The mother of medicine

The development of chemistry

A golden era of research

A new attempt

A medical treasure chest

Medicinal plants and natural substances such as fungi and minerals have been used for centuries to treat injuries and diseases. Their use is an expression of the profound bond between humans and nature and mirrors the cultural and scientific development of mankind. At first, magical, god-like powers were attributed to medicinal plants. Then Egyptian, Greek and Persian physicians incorporated them into a rational approach to medicine. This was the case until the first isolated natural substances were chemically analyzed in the early 19th century and became the forerunners of today’s pharmaceutical indus-try. Through the ability to isolate pure substances from plants, natural substances became the focus of pharma-ceutical sciences. This trend continued unabated until the rapid methodological advances in synthetic chemistry. With the development of the latest technologies that have enabled the analysis of complete plant genomes and microorganisms, the door to a new era in the research of natural substances seems to be opening.

Text by Goran Mijuk, photos by Jan Raeber

Table of contents

The mother of medicine

The development of chemistry

A golden era of research

A new attempt

This article was originally published in April 2014.

It must have been a hectic day in the laboratory of London’s St. Mary’s Hospital when Alexander Fleming got ready to leave for his summer vacation. It is no longer possible to say exactly what went on, too much has happened since then, but there were letters to write and send, and the last experiments that the Scottish bacteriologist had conducted likewise had to be documented and properly written up. It occurred to him that someone ought to have carried out a thorough cleaning of the lab, but that never happened. Fleming closed the door behind him, said goodbye to his colleagues, went to the station and sat down on the train that took him to the southern coast of England, where he planned on relaxing for the next few weeks. A Petri dish with a bacteria culture, an item he had forgotten all about in the last few hectic hours, remained where it was, unnoticed.

This, or something like it, is how one of the greatest discoveries of medical research could have started. Fleming later recalled the exact details about September 28, 1928, the day he returned from his vacation and with some astonishment viewed the mess he had left behind in the laboratory. As he stated years later when he had already been awarded the Nobel Prize for his discovery of penicillin, he would hardly have thought that this day would mark a fundamental change in the history of medicine. “However,” remarked the Scottish researcher laconically, “that’s exactly what happened.”

Instead of simply throwing away the forgotten and apparently dirty Petri dish with the staphylococci, he examined it in more detail. He noticed that a mold had developed in the middle, and all around it the dangerous staphylococci had died. His assistant pointed out that this could perhaps be exactly the thing they had been searching for all this time: a powerful substance that would kill bacteria.

Fleming, who served in the Royal Army Medical Corps during World War I, had dedicated himself to bacteriology and was persistent in his search for an effective antiseptic. During the war, he had witnessed in person how doctors could only stand by and watch as hundreds of thousands of soldiers died from bacterial infections. Even a slight wound incurred through a cut with a razor blade could easily prove fatal.

Fleming first looked for what are known as autovaccines and in doing so addressed the question of how body orifices such as the eye are able to fight off the onslaught of bacteria and other foreign bodies. He then discovered the lysozyme enzyme, which appears in many human bodily secretions such as tears and can kill bacteria. The discovery of penicillin from the mold of the Penicillium genus, which was much more effective than lysozyme, proved a real scientific breakthrough and was to revolutionize medicine.

Turnip from the Vienna Dioscorides.

The mother of medicine

The history of medicine would be inconceivable without medicinal plants. Their use is documented on clay tablets in Mesopotamia dating back as far as 3000 B.C. The Papyrus Ebers from Egypt, which has been dated at 1500 B.C., lists more than 800 medicinal plants and describes their use and even their dosages in detail. This scroll, almost 20 meters long, discusses the treatment of eye diseases, tumors and injuries such as broken bones and burns, and also contains information about anatomy. Even psychological ailments such as melancholy found their way into this early medical atlas, which today is preserved in the University Library in Leipzig. Similar compendia were also drawn up at around the same time in China and India, where the Ayurvedic system of medicine was developed.

