How was penicillin discovered bread

Perspective from Theodore C. Eickhoff, MD

Source/Disclosures

Source: Fleming A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation ofB. influenzae.British Journal of Experimental Pathology. 1929;10:226-236. Haven KF.Marvels of Science: 50 Fascinating 5-Minute Reads. Connecticut: Libraries Unlimited; 1994:182.

Perspective from Theodore C. Eickhoff, MD

Source/Disclosures

Source: Fleming A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation ofB. influenzae.British Journal of Experimental Pathology. 1929;10:226-236. Haven KF.Marvels of Science: 50 Fascinating 5-Minute Reads. Connecticut: Libraries Unlimited; 1994:182.

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This year marks the 80th anniversary of the discovery of penicillin, the first naturally occurring antibiotic drug discovered and used therapeutically.

It all started with a mold that developed on a staphylococcus culture plate. Since then, the discovery of penicillin changed the course of medicine and has enabled physicians to treat formerly severe and life-threatening illnesses such as bacterial endocarditis, meningitis, pneumococcal pneumonia, gonorrhea and syphilis.

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Often described as a careless lab technician, Fleming returned from a two-week vacation to find that a mold had developed on an accidentally contaminated staphylococcus culture plate. Upon examination of the mold, he noticed that the culture prevented the growth of staphylococci.

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An article published by Fleming in the British Journal of Experimental Pathology in 1929 reads, “The staphylococcus colonies became transparent and were obviously undergoing lysis … the broth in which the mold had been grown at room temperature for one to two weeks had acquired marked inhibitory, bactericidal and bacteriolytic properties to many of the more common pathogenic bacteria.”

Fleming described the colony as a “fluffy white mass which rapidly increases in size and after a few days sporulates” and changes color from dark green to black to bright yellow.

Even in the early experimentation stages, penicillin had no effect against gram-negative organisms but was effective against gram-positive bacteria.

Published reports credit Fleming as saying: “One sometimes finds what one is not looking for. When I woke up just after dawn on Sept. 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I guess that was exactly what I did.”

Though Fleming stopped studying penicillin in 1931, his research was continued and finished by Howard Flory and Ernst Chain, researchers at University of Oxford who are credited with the development of penicillin for use as a medicine in mice.

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Penicillin helped reduce the number of deaths and amputations of troops during World War II. According to records, there were only 400 million units of penicillin available during the first five months of 1943; by the time World War II ended, U.S. companies were making 650 billion units a month.

To date, penicillin has become the most widely used antibiotic in the world. – by Katie Kalvaitis

References:

Fleming A. On the antibacterial action of cultures of a penicillium, with special reference to their use in the isolation of B. influenzae. British Journal of Experimental Pathology. 1929;10:226-236.

Haven KF. Marvels of Science: 50 Fascinating 5-Minute Reads. Connecticut: Libraries Unlimited; 1994:182.

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Theodore C. Eickhoff, MD

It is interesting that using penicillin for the treatment of infections like pneumococcal pneumonia and bacterial endocarditis never had a randomized, controlled trial because the difference with treatment was so clearly apparent that no one even thought of doing a randomized controlled trial.

Theodore C. Eickhoff, MD

Infectious Disease News Editor Emeritus

Professor of Medicine

Division of Infectious Disease

University of Colorado Health Sciences Center

Disclosures: Eickhoff reports no relevant financial disclosures.

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The ancient Egyptians were a generous bunch. They gave us the pyramids, mathematics, quite a bit of eyeliner, and an astonishingly advanced system of medicine. Their medical texts detailed basic surgery and how to treat brain injuries. But the most intriguing bit of health advice in their repertoire? Covering wounds with moldy bread to fight off infections. The ancient Egyptians may have actually stumbled upon the antibiotic principle behind penicillin almost 5,000 years before modern medicine did.

On a normal day in 1894, Ernest Duchesne noticed something strange. The Arab stable boys at his army hospital stored horse saddles in a dark, damp room, rather than somewhere cool and dry. The boys explained that it was so mold would grow and heal the saddle sores on their horses.

