How are drugs invented? Part I — Historical perspective

Source: FDA

This article is the first of a two-part series that will try to explain how drugs or medicines are discovered and/or invented. In the first part, I will talk about the origins of drug discovery, the modern pharmaceutical industry, and some of the methods used in today’s process. The second part is devoted to an overview of the modern techniques of drug discovery and why the process is so expensive and risky. I will use the terms drug discovery and drug invention more or less interchangeably because the process has elements of both.

Kodiak bear ( © Omar Stradella 2015)

Evidence of drugs in ancient times

If we could be able to lift the veil of time, we would find that the first drugs came from the natural world simply because it was the source of most of our ancestors’ resources. Although the ability to manufacture objects is a characteristic of humans, nature was our main inspiration, especially early on. The observation of animal self-medicating behavior most likely lead us to the discovery of early treatments. In animals, self-medicating behavior “is the defense against parasites by one species using substances produced by another.”(1) Self-medication can be classified into four categories according to the mode of contact: ingestion, absorption, topical application, and proximity. For example, Kodiak bears (Ursus arctos) chew the root of Ligusticum, spit the resulting mixture of saliva and juice onto their paws and rub it thoroughly into their fur. Ligusticum is believed to have anti-bacterial and anti-viral properties and it is routinely used by humans to those effects. Chimpanzees sometimes suffering from parasite related diseases ingest shoots of a plant (Vernonia amygdalina) that contains antiparasitic compounds.(2)

Animals “learn” to self-medicate through natural selection and social learning. Humans are obviously very good at social learning and even at learning from other species. A relatively recent example of human learning from animal self-medication goes back to about a century ago when a Tanzanian medicine man, Babu Kalunde, discovered an important treatment that saved the lives of many people in his village, who were suffering an epidemic of a dysentery-like illness. He learned about the potential medicinal value of a plant known to the WaTongwe as mulengelele by observing a similarly sick young porcupine ingest the roots of the plant. Before these opportune observations, Babu Kalunde and the people of his village had avoided this plant, which they knew to be highly poisonous. After telling the villagers his story of the porcupine, however — and taking small doses of the plant himself — he persuaded them to use the plant on the sick. To this day, the WaTongwe use the roots of mulengelele as medicine.(3)

There are historical and archaeological records that hint at human self-medication throughout history. In the late 1950s, archaeologists discovered and explored an ancient site (~ 60,000 BCE) called Shanidar Cave in today’s Iraq, where several Neanderthal remains were found. One of them was Shanidar IV, a Neanderthal male that appeared to be buried in a ritual manner(4). Researchers found many types of plant pollen, most of them later identified as coming from plants that are recognized today as having medicinal properties(5). Plants with psychotropic activity, Dermatophyllum secundiflorum (red or mescal bean) and Ungnadia speciosa (Texas buckeye), were found stored in caves in Northeastern Mexico Trans-Pecos Texas dated as early as 8500 BCE(6). Ancient Chinese and Egyptian papyri describe medicinal uses of plants as early as 3000 BCE. Ancient Egyptians wrote the Ebers Papyrus containing information on over 850 plant medicines, including willow, garlic, juniper, cannabis, castor bean, aloe, and mandrake(7).

Some inorganic substances were also used as therapies or preventatives. For example, as early as 3000 BCE Egyptians used copper to sterilize water and wounds. Various iron remedies were used in Egypt about 1500 BCE, around the same time that zinc was discovered to promote the healing of wounds. Kohl (lead sulfide) was used since the Bronze Age to treat eye infections(8).

A page of the Badianus Manuscript

Drugs in medieval and early modern times

Although Benedictine monasteries were the primary source of medical knowledge in Europe and England during the Early Middle Ages, most efforts were focused on translating and copying ancient Greco-Roman and Arabic works, rather than creating substantial new information and practices. But at the same time, medical schools (Bimaristan) began to appear around the 9th century in the medieval Islamic world (Persians and Arabs) which was generally more scientifically advanced than medieval Europe at the time.