This knowledge, however, relied to a large extent on the belief in magic during those early days, when nature was not only perceived as bing full of mystery but also as fearful and threatening. The Greek poet Homer coined the word pharmakon, which is the root of our term “pharmacy,” but he understood it more as a magical treatment that can be both a poison and a remedy. These thoughts were echoed later in the famous statement by Paracelsus, who reportedly said that “all things are poison, and nothing is without poison; the dose alone makes a thing not poison.” While battling the sorceress Circe, who had turned his sailing companions into swine on the voyage from Troy to Ithaca, Odysseus received from Hermes a kind of “pharmaceutical” counterspell originating with the gods:

As he spoke, Hermes pulled the herb out of the ground and showed me what it was like. The gods call it Moly, it is hard for mortal men to uproot it, but there is nothing the gods cannot do. (Odyssey, Book X, 302–305).

Under the influence of the philosophy of Plato and Aristotle, a rational approach to medicine developed in Greece and Rome. Increasing emphasis was placed on logic and a systematic approach, and magical powers were pushed further into the background, albeit not completely discounted. The De Materia Medica by Greek physician Dioscorides – who lived during the reign of Nero and Claudius and was able to travel throughout the Roman Empire in his capacity as a military physician – represents a climax of medical history at this stage. In his book, Dioscorides lists roughly 1000 medications, among them some of animal and mineral origin, which were available for use in more than 4000 applications.

Systematically structured, the book remained the standard medical reference in the West for more than a century and a half. It also formed the foundation for research activities in Baghdad, which after the fall of Rome became the center of medical knowledge. Europe, on the other hand, sank into the chaos of the Migration Period, from which the continent only started to recover in the early 11th century. Only the tireless efforts in Christian monasteries to translate and transcribe Byzantine, Persian and Arabic books made it possible for Europe to reemerge from a centuries-long cultural decline characterized by war, disease and famine, and to reconnect itself to the developed world and push ahead independently with research during the Renaissance.

Only a few decades after the plague had claimed the lives of a third of Europe’s population the invention of the printing press accelerated scientific progress. It ignited a hitherto unknown zeal for discovery that continues to this day and has gripped an entire world in which knowledge means not only power but also progress, prosperity and health.

Books about herbs, such as the Historia Stirpium (Basel, 1542) by German botanist Leonhart Fuchs with his true-to-life illustrations of plants and their traditional uses served to preserve knowledge about medicinal plants. In addition, physicians such as Paracelsus, who taught in Basel, rebelled against tradition and questioned conventional medical teachings, laying the foundation for a new approach to medicine. They created the basis for modern chemistry through ideas such as quinta essentia, which postulated that medicinal plants derived their efficacy from their ingredients.

An illustration from Leonhart Fuchs’ famous book about herbs, dating from 1543.

The development of chemistry

“Magic” was the kernel of medieval alchemy, but its proto-scientific method of testing and experimenting gained ground in modern times. Alongside the attempt to understand the world in a rational manner using principles and theories, scientific experiments took on growing importance. Assertions no longer stood without being challenged, but were examined in laboratories. Science as an experimental methodology started to run its course, the authority of the church was questioned, and even the highly esteemed authors of ancient times were put to the test. Old habits and beliefs were stripped away.

The great French chemist Antoine Laurent de Lavoisier discovered oxidation during his experiments that originally proceeded from the alchemistic theory of phlogiston. Contrary to what alchemists had originally assumed, combustion does not involve the release of a substance (phlogiston), but the addition of oxygen. Scales and thermometers had been sufficient to cause the collapse of a concept based on scholarly works such as those of Thomas of Aquinas. Anyone who doubted it was free to repeat the experiment for themselves. Tradition was subjected to the test of verification in the laboratory.

During the course of his ground-breaking research, Lavoisier described the elements as basic substances that could not be broken down any further. His discovery thus undermined centuries-old “knowledge” and proved that water, air, fire and earth were not indecomposable elements as the Greek philosophers had taught.

This way he created the foundations of modern chemistry. In Germany, it was Sigismund Friedrich Hermbstaedt who picked up and spread Lavoisier’s ideas. At the same time, following the Paracelsus model, he called upon his colleagues to search for active substances in medicinal plants. Although modern chemistry began in France with Lavoisier, it was a young German pharmacist’s assistant named Friedrich Wilhelm Sertuerner who – totally surprisingly – for the first time successfully extracted the active substance from a medicinal plant. He isolated crystalline morphine from opium poppies, whose medical effect had already been mentioned in the Papyrus Ebers. In so doing, he set off a boom in natural substances just as Fleming would do some 100 years later.