Three years later, Duchesne submitted his doctoral dissertation on that very topic: “Contribution to the Study of Vital Competition in Microorganisms: Antagonism Between Molds and Microbes.” Perhaps a catchier title would have shined the spotlight on the young, unknown Duchesne, whose army service prevented him from performing further research. Instead, Alexander Fleming got credit for discovering penicillin’s moldy antibiotic properties.

In 2006, Anna Hingley spent 145 days in the saddle to become the first woman to cross the punishing Australian Outback on horseback.

Perhaps more notable than Alexander Fleming’s discovery of penicillin is his proving just how important a vacation can be for our health. After returning from a refreshing trip in September 1928, Professor Fleming found a bluish-green mold surrounded by a ring of repressed bacterial growth in a petri dish that had been mistakenly left open in his laboratory at St. Mary’s Hospital in London. Fleming grew a pure culture of the mold and discovered it to be an antibacterial agent that would eventually become penicillin, the most widely used antibiotic class to date.

If not for a single moldy cantaloupe from Peoria, Illinois, the 1944 invasion of Normandy may have had a less successful outcome for the Allied troops. A rotting melon found in an unassuming market’s garbage proved to be a superior specimen, containing the strongest strain of penicillium found to date. Researchers were able to help the U.S. War Production Board produce 2.3 million doses of penicillin in time for D-Day by mixing penicillium into the culture medium with a nutrient-rich corn steep liquor. An estimated 15% of Allied lives were saved due to penicillin’s ability to remedy infected wounds suffered on the battlefield.

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Considered a weed by some, the sun-loving, sweetly aromatic Sweet Annie or Sweet Wormwood plant is more than just a fluffy, yellow-headed flower–it’s a treatment for malaria. Extracts of the plant were first described as a treatment for fever in Chinese texts found in a dusty Mawangdui Han Dynasty tomb dating back as far as 200 BCE. In the middle of the fourth century, it was recognized for its malarial-fighting properties, garnering 43 mentions in noted Chinese physician Ge Hong’s Handbook of Prescriptions for Emergencies. Today, it’s at the heart of artemisinin-based combination therapy.

In 1967, Viet Cong soldiers were suffering. Malaria was running rampant in the thick heat of North Vietnam, and something was desperately needed to soothe the aches and pains of these men. At the request of Ho Chi Minh, Mao Zedong commanded a research program by the name of Project 523 to find a treatment among the traditional medicines of China and get the soldiers back on their feet. In 1972, the program’s plant screening and botanical preparations led to the discovery of artemisinin in the leaves of the Sweet Annie. Among the 5,000 traditional Chinese medicines researched, it was found to clear malarial parasites from the sick faster than any other medicine.

By learning from nature’s designs and building off of them, we now have the ability to create something called a semisynthetic derivative. It’s a compound that begins as a natural product (like the artemisinin in the Sweet Annie plant) and is modified using organic chemistry to produce a related but different compound. Artemether is a semisynthetic derivative of artemisinin, and lumefantrine is a synthetic compound. By combining these two molecules, Novartis—together with Chinese institutes—has developed an artemisinin-based combination therapy that reduces the likelihood that malaria will become resistant, since the parasite would have to evolve to resist the two at the same time. Take that, malaria.

After working with the World Health Organization to make its ACT available without profit for the countries that needed it most, Novartis introduced the treatment to Zambia, where 1,000 children were dying from malaria every week. After just a few months, the locals took to calling it “Kwa tenwa” which translates to “I’m happy.” With the treatment’s help, plus an adequate number of mosquito nets, malaria mortality in children dropped by 50%.

In addition, scientists noticed that Zambian mothers were crushing the ACT tablets and mixing them with milk or honey to make them appeal to their finicky babies. Knowing that two-thirds of malaria patients were children, the team quickly developed a sweet-tasting dispersible tablet that goes down with a touch of water.

For more on Novartis’ remarkable antimalarial efforts, visit malaria.novartis.com.

The name “Zambia” comes from the Zambezi River, which creates the country’s southern border.

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The ancient civilizations responsible for the origins of law and religion also laid the foundations of medicine by exploring the natural world around them.

