolved a way to limit cholesterol synthesis to protect themselves against attacking microbes that might require cholesterol or one of its precursor molecules for growth.

Endo knew that simply finding an active substance was just the half of it. He needed an active substance that was safe enough for continual ingestion, because he realized that maintaining low cholesterol might require lifelong therapy for many individuals. Researchers were gravitating to Actinomycetes, now more specifically known as Actinobacteria, because they had produced many antibiotics. There had been safety concerns with some antibiotics made from the Actinobacteria; for example, streptomycin occasionally produced the side effect of hearing loss. Endo thought, "There is no precedent in which Actinomycetes are used for production or processing of food. That made me worried about Actinomycetes." In contrast, some molds and mushrooms are edible. As a boy Endo learned most poisonous varieties are also eatable if you boil them and discard the water. While they had yielded considerably fewer antibiotics, the ones they had produced, such as penicillin, were remarkably safe. Endo says, "I chose mold and mushrooms as microbes which had strong possibility to produce cholesterol synthesis inhibitor and I did not choose Actinomycetes, although it was against the trend of those days." Then he set out to study a few thousand strains of fungi over a two-year period in search for one.

Key Experiment or Research
There was no shortage of molds to investigate. The problem would be how to effectively analyze them. Endo devised a step by step plan to eliminate any unpromising specimens until he was left with only substances that fit his hypothesis. He set off to culture a hundred species of fungi in separate flasks for a week. Then he performed the first test to see if any of the cultures inhibited cholesterol synthesis. Endo and his two assistances used rat liver extracts with acetic acid to produce cholesterol. The precursor molecule was made radioactive so that the cholesterol produced could be measured. This allowed the controls and the broths to be compared so any significant difference in cholesterol could be attributed to the specimen.

Now with a group of candidates that lowered cholesterol, they discarded ones that didn't fit their needs for other reasons. Not all the substances that demonstrated cholesterol inhibition were potential drugs. They wanted substances that were safe and cheaply reproducible. Endo also examined the inhibitory broths for their active substances and discarded those that contained large molecules or that were unstable when heated. Those that reproduced poorly were also discarded. He then discarded broths that did not show early stage cholesterol synthesis inhibition. This left substances that had the best potential for later becoming effective drugs.

The remaining candidates were tested to see if the product of the broth had inhibited the HMGCR enzyme. To isolate and purify the active substances in the molds, Endo then used various organic solvents as well as various chromatographies. Some of the active substances Endo and his team isolated could be identified as known substances. They usually discarded these since their properties were generally known and could be looked up in books. Endo and his team selected only novel substances that greatly inhibited the HMGCR enzyme for further research. Finally, there was testing to see if the substances were safe and didn't show any immediate side effect problems.

Endo's team investigated 2,600 culture broths. They had found three strains of mold that passed the first five tests. But when they isolated the active substances, they found they had isolated oxalic acid and maleic acid. These would not work. It was common knowledge that many fungi produced these acids and a similar level of inhibitory activity was recognized in all of these organic acids. Endo recognized they needed to eliminate these known active substances before running the tests. Endo changed their procedures, adopting an improved method whereby ‘extracts' from which the organic acids had already been eliminated from the cultural broth were used.

After two and a half years they had analyzed 6,392 strains of fungi. Three candidates were left, all chemically very similar. One, labeled ML236B, was the most active as an inhibitor. It was this substance that was later renamed compactin and that was the first discovered statin.

The Science Behind the Discovery
The Problem is Heart Attacks and Strokes
Coronary Heart Disease (CHD), which causes most heart attacks, is the leading cause of death in the United States. Heart attacks and ischemic strokes are caused by the excessive build up of cholesterol on the artery walls. The cholesterol is carried through the blood stream by proteins known as low density lipoproteins (LDL). If there are too many LDL particles in the blood, cholesterol can build up on the walls of the coronary arteries, triggering an inflammatory response, causing pimple-like lesions to form on the artery walls, and eventually blocking the free flow of blood due to clotting. Over two-thirds of the people living in the industrialized world have enough LDL cholesterol in their bloodstreams to cause this kind of inflammation, especially when they have other factors such as high blood pressure and diabetes. Overexposure to cigarette smoke also increases the chance of vessel damage resulting in higher rates of inflammation.