His revolutionary discovery led to a quantum leap in medicine. At the same time, it marked the birth of alkaloid chemistry, which searches for highly effective secondary metabolites in plants. As a result, during the 19th century, further active substances were obtained: colchicine, which is extracted from the autumn crocus, as well as caffeine, nicotine and codeine, which is likewise extracted from the poppy.

Cocaine was also extracted as a pure substance. It was first used in the tonic and patent medicine Vin Mariani and then in John Pemberton’s French Wine Coca, which later conquered the world as Coca-Cola. It thus became the elixir of life for high society at the end of the 19th century. Exceptional achievements also resulted from the work of the French chemists Joseph Bienaimé Caventou and Pierre-Joseph Pelletier. In addition to caffeine, they extracted chlorophyll and strychnine, and they also succeeded in extracting the active ingredient quinine from cinchona plants and thus introducing to the market a medication for malaria that could be given in regulated doses. Their scientific success prompted them to establish the first pharmaceutical company in the world.

The salicylic acid extracted from myrtle and willow bark is used to alleviate the fever and headaches that accompany colds and flu. Both medicinal plants had already been used as medication by Egyptian physicians and Hippocrates. However, because of its side effects, salicylic acid initially had no success on the market. Its break-through became possible thanks to further developments by the young Bayer chemist Felix Hoffmann. The result was acetylsalicylic acid, which was introduced to the market in 1899 as Aspirin® and became the most successful medication in history.

Their discoveries are milestones in the history of research into natural substances and medicine as a whole. Right: Friedrich Wilhelm Sertuerner.

A golden era of research

Research into plant-based natural substances was already very advanced when Fleming discovered penicillin from mold in the 1920s. Fleming’s publication, however, initially received little attention. The English physician Cecil Paine was the only one who experimented with the mold extract and was the first doctor to successfully treat patients – though he was not acknowledged to have done so until later. The discovery only gained momentum when researchers such as Howard Walter Florey and Ernst Boris Chain, who together with Fleming received the Nobel Prize in Medicine for their research into penicillin, developed the basic principles for isolating the active substance and the industrial production of penicillin. This saved the lives of hundreds of thousands of soldiers in World War II and for decades turned out to be the miracle weapon of medicine.

The work of Florey, Chain and Fleming revolutionized pharmacology and prompted the global research community to search continuously for new natural substances and study their effects.

The predecessor companies of Novartis also worked intensively with natural substances in those early days. Great successes were achieved under the direction of Arthur Stoll, a researcher at the ETH Zurich, who in 1917 built up the Pharmaceutical Department at Sandoz, a company that until then had been active primarily in the dye business. In particular, work with ergot led to revolutionary developments. Ergot is a fungus that lives as a parasite on rye and other grasses and whose medical efficacy had been known since the Middle Ages. The active ingredient ergotamine was successfully isolated from ergot back in 1918, and only a few years afterwards Gynergen® was launched on the market to prevent post-partum hemorrhaging and later to treat migraines. More recently, Albert Hoffmann conducted further research into ergot and isolated his famous LSD, which turned the world topsy-turvy. Stoll also encouraged research into digitalis (foxglove), which had already been used back in ancient Egypt to treat heart failure and associated edema. The medications developed as a result – Digilanid® and Digoxin Sandoz® – are today successful products for treating heart failure.

During the golden era of research into natural substances, scientists around the world intensively sought medicinal plants and molds and tested them for their pharmaceutical effects. For instance, they found a substance in the Pacific yew tree that would later be successfully used by Bristol-Myers Squibb for cancer treatment under the name Taxol® (paclitaxel). In 1969, researchers at Sandoz ran across a fungus with immunosuppressive properties. This fungus, from which the active substance cyclosporine would later be developed, came to the market as Sandimmune® and revolutionized transplant medication. It came from a soil sample that Sandoz researcher Hans Peter Frey brought back with him to Basel from his vacation in Norway. Ciba also enjoyed major successes and in the 1950s brought Serpasil® to the market, a sedative whose active ingredient comes from Indian snakeroot and had already been used in Ayurvedic medicine. In addition, Rimactane® (rifampicin), a potent antibiotic that is still used in the treatment of tuberculosis, was developed in close collaboration with the ETH Zurich.