Mesopotamian cuneiform tablets describe symptoms, diagnoses, and treatments, many involving plant and animal extracts. The Ebers Papyrus describes over 800 preparations and strategies for relieving the suffering of ancient Egyptians. Disciples of Dhanvantari, the Hindu “Father of Medicine”, dispensed Ayurvedic wisdom across the whole of the Indian subcontinent. And Huang Ti, the legendary Yellow Emperor of China, is said to have compiled his famous Canon of Medicine as early as 2600 B.C.E.

Lucky for us, early healers were generous with their notes, leaving valuable clues for their modern counterparts to follow. In many cases, the same active ingredient that made ancient remedies effective has been harnessed by modern scientists in the pursuit of new treatments for disease.

Works of Hippocrates (c. 460–370 BCE), Dioscorides (c. 40–90 CE), and Galen (c. 129–200 CE), whose observations guided civilizations’ practices for centuries.

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There’s a lot to shiver about when you live in the frigid, windy Andes of Peru. In 1631, Agostino Salumbrino, a Jesuit priest living in Lima, noticed the local Quechua people’s remedy to still their shivering bodies when temperatures dipped — chewing the bitter bark of the cinchona tree. So when Salumbrino saw malaria’s shake-inducing fevers while training in Rome, he immediately sent for cinchona bark from Peru. And even though shakes from the cold are entirely unrelated to malarial shivers, remarkably, this “fever tree bark” turned out to be the cure. Why? It contained a curious ingredient called quinine sulfate.

While it’s never polite to interrupt, quinine gets the exception. In order for the malaria parasite to duplicate and survive, it eats hemoglobin and releases a waste product called heme. Quinine sulfate is thought to work by inhibiting the parasite’s ability to get rid of the toxic waste, interrupting its reproductive pattern. Once the parasite can no longer replicate itself, the body is better able to fight off the original infection.

As soon as King Charles II of England began using quinine sulfate to treat his malaria, the entire British Empire embraced it, including those fighting in the sticky, humid outpost of colonial India. To offset quinine sulfate’s bitter taste, British soldiers began mixing the powder with a tonic of sugar and soda water. At the same time, gin was regaining respectability, so it wasn’t long before a colonial official combined his daily dose of quinine tonic with a ration of gin. And thus, the beloved gin and tonic was born.

Cheers to that.

Because of the quinine molecules in the tonic half of gin and tonic, the drink glows fluorescent blue under ultraviolet light.

While a synthetic derivative of quinine called chloroquine is still used to treat malaria today, after 40 years, it has lost much of its effectiveness. According to the World Health Organization, resistance to artemisinin, the key compound in the current standard treatment, has now been detected in Southeast Asia, a high-risk area. Even today, malaria claims 660,000 lives each year, with 90% of cases found in Africa, where children and pregnant women are most susceptible.

Nature’s history of outsmarting malaria treatments makes it critical to stay one step ahead of the parasite. Novartis provides unprecedented access to antimalarials and is leading the way in its efforts to bring the next generation of medications to market. And with rapid-diagnostic tests that help people confirm and treat malaria cases faster in remote areas, it’s not unreasonable to think the end of malaria may not be far off.

For more on Novartis’ remarkable antimalarial efforts, head over to malaria.novartis.com.

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Cheerful daffodils are synonymous with springtime, signifying nature’s rebirth after the long winter. Surprisingly, daffodils are also becoming increasingly synonymous with a promising treatment for Alzheimer’s. Galantamine, a natural extract present in daffodils’ leaves and bulbs, has been shown to slow the breakdown of neurotransmitters in the brain. And while it cannot cure dementia, which affects the elderly in every country in the world, it has been found to improve memory, awareness, and communication skills.

In his Enquiry into Plants, the ancient Greek botanist Theophrastus refers to the daffodil by its Greek name, Narcissus. In mythology, the handsome Narcissus spurned the mountain nymph Echo and was punished by being lured to a pond where he fell hopelessly in love with his own reflection. The flower that sprouted where he died is known today as Narcissus poeticus, or the Poet’s Daffodil.

If you spot the first daffodil of spring in Wales, legend has it your next year will be filled with wealth.

Until recently, most of the world’s supply of daffodils came from the Balkans. In the 1950s, a Bulgarian pharmacologist saw villagers rubbing their foreheads with the leaves and bulbs of the yellow flower to ease nerve pain — a practice that dates back to Homer’s Odyssey. This was enough to prompt further study, and in 1958, a compound developed from the daffodil was approved for use in Bulgaria.