Cholesterol Diseases
Normally the LDL receptor, a protein found in the liver, binds LDL particles and removes excess LDL from the blood. The process where LDL is taken up by the LDL receptors resulting in the removal of the bound cholesterol is known as LDL receptor pathway.

One in a million people are born with two mutant genes that cause them to have very few LDL receptors. People with homozygous FH (familial hypercholesterolemia) have livers that remove very little cholesterol from their blood, resulting in cholesterol levels six to ten times higher than normal (1,000 to 2,000mg/dl). These people often begin having heart attacks as children. One in 500 people have one mutant gene that causes heterozygous FH. They have twice the cholesterol levels from birth of most people, and begin having heart attacks in their 30's or 40's.

These people provided evidence of cholesterol's role in cardiovascular disease.

Despite two normal LDL receptor genes, two out of three people in Western societies maintain dangerously high levels of LDL. This can be attributed to high-saturated fat diets in those genetically predisposed to diet-induced elevations in LDL. When too much cholesterol builds up in the liver, the cells stop producing LDL receptors by a feedback mechanism. With fewer receptors to remove the LDL, it accumulates in the blood stream. Removing cholesterol and saturated fats from the diet often results in a minimal decrease in blood levels of LDL, so does not prevent cardiovascular disease.

Endo's Research to Inhibit Cholesterol Synthesis
Endo set out to solve this problem by trying to find a drug that would inhibit cholesterol synthesis. This led him to the discovery of compactin, the worlds first statin. Interestingly, statins inhibit the synthesis of cholesterol in the liver, which causes the LDL receptor genes in the liver to become more active. As a result the liver expresses more LDL receptors, which pull more LDLs out of the blood, lowering blood cholesterol levels.

As noted above under key insights, Endo's hypothesis was to avoid studying Actinobacteria, which was popular at the time, and instead to study fungi. Endo reasoned that fungi produced safe drugs such as penicillin, perhaps due to qualities in them that made many of them edible.

Animal Testing
After the discovery, Compactin needed to undergo testing to ensure it was both safe and effective as a drug. The first subjects tested were rats. Sadly testing showed that although the drug was safe, it was not effective in lowering cholesterol. Oddly, rats are not good animals for testing cholesterol. Their bodies do not act the same as humans in regulating cholesterol. For two years Endo was discouraged. Then one day he ran into a coworker at a nearby restaurant who experimented with chickens. Over drinks he learned about the work and realized,"if the eggs hens lay are so rich in cholesterol, it meant they had to synthesize a lot of it. That meant they should have a lot of cholesterol in their blood, just like humans." Endo began tests using the discarded chickens from his associate's experiments. The results were positive as Endo elated afterwards, "My team and I shouted with joy and toasted our success when we discovered the dramatic effect of Compactin!"

Human Tests
Ready for human trials, politics at Sankyo prevented a straightforward trial. Instead, the first human tests were carried out without informing Sankyo. During 1978, the drug was tested on several patients with genetic abnormalities that make their cholesterol levels threateningly high. The drug performed extremely well and Sankyo put it back on track to become a commercial drug.

The idea that cholesterol was a risk factor for coronary heart disease was controversial throughout the 1970s and 1980s. British researcher Gilbert R. Thompson recalls that the head of medicine at Hammersmith Hospital where he worked was "virulently anti-cholesterol," meaning he didn't think it was a major risk factor. Another would tell anyone who asked, "This relationship between cholesterol and heart attack, might it not be that the heart attack put the cholesterol level up?" The evidence that people with FH (familial hypercholesterolemia) had clogged arteries and heart attacks as early as childhood was based on too small a data set for many scientists. It would take large, long-term studies to prove that high cholesterol causes atherosclerosis, which leads to heart attacks and strokes.

Endo's statin was the first cholesterol lowering drug that had few side effects, and therefore could be given to people with elevated, but not immediately dangerous, levels of cholesterol for a long enough time to see if it was effective at reducing coronary heart disease. Results from the Scandinavian Simvastatin Survival Study (4S) arrived in 1994. It followed 4,444 patients with high cholesterol, some given a statin while others were not, in a double-blind trial lasting more than five years. The lipid study provided significant evidence that lowering cholesterol saves lives. A similar study in Scotland using pravastatin, another statin drug developed by researchers at Sankyo, confirmed those results. After this, doctors started prescribing statins widely.