The 15th-17th centuries were the great age of herbals (books of herbal medicines), many of them available for the first time in English and other languages. The two best-known herbals in English were The Herbal or General History of Plants (1597) by John Gerard and The English Physician Enlarged (1653) by Nicholas Culpeper.

The Age of Exploration introduced new medicinal plants to Europe. The Badianus Manuscript was an illustrated Mexican herbal written in Nahuatl and Latin in the 16th century(9).

From the 17th to 19th centuries, mercury in its elemental form or compound form, usually mercurous chloride, was used to treat yellow fever, typhus, and syphilis. Mercurous chloride was also used as a diuretic during the Renaissance period.

The problem with herbals and early inorganic substances

Herbs typically contain a complex mixture of many chemical compounds, some have a therapeutic effect, others are inactive, and yet others can be toxic.

The fact that sometimes different herbs, or different parts of one herb, or even different preparations of one herb would have different therapeutic properties (or not at all), probably lead to the development of the “active principle or ingredient” notion: the chemical constituents present in crude animal or plant preparations that are responsible for their biological activity. Herbs’ active principle contents can depend on many factors, including strain, cultivation/harvesting conditions, development stage, plant anatomy, etc. which means that herbs have variable and often unpredictable potency and toxicity. The active principle idea helped with these problems to some extent because it enabled the development of herb extract standardization through active principle quantitative determinations. It also enabled the detection of counterfeits (passing one cheap inactive herb for another active and more expensive), the determination of cause of poisoning, and the possibility of increasing the potency of the extracts through different preparations.

Most early inorganic compounds were simply toxic, and that was the primary way that they worked since they were frequently used as antibacterials or antiparasitics. For that reason they had very limited therapeutic use.

The other problem with herbals and early inorganics was the lack of any kind of systematic testing. Their proclaimed efficacy was based on anecdotal evidence. An herb could be effective to treat a specific ailment but completely useless to treat a different one with similar symptoms that could lead people to believe to be the same disease.

Early chemistry

Wood tar has been used by mariners as a preservative for wood and rigging for at least the past six centuries. From the beginning, Britain’s colonies in North America were encouraged to produce pine tar and pitch and to collect gum from pine trees for later shipment to England. Consequently, by 1725 four-fifths of the tar and pitch used in England came from the American colonies. Unfortunately, in 1776 the American colonies revolted, declared independence, and the supply of pitch and tar stopped. Meanwhile, the English shipbuilding boom restricted the use of the forests to the Navy shipyards so an alternative source of fuel, coal, had to be used that, under certain circumstances, would produce a tarry liquid that could replace the wood tar. At about the same time, it was discovered that coal distillation produced a combustible gas that was later used to provide artificial illumination to houses, factories, and streets. All this coal distillation produced large quantities of waste, among them a flammable liquid hydrocarbon mixture known as naphta that Charles Macintosh used to dissolve rubber and coat and cover fabric, thus creating the Mackintosh raincoat.

What does all this have to do with drug discovery? Rubber, which was obtained from the rubber tree (Hevea brasiliensis), was cultivated in regions where malaria was endemic and, at the time, the only cure for malaria was the bark of the cinchona tree (Cinchona spp.) from Peru that contained the active principle known as quinine. Failure to cultivate the cinchona tree in other rubber production regions, like India, created the desire for an artificial synthesis of quinine. At the beginning of the 1850’s several chemical compounds were identified in the coal production waste that were similar in structure to quinine. In 1856, William Perkin at the Royal College of Chemistry in London, while trying to synthesize quinine, accidentally created mauve, the first artificial dye. Suddenly there was an explosion of dyes from coal that propelled not only the fashion industry but the study of synthetic chemistry as well and gave birth to the idea that changes in chemical structures could lead to new compounds with novel properties. This brings us to the invention of Aspirin.