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To hear Hollywood tell the story, history’s great explorers set sail for the promise of wealth, glory, and freedom. But in truth, many were searching for molecules—organic compounds locked in the spices of the East Indies, the coffee berries of the Andes, the cacao pods of West Africa, the bark of exotic trees, and the leaves of poisonous plants.

Naturalists classified them, aristocrats collected them, pharmacists isolated them, and, in time, chemists synthesized them, teasing apart the chemical complexity that came to inspire the age of modern medicine.

The famous botanical illustrators who accompanied the HMS Endeavor and the HMS Beagle, together with the anonymous men and women who preceded them, blended art and science, observation and imagination.

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As is the case with most naturally derived products, digoxin treads a fine line between toxicity and therapeutic treatment: All parts of the foxglove plant, from which it is derived, are poisonous, but digoxin can increase the strength of heart muscle contractions and save the lives of people being treated for congestive heart failure and cardiac arrhythmia. Although many treatments are now synthesized, digoxin is still derived from the deadly foxglove plant today.

While serving as a physician at the Stafford Royal Infirmary, William Withering fell in love with one of his patients, a botanical illustrator, which resulted in the literal marriage of medicine and botany. Withering later observed that a patient suffering from congestive heart failure recovered after being treated with an herbal remedy provided by “an old woman in Shropshire, who had sometimes made cures after the more regular practitioners had failed.” He deduced that the cardioactive ingredient in the plant mixture was the foxglove leaves. His findings were published in 1785, and are widely considered to be a turning point in diagnostic medicine.

Vincent van Gogh, the tormented artist who died by suicide in 1890, had a complex and varied medical history: in his letters he complained of poor digestion, insomnia, and depression, which has drawn speculation from psychiatrists and biochemists as well as art historians. Ultimately, his art must speak for itself, but his last paintings offer tantalizing clues as to his debilitating ailments and afflictions. The yellowish halos that illuminate his Starry Night painting are a recognized symptom of digoxin poisoning, and in the portrait of Old Dr. Gachet, his sad-eyed physician is seen clutching what appears to be a sprig of foxglove.

Van Gogh painted flowers, landscapes, and himself, mostly because he couldn’t afford to pay models to pose.

During World War I, well before she became the most famous mystery writer in the world, Agatha Christie volunteered as a nurse in a military dispensary. Christie’s knowledge of medicine undoubtedly helped Lady Westholme dispatch Mrs. Boynton with a lethal dose of foxglove extract in Appointment with Death (1938). She worked in the pharmacy of University College Hospital in London during World War II, and soon after finished off another cast of characters by means of strychnine, arsenic, cyanide, and thallium.

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Everyone remembers the scene in The Wizard of Oz where Dorothy and her friends venture into a great meadow of scarlet poppies: “Presently her eyes grew heavy and she felt she must sit down to rest.” Dorothy had succumbed to the power of Morpheus, the god of sleep and dreams, for whom the powerful opioid analgesic is named. Morphine acts on the central nervous system to reduce pain and is known to induce feelings of euphoria—as Dorothy and her friends discovered.

Dorothy’s slippers were actually silver in L. Frank Baum’s 1900 novel The Wonderful Wizard of Oz. They were changed to ruby in the film in order to take advantage of Technicolor’s new “wow” factor.

Opium was heavily prescribed by Paracelsus, an occult Renaissance alchemist who originally named it laudanum, from the Latin “to praise,” for its wondrous power to reduce pain and suffering. Nearly three centuries later, in 1804, a pharmacist’s assistant named Friedrich Sertürner successfully extracted morphine from the resin of the opium poppy in what is regarded as the first isolation of a plant alkaloid in history. This meant that a natural product could now be purified and administered in controlled doses.

Heinrich Emanuel Merck, whose ancestors had been apothecaries since 1668, began the commercial production of morphine in 1827. Sold as a pain reliever out of a handsome, gabled house in the Hessian city of Darmstadt, morphine was the flagship product of Merck’s “Cabinet of Pharmaceutical and Chemical Innovations.” By the 1850s the chemist’s laboratory had given way to a steam-driven factory with 50 employees and was exporting its “fine chemicals” to the rest of Europe and America, marking the beginning of the modern pharmaceutical industry.

