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Akira Endo - Statins:
This one was a struggle. A relatively new drug class, statins became widely recognized in the early 1990s and have since been progressively used by older patients. Concerning people over the age of 20 (~74 percent of the US population), in 1993, approximately 3 percent were on a statin; by 2006, nearly 10 percent of this population was taking a statin. To determine total potential beneficiaries, I found annual US population data from 1993 – 2008, totaled 74 percent of this figure, then I calculated 3 percent of this total for roughly the first few years, with an incremental increase over the years up to 10 percent for 2008. This figure was extrapolated to include all developed countries with similar lifestyles, healthcare systems, availability and use of statins. Interestingly, although statins have been introduced in a number of other large populations (China, India, etc.), their effects were less dramatic due to differences in genetics, diet and lifestyles and were therefore not included in our final total. The data came from a large-scale empirical study in Europe published in 1995 known as the Scandinavian Simvastatin Survival Study, or 4S, which estimated statins reduced the risk of death by 30 percent. This reduction was largely attributed to reduction in the risk of death from coronary heart disease and major coronary events. While there is controversy over the benefits of statins to people with high cholesterol but a low risk of having a heart attack, there is ample proof of their benefit to those with high risk factors.
--Amy R. Pearce, PhD
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(November 14, 1933 - )
Born in Japan
Year of Discovery: 1972
Scientist Finds Drug that Changes the Lives of Heart Patients
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 proved 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 within over the past couple of decades.
Coronary heart disease (CHD) affects about 14 million people in the United States. 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. CHD caused 452,300 deaths in 2004 and is the single leading cause of death in America today for men and women or about 71% of all heart disease deaths. Over 15 million Americans have had a heart attack or anginaheart related pain (angina). An estimated 1.2 million Americans will have a heart attack this year alone. From 1994 to 2004 the death rate from coronary heart disease declined 33 percent. This dramatic decline can be largely attributed to statin drug use, which was birthed by Akira Endo.
by Adam Allie
Table of Contents
Key Experiment or Research
Quotes by Akira Endo
Quotes About Endo
Excerpt from Scienctists Greater than Einstein
The Science Behind the Discovery
Key Contributing Scientists
Science Discovery Timeline
Recommended Books About the Science
Books by Akira Endo
Books About Endo
Major Academic Papers
Links to Science and Related Information on the Subject
Click the image to view Akira Endo's Lasker Foundation interview
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.
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 was the first discovered statin.
About Growing Up
"We lost the war. Even adults did not know what to do. We did not have food and clothes. Everything was called off. Even kids lost their dream. It was so hard that even kids did not have hope."
"I negotiate with my father personally about going to a high school. And I rampaged until he said yes." Hatakeyama asked, "What did you do as rampage?" Endo replied with strong, clear eyes, "I wore boots and walked and rampaged on a rolling board (for Japanese rice cake)."
In college "sometimes I was too hungry to concentrate, and I could not hear a lecture. Also, sometimes I felt dizzy and crouched down in a hallway to keep from fainting."
"At that time, doing research on nucleic acids and proteins was very popular among other researchers, so I avoided researching those topics. I chose the biochemistry of lipids (cholesterol and fatty acid) as my research theme. The reason why I chose this theme was that not so many researchers were researching it. This meant I did not have much competition."
"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."
"We received no response from Merck and had a feeling of dread that maybe they were contriving a plot of some sort."
"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 and sweat.... The discovery and development of statin 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."
"My team and I shouted with joy and toasted our success when we discovered the dramatic effect of compactin!"
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."
"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."
"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."
"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."
The Fly-Catching Mushroom
As a boy, Endo's grandfather taught him that some poisonous toadstools could be eaten after boiling out the poisons. He found this mysterious and the idea stuck with him. A few years later while he was in high school on a summer break, he devised his own experiment. He boiled a fly-catching mushroom, and put the cooked mushroom on one plate and its broth on another. Flies were attracted to both, but only those that drank from the broth died. "I confirmed that the poisonous ingredient of Tricholoma muscarium Kawamura (which kills flies, not humans) is water-soluble, like my grandfather said," Endo recalled.
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.
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."
The Doctor Knew Not His Patient
Through it all, Endo has kept a good humor. In 2004, a Festschrift was held in Japan to honor Endo. Festschrift is a German word meaning "celebration publication." Many relevant scientific articles and memoirs of people with whom he had associated were put together and published, and a dinner was held in his honor. When it was Endo's turn to speak he said, "Today I have good news and bad news. The bad news is that my cholesterol levels have reached 240 mg/dl. Maybe I had Sukiyaki or Shabushabu too often! ...The funny thing is that the doctor said, ‘Don't worry! I know some very good drugs to lower your cholesterol.'"
Double Cherry Blossom Blooms
Most of his time was spent with his grandparents, who lived with the large family on the farm. He slept in their room and listened to their stories. His grandfather was well liked in the community, and did fortune telling and amateur doctoring on the side. Since there was no local doctor in the area, he would dispense drugs and cures for minor injuries and sickness. In the autumn when Endo was in the fourth grade, his beloved grandmother became sick. At night, she took his hand and said, "Grandma's disease is the one which cannot be cured" and made him touch her belly. He would place his fingertips gingerly on her belly and feel a small crunchy thing. His grandfather could not cure it, nor could the professional medical doctor they sent for. Day by day the crunchy thing got bigger and Endo's grandmother got thinner.
That May the double cherry blossom tree in Endo's backyard bloomed gloriously, and his grandmother was released from the pain of cancer. He thought, "I want to become a doctor to help people who are suffering from diseases."
The company Akira Endo worked for when he discovered compactin, the Sankyo Corporation was founded at the turn of the century by Dr. Jyokichi Takamine, who in 1912 donated the 3,000 cherry trees that now so extravagantly mark springtime in Washington D.C.
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.
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
Worldwide sales of statin drugs have far surpassed $100 billion.
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.
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 the 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. He began looking in them for cholesterol inhibitors using the following steps:
1) Grow one hundred culture broths in flasks.
After analyzing 6,392 strains of fungi, the best candidate was at first labeled ML236B, later to be named compactin.
As the first stain drug, its chemical structure is the basis that all later statins would be based upon.
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!"
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. John McMichael 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.
For the past decade there has been a controversy over whether lowering cholesterol for those not at risk of a heart attack is worthwhile. Some have suggested that everyone should take a statin. Others claim that there are enough side effects and expense to discourage such use. A recent 2008 study (by Dr. Paul Ridker of Brigham and Women's Hospital in Boston ( http://www.latimes.com/news/science/la-sci-statin10-2008nov10,0,802569.story ) of nearly 18,000 patients found a marked decrease in death by heart disease in those taking statins.
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, their oldest son being named Tadasu. He left Sankyo at the end of 1978 for the Tokyo University of Agriculture and Technology. Today he is retired, living in Tokyo.
1949 - John Gofman linked lipoproteins to the causation of heart disease
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Very cool interactive 3D model of a statin
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How statins work
Coronary Heart Disease
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http://www.nationmaster.com/encyclopedia/Akira-Endo-(biochemist)#_note-JapanPrize - October 7, 2008
http://nobelprize.org/nobel_prizes/medicine/laureates/1964/bloch-bio.html - October 7, 2008
http://www.utsouthwestern.edu/utsw/cda/dept14857/files/114532.html - October 21, 2008