In the second half of the 1980s there was widespread acceptance of the view that infectious diseases could now be treated effectively with penicillin and its successor substances. Consequently, research into antibiotics was largely abandoned around the world, and the focus of research shifted to other families of diseases. In addition, new technological developments enticed many researchers and companies to investigate synthetic molecules from combinatorial chemistry, which opened up new opportunities in medical progress.

Marigold (Calendula officinalis). Calendula glycosides have anti-inflammatory and antibacterial properties, contribute to better wound healing and help fight skin rashes.

A new attempt

The decline of research into natural substances in the 1980s cannot, however, be explained only with the rise of combinatorial and synthetic chemistry, which were supplemented with technical innovations such as high-throughput screening.

Based on its complexity, research into natural substances is extremely challenging for every scientist in this field. Cultivating and extracting microbial natural substances in fermenters requires a great deal of skill and experience. Even today, many experts wishing to decode a structure have a tricky job, and the chemical transformation of a natural substance often only succeeds after extensive investigation. In many cases, this success represents a major scientific achievement.

In addition, extracting sufficient amounts of a plant-based natural substance, for example from trees, can also have a serious negative impact on the environment. For instance, while Sandoz was able to cultivate fields of rye relatively easily in order to obtain adequate amounts of ergot to produce ergotamine, Bristol-Myers Squibb’s manufacture of paclitaxel from Pacific yew trees involved significant difficulties until a semi-synthetic process was developed. The active substance was initially only extracted from tree bark and even then just in small amounts. Peeling the bark off trees that were sometimes more than 100 years old created environmental problems on top of the difficulties of extraction. The New York Times got to the heart of the matter when it wrote, “Save a Life, Kill a Tree?” Even Alexander von Humboldt, during his famous trip to South America, pointed out the dangers of massive clearing of the cinchona trees used to manufacture quinine.

Many companies ceased operating in this area because the legal issue surrounding the natural occurrence of natural substances, as opposed to self-synthesized basis substances, remained unresolved for a long time. To whom do natural substances actually belong? To the person who discovers them or the country in which the biological sources are located? For Novartis, this was never a reason to discontinue research into natural substances. On the contrary, the 1992 Climate Summit in Rio de Janeiro initiated a biodiversity agreement setting out global legislation concerning biological diversity and its sustainable use and therefore providing the requisite legal clarity. Novartis was the first company to implement the agreement as ratified by Switzerland, for it saw in this the opportunity to incorporate research on natural substances into research partnerships – and at the same time emphasize the importance of an intact environment for this type of quest for active substances.

Successful developments based on natural substances – such as the cancer medication Afinitor®, Exelon® against Alzheimer’s disease, and the malaria medication Coartem® – underscore time and again the innovative power of research conducted by Novartis. The same holds true for KAE609, a potential successor product for Coartem that is inspired by natural substances but is obtained synthetically.

“Based on the conviction that these molecules will continue to play an important role in the life of future research projects, we have obtained the support of our management to realign research into natural substances at Novartis,” says Frank Petersen, Head of the Natural Products Unit. Innovative technologies have therefore been applied to the chemistry of natural substances in order to accelerate the isolation of novel substances in the smallest concentrations and facilitate the identification of active substances.

Novartis will continue to develop this field of research. Natural substances are very productive for research, as together with their chemical derivatives they make up approximately 30 percent of today’s pharmaceuticals. Through their evolutionary development, each natural substance has the capacity to modulate cellular processes. In many cases, these modes of action are totally surprising and hold great potential for companies that study these molecules on a scientific basis.

“The technologies of genome sequencing and gene synthesis are the technological driving forces behind synthetic biology. They will also fundamentally alter research into natural substances,” explains Petersen. This will help track down “sleeping” genes in natural substances and adapt them synthetically to activate and change them in specific ways. For instance, substances are being extracted with effects that research has so far not been able to investigate. “We are, so to speak, standing in front of a door that we have been one of the first to open. We do not yet have any idea what we will find behind it. We simply know that it is certain to be a new chapter in the research of natural substances,” concludes Petersen.

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