Rediscovered in the 19th century, morphine became the opiate of choice of the Romantic poets, including Byron, Shelley, Keats, Coleridge, and Elizabeth Barrett Browning. In his Confessions of an English Opium Eater (1821), Thomas de Quincey confesses his first experience with the medicine that he described as “A panacea for all human woes … happiness might now be bought for a penny, and carried in the waistcoat pocket.”

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The Aspirin Foundation estimates that 100 billion aspirin tablets are swallowed every year. Indeed, we are living in what the Spanish philosopher José Ortega y Gasset called “The Aspirin Age.” This wonder drug, used to treat everything from toothaches to stroke, was the very first mass-produced, over-the-counter synthetic medicine.

Although Hippocrates was clever and kind enough to prescribe willow bark infusions to ease the pain of childbirth, the modern discovery of aspirin is usually traced to an English clergyman, Edward Stone, in 1763. While strolling in his native Oxfordshire, Stone succumbed to a violent headache and found that chewing the bitter-tasting bark of a willow tree relieved his symptoms. Finding no ill effect, he administered the drug to 50 of his parishioners in what could be considered the world’s first clinical trial.

Hippocrates had such an impact on medical history that to this day, all newly qualified doctors still take what is called the “Hippocratic Oath,” swearing to practice medicine honestly.

In 1897, during the great age of science-based chemistry, scientists working for the German company Bayer isolated salicylic acid and found a way to alter it chemically to reduce gastrointestinal distress. Just two years later, with Bayer shifting its operations from chemical dyes to pharmaceuticals, the company registered the name “Aspirin” and began distributing the white powder to hospitals and clinics. Tablets followed soon after in 1900. In 1915, aspirin became available to the public without a prescription. Today, it is the most widely used medication in the world, with an estimated 40,000 tons produced annually.

Prince Alexei, the only son of Tsar Nicholas and Alexandra Romanov, was born with genetic hemophilia, a condition that inhibits blood clotting. Alexei’s medical condition became the obsession of his parents, whose search for a cure led them to the Siberian mystic Grigori Rasputin. In 1907, in the throes of a particularly grave crisis of Alexei’s, Rasputin advised the Czarina, "Do not allow the doctors to bother him too much." It is believed the young prince was being treated with aspirin, now known to be a blood-thinning agent. By saving his life, the wild-eyed faith healer planted himself in the royal court, where his influence became the object of popular resentment.

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People have been using plants and natural organisms to heal themselves, cure themselves, and comfort themselves for thousands of years. But knowledge of the active ingredients in such remedies is surprisingly recent.

The beginnings of modern medicine lie in the 18th century Age of Enlightenment, as natural philosophers were evolving into scientists, and trial and error were yielding to systematic experimentation. The 19th century saw a shift from the local apothecary to the laboratory and the factory as chemists learned first to isolate, then synthesize, and finally manufacture nature’s exquisite molecules.

Treatments first displayed in utilitarian jars that lined the shelves of the village apothecary were later sold in imaginative bottles that touted the patent medicines of the 19th and 20th centuries. Pharmaceutical packaging today is designed to safeguard the purity and activity of the products themselves.

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In 1992, John Eng, a clinical endocrinologist and research scientist at the Bronx Veterans Administration Medical Center, ordered a sample of dried lizard’s venom from a mail order house in Utah. Building on research undertaken at the National Institutes of Health during the previous decade, Eng discovered that the secretion contained two compounds that stimulate the body's production of insulin, a hormone that helps cells process blood sugar. Luckily for Gila monsters everywhere, lizard spit has now been fully synthesized. The result is exenatide, one of the most promising treatments for diabetes to date.

It’s against Arizona state law to harm a Gila monster.

In an effort to convince fellow members of Congress of the importance of federally funded basic research, Representative Jim Cooper of Tennessee instituted the Golden Goose awards to showcase examples of “seemingly obscure studies that led to major breakthroughs and resulted in significant social impact.” In 2013, the Golden Goose was conferred upon Dr. John Eng for his discovery of exendin-4 in Gila monster venom, which now aids diabetics as the fully synthetic exenatide.