Personal Information
Akira Endo was born on November 14, 1933, in the Akita Prefecture of northern Japan. He was raised on a farm during World War II. Times were difficult and Endo had to fight to go to high school and college. He graduated from Faculty of Agriculture of Tohoku University in March 1957 and went to work at Sankyo, quickly making a name for himself by performing commercially successful work with pectinase. His reward was a two year study stint in the United States. A year after he returned he began the research that would produce statins. He married Orie and together they raised three children. He left Sankyo at the end of 1978 for the Tokyo University of Agriculture and Technology. Today he is retired, living in Tokyo.

Science Discovery Timeline
1949 - John Gofman linked lipoproteins to the causation of heart disease
1964 - Konrad Bloch received the Nobel Prize for research in cholesterol biosynthesis
1969 - Endo hypothesized fungi would be the best place to look for a cholesterol inhibitor
1971 - April - Endo began investigating fungi
1972 - Fall - Endo finished analyzing 6,392 strains of fungi and isolated compactin, the first statin drug
1974 - January - Sent compactin to be tested for toxicity and efficacy at Sankyo's Central Research Laboratory
1974 - February - Informed there were no toxicity problems, but that compactin had not lowered the cholesterol levels in the rats at all
1976 - January - Finally understood why the drug didn't work in rats
1976 - February - Began testing on chickens: "My team and I shouted with joy and toasted our success when we discovered the dramatic effect of compactin!"
1976 - April - drug company Merck, Sharp & Dohme expressed interest, so they divulge their secrets.
1977 - Sankyo was hesitant to proceed with compactin due to dog tests
1978 - Clandestine human trials were successful
1978 - Fall - Sankyo put compactin back on track to be a drug
1978 - December - Endo left Sankyo for the University of Tokyo of Agriculture
1979 - February - Endo discovered another statin - monacolin K, then patented it
1979 - September Merck claimed they had already discovered monacolin K and had named it lovastatin
1987 - Merck began selling lovastatin (patents differ depending upon the country, allowing them to sell it in some countries)
1994 - Simvastatin Survival Study (4s) proved statins safe, effective, and revolutionary
2006 - Total Statin sales far surpassed $100 Billion

Books by Akira Endo
Designed by Nature - The Birth of the Greatest New Medicine in History. Tokyo: Medical Review Co., Ltd. (Japanese). By Akira Endo.
The Discovery of the New Medicine Statin - A Challenge to Cholesterol. Tokyo: Iwanami Shoten. (Japanese). By Akira Endo. 2006

Books About Endo
Scientists Greater than Einstein: The Biggest Lifesavers of the Twentith Century. Linden Publishing, 2009. By Billy Woodward, Joel Shurkin, & Debra Gordon
The Most Acknowledged Medicine of the World. Tokyo: Shogakukan, 2007. (Japanese). Yamauchi, Kimiko Yamauchi

Awards
Young Investigator Award in agricultural chemistry (Japan), 1966
Heinrich Wieland Prize for the discovery of the HMG-CoA reductase inhibitors (West Germany), 1987
Toray Science and Technology Prize (Japan), 1988
Warren Alpert Foundation Prize (Harvard Medical School, U.S.A), 2000
22nd Japan Prize (Science and Technology Foundation of Japan) 2006
Lasker~DeBakey Award for Clinical Medical Research 2008

The Major Academic Paper That Announced the Discovery
A New Type of Cholesterolemic Agent Produced by a monoacus Species. Journal of Antibiotics. 32(8): 852-854. Endo, A. 1979. Monacolin K.

Curriculum Vitae
1957 BA, Tohoku University
1957 - 1978 Research Fellow, Sankyo Co.
1966 PhD in biochemistry, Tohoku University
1966 - 1968 Research Associate, Albert Einstein College of Medicine
1979 -1997 Professor, Tokyo University of Agriculture and Technology
1997 - (Present) President of Biopharm Research Laboratories

Links to Scientist & Science Information on the Subject
Akira Endo's Home Page
https://en.wikipedia.org/wiki/Akira_Endo_(biochemist)
A Historical Perspective on the Discovery of Statins
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108295/