Dr. John Eng was not the first medical researcher to be fascinated by the Gila monster. George Emory Goodfellow, coroner and chief physician in the Wild West town of Tombstone, Arizona, offered $5 for Gila monster specimens. In 1891, having subjected himself to a bite, he wrote to Scientific American, “The belief in the [deadly] poisonous nature of the lizard [is] purely mythical and superstitious, the remnant of primitive man's antagonism to all creepy things.”

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In the dark tragedy Macbeth, three witches concoct a noxious brew that includes “eye of newt and toe of frog, wool of bat and tongue of dog.” Easy enough. For good measure, they also tossed in “slips of yew, sliver’d in the moon’s eclipse.” But what exactly is that? Four centuries later, as part of a U.S. Department of Agriculture screening program, botanist Arthur Barclay stuffed fifteen pounds of needles, twigs, and bark of a Pacific yew tree into a sack and shipped it back to the USDA in Maryland. Paclitaxel, a molecule derived from the tree, would prove to be a natural source of a widely used anti-cancer treatment.

Shakespeare invented the word “addiction.”

Across the ocean, Pierre Potier and his team at the French National Centre for Scientific Research discovered a substance similar to paclitaxel in leaves of the European yew tree Taxus baccata. Rhȏne-Poulenc developed and launched its own drug based on this substance. This class of medicines has become one of the most widely used anti-cancer treatments of all time.

In the future, we may look back at the drip-drip-drip of the intravenous chemotherapy infusion the same way we look at the medieval practice of bloodletting, or the ancient technique of trepanation, where surgeons would bore a hole in the skull to release demonic spirits. For the time being, however, medicines derived from the Pacific and European yew trees remain highly effective treatments for breast, ovarian, lung, and prostate cancer, and their discovery represents a milestone in modern, science-based medicine.

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In medieval times, “St. Anthony’s Fire” was the name given to an ailment that afflicted sufferers under the benevolent care of the Order of St. Anthony. In addition to physical symptoms, these wretched souls experienced mania, psychosis, and a loss of contact with reality. The source, we now know, was a toxic fungus, ergot, that typically grows on rye and is used to synthesize a powerful chemical known as ergotamine. This substance—isolated in 1918—became the first drug to emerge from a newly created research department at Sandoz (now a part of Novartis). Ergotamine reduced bleeding after delivery and later became a powerful medication against migraines.

On April 16, 1943, a Swiss biochemist experienced the world’s first acid trip. In 1938, as part of a systematic research program at Sandoz that aimed to identify a substance that would strengthen blood circulation, Albert Hofmann synthesized a series of ergot alkaloids, using ergotamine as one of his starting materials. He called the twenty-fifth synthesis “lysergic acid diethylamide 25,” better known as LSD. Five years later, having accidentally ingested a quantity of the substance, he sent a report to his superior, Professor Arthur Stoll, reading, “I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors." Sandoz Laboratories marketed LSD in the 1950s under the brand name Delysid as medication to support psychotherapy.

Ken Kesey, author of One Flew Over The Cuckoo's Nest, became involved with LSD in the early 1960s and formed a famous group of users called the Merry Pranksters.

Albert Hofmann, who would go on to become director of the natural products division at Sandoz Laboratories (now a part of Novartis), referred to ergot alkaloids (LSD) as “my problem child.” As it filtered out of the research laboratory, where purity and proper supervision could not be controlled, LSD came to take on a second life in 1960s counterculture. Shunned by funding agencies and prohibited by law, research came to a halt. Only now, some 65 years after Albert Hofmann’s self-experiment, is LSD returning to research labs—at Harvard (2008), the University of California, San Francisco (2009), and in the UK and Switzerland—where it’s being studied for possible use in the treatment of alcoholism, depression, cluster headaches, and end-of-life anxiety.

Believe it or not, ergot alkaloids are regularly used for new moms. Since the 1940s, almost every woman who gives birth immediately takes a derivative of lysergic acid. This medication constricts blood vessels, causing smooth muscle tissues to narrow, which greatly reduces bleeding after delivering a bustling baby boy or girl.

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By the 1980s, many members of the scientific community believed that the heyday of natural products research was over. The prevailing thinking was that natural products were primarily valuable as tools for discovering antibiotics, and the vast arsenal of antibiotics on the market had already conquered bacterial infections.

Add to that, the onset of combinatorial chemistry. Now chemists could synthesize thousands of different molecules in one fell swoop, creating countless new compounds that, in theory, could serve as starting points for medicines. These compounds could be isolated more easily than those found in nature and used in a variety of experiments, including high throughput screens, making them compatible with emerging automation technologies. So after generations of taking inspiration from natural products, medicine’s R&D establishment, like the pop music of that decade, went synthetic.

Novartis, on the other hand, made a bet. Instead of shutting down its natural products group, which had been in existence since 1917, Novartis continued to invest in it. After all, nature boasted a great track record, and the group, led by Frank Petersen, believed it still had more to offer. Armed with that conviction and the insight that nature’s molecules are architecturally complementary to synthetic ones (with the added benefit of a reduced likelihood of interacting with anything other than their intended targets), they paved the way forward. In the early 1990s, Petersen’s team set out to harness the recent technology boom to unlock new approaches for producing, isolating, and using nature’s molecules to create cutting-edge medicines.

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The tricky mosquito-borne parasite we call malaria starts in the blood and then moves to the liver, where it reproduces before returning to the blood. Most antimalarials on the market today only target the blood stage, allowing the parasite to linger in the liver. After lying dormant for months or years, these wily parasites can reinfect the blood and resume the cycle of destruction.

According to the Guinness Book of World Records, the world’s largest tomato tree was grown in an experimental greenhouse at Walt Disney World Resort.

Researchers at the Novartis Institutes for BioMedical Research are looking for a treatment that targets both stages of malaria to kill the parasite for good. With help from some robots, they recently doused blood-stage malaria parasites with 12,000 different natural compounds, 275 of which successfully inhibited the parasites’ growth. Next, they applied all 275 compounds to liver-stage malaria parasites. A chemical called cladosporin—which had been isolated from an unassuming fungus—stood out as being effective against both stages of the disease. Who knew the rotting tomato in your kitchen could expose a parasite’s Achilles’ heel?

Once scientists knew that cladosporin worked, they wanted to know why. So they applied themselves to finding the target of cladosporin, the precise protein it hits in cells. For this detective work, they turned to baker’s yeast, the very species we use to make bread rise. They determined that cladosporin binds a protein called lysel-tRNA synthetase. Groups dedicated to eradicating malaria continue to investigate this promising new target.

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In 1969, Hans Frey, a biologist at Sandoz (now a part of Novartis), took his wife on vacation to Hardangervidda, a mountain plateau in Norway. With a year-round alpine climate, the area is home to some of the world’s most beautiful scenery and largest reindeer herds. So when Hans’ wife stopped to photograph the stunning flora and fauna, Frey collected souvenirs of his own—more than 50 soil samples he hoped would prove scientifically relevant. And lo and behold, one did. The fungus Tolypocladium inflatum produces cyclosporin, which is now used to prevent rejection in organ transplants.

Both male and female reindeer grow antlers. In fact, reindeer are the only kind of deer where this happens.

The human immune system is a bit like a bouncer at a club—it doesn’t let just anybody in. When an organ is transplanted into the body, T cells go into attack mode and actively try to fight the outsider in case it’s dangerous. So how do you sneak a foreign organ past these vigilant T cells? When cyclosporin is introduced into the body, it prevents T cells from producing chemicals called cytokines, which are attack signals. This allows the organ to be accepted into its new home like a VIP.

While it is, quite literally, a lifesaver, cyclosporin can cause problems when paired with an unassuming breakfast item—the grapefruit. Normally, our bodies absorb only a small amount of the active ingredient in a pill due to an enzyme in our gut poetically called CYP3A4. Grapefruit contains furanocoumarins, which are natural chemicals that inhibit this enzyme, causing the absorption of way more of the medicine than intended.

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Scouring Easter Island (locally known as Rapa Nui) for plant and soil samples in 1964, Canadian scientists unearthed new species of bacteria. Later, in Montreal, Ayerst researchers found that a compound produced by Streptomyces hygroscopicus—a bacterium in one of the samples—was a potent antifungal agent. Researchers named it rapamycin after the island where it was discovered. The compound showed other surprising effects—it suppressed the immune response. Scientists decided to test this out in a different field—organ transplantation. They hypothesized that by keeping the immune system in check following a transplant, the new organ would not be rejected. Clinical trials proved them right

The famous Moai statues of Rapa Nui are enormous, rising up to 40 feet (12 meters) tall and weighing 75 tons.

Scientists are data-driven explorers; they like to know how things work. So they set out to discover which cellular protein rapamycin was hitting. But it’s tricky to track a microscopic marksman whose target resides in a complex environment. After all, a cell resembles a bustling city, teeming with proteins going about their business. In 1991, investigators finally succeeded. They found that rapamycin binds a protein that they didn’t know existed, naming it “target of rapamycin,” or TOR.

Teams began mapping TOR’s interactions with other components of cells and uncovered a network of proteins—a molecular signaling pathway—that plays a critical role in development and disease. It turns out that TOR is a regulator that controls cell metabolism and growth. This finding led scientists to investigate additional uses of rapamycin, especially for the treatment of cancer.

Rapamycin, like some other natural products, serves as a wedge for biologists, helping them to pry apart murky aspects of biology and understand how our cells work. Natural products are essentially chemicals that have been optimized by millions of years of evolution to bind important biological targets—proteins. These proteins are embedded in core molecular pathways that regulate the fundamental activities of cells.

The discoveries of rapamycin and its target, TOR, are fundamental to biology. Scientists at various institutions and companies, including Sandoz, which later became part of Novartis, have developed semi-synthetic derivatives of rapamycin that are being investigated for their uses in a variety of seemingly unrelated diseases. The molecular connections between these diseases were unknown prior to the discovery of rapamycin and the TOR pathway.

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What’s happening in the labs of Novartis today? By painstakingly cataloguing and experimenting with approximately 15,000 natural products, scientists are cracking open a treasure chest of disease-fighting riches using the most advanced methods and technologies.

How do they put these riches to work? First, researchers use them in massive screening campaigns. They place diseased cells into thousands of different compartments, add a natural compound or synthetic chemical to each compartment, and look for interesting responses called “hits.”

The next step is to examine the hits in order to identify the biological target of the natural compound or synthetic chemical used in the compartment. In other words, to which cellular protein does it bind to achieve the interesting response? This protein likely plays a role in the disease.

Novartis researchers rely on yeast genetics for this detective work. That’s right; the same yeast you use to make bread also serves as an important tool in biomedical research. Yeast cells are shockingly similar to human cells, with many components—including many genes—in common. Yeast cells, however, are easier to grow and manipulate in the lab, so they’re often used as a proxy.

A global consortium of researchers created a collection of 6,000 yeast strains, each missing a copy of a different gene. Like human cells, yeast cells have two copies of each gene, so a missing copy doesn’t mean that the gene is entirely absent. The cell just produces less of the protein encoded by the gene. And that makes it exquisitely sensitive to chemicals that target the protein.

Scientists apply the natural compound or synthetic chemical of interest to the entire collection of yeast cells and wait. When one or more of the strains die, BAM, there’s your target. The team explores the protein target, including its position in molecular pathways, to identify opportunities for intervention. In some cases, the natural compound or synthetic chemical itself serves as the starting point for a new medicine.

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In the decade since the completion of the Human Genome Project, genetic sequencing has become so fast and affordable that it’s feasible to sequence the genes of pretty much anything and everything. Driven by this monumental advance, Frank Petersen and his team at Novartis are peering into the genomes of microorganisms, which are major producers of natural products. What they see is surprising, even to them.

It turns out that microorganisms harbor genes for natural compounds they don’t produce in ordinary conditions. Many of these genes code for molecules with outlandish structures that scientists have never encountered—structures optimized by evolution for unknown biological targets. This means that the Novartis catalogue of pure natural products—the largest in the world—is just the tip of the iceberg. Petersen’s group is now working to coax microorganisms to produce their hidden treasures.

This planet we’re lucky enough to have landed on is teaming with life, in all its imaginable and unimaginable forms. We’re all products of nature, splendidly individual but remarkably intertwined. As keepers of the world’s largest and constantly growing database of natural products, Novartis scientists have a unique window into molecules that both distinguish species and connect them.