The leaves and bark of the willow tree (Salix spp) have been mentioned in ancient texts from Assyria, Sumeria, and Egypt as a remedy for aches and fever and used for that purpose over the centuries. Following the active principle idea, Johann Buchner, in 1828, extracted a chemical compound from the willow bark as yellow crystals that he named Salicilin. In 1876, Thomas Maclagan conducted one of the first clinical trials that treated eight rheumatic fever patients with Salicilin, showing that it had anti-inflammatory and antipyretic effects but also a strong gastritis side effect. Building on the idea that chemical changes can lead to new properties, Raffaele Piria, in 1838 produced Salicylic acid from hydrolysis and oxidation of Salicilin, and finally in 1897, Felix Hoffman synthesized Acetylsalicylic acid by acetylating Salicylic acid itself. Since Hoffman obtained the Salicylic acid from leaves of a meadowsweet plant in the Spirea genus, he named the new compound Aspirin (a[cetyl] spirea). Aspirin was not only effective in reducing pain and fever but also had significantly reduced the gastritis side effect.

Chemistry in modern times

The late 19th century saw an explosion in both the quantity of production and the variety of chemicals that were manufactured. Large chemical industries also took shape in Germany and later in the United States. Now we found ourselves at the dawn of the 20th century in the presence of a thriving chemical industry that fed on novel chemical research.

Scientists had been experimenting with aniline dyes on cells and tissues because they could enhance the detection and study of particular cell structures under the microscope. The selective affinity of dyes for certain biological tissues and cellular structures led Paul Ehrlich, a medical student at the University of Strasbourg (between 1872 and 1874), to postulate the existence of “chemoreceptors.” Ehrlich later argued that certain chemoreceptors on parasites, microorganisms, and cancer cells would be different from analogous structures in host tissues, and that these differences could be exploited therapeutically by the use of specific chemical compounds (“magic bullets”). The question was how to find these “magic bullets”? In 1901, Ehrlich tested hundreds of dyes on mice looking for “magic bullets” to kill the sleeping sickness trypanosome. This process of testing a large number of compounds looking for a few with a particular effect is now known as screening and it still plays an important role in drug discovery as we will see in the second part of this article. Ehrlich screening led to the discovery, in 1904, that the dye known as Tryptan Red was able to kill the sleeping sickness trypanosome.

Inorganic arsenic compounds had been used since at least 2000 BCE as both medicines and poisons. By the early 1900s, physicians were using arsenicals to treat pellagra and malaria. In 1859, in France, while developing aniline dyes, Antoine Béchamp synthesized a chemical that was later identified as Arsanilic acid and named Atoxyl, the first organic arsenical drug. Atoxyl proved to be a successful treatment for sleeping sickness and 40 to 50 times less toxic than arsenic acid. But a small number (~2%) of patients would become blind due to optic nerve atrophy. In 1906, Ehrlich, looking for a better compound, synthesized and tested hundreds of derivatives of Arsanilic acid to kill the malaria plasmodium. Out of all the tested compounds, number 606 (Arsphenamine) proved to be very effective. In 1909, he tested Compound 606 on syphilis infected rabbits and was able to kill the spirochetes with a single dose. Compound 606 was released as Salvarsan for the treatment of syphilis and African trypanosomiasis. Later, in 1913, an even less toxic compound (Compound 914) was released as Neosalvarsan and became the most effective treatment for syphilis until antibiotics become available in the 1940s.

Nevertheless, the natural world continued to be a source of new drugs. In 1929, Alexander Fleming described his serendipitous discovery of penicillin(10): “While working with staphylococcus variants a number of culture plates were set aside on the laboratory bench and examined from time to time. In the examinations these plates were necessarily exposed to the air and they became contaminated with various micro-organisms. It was noticed that around a large colony of a contaminating mould the staphylococcus colonies became transparent and were obviously undergoing lysis.” Fleming used the word penicillin as a short name for “mould broth filtrate,” but it was not until 1938 that Howard W. Florey and Ernst Boris Chain isolated and characterized the substance responsible for the antibacterial effect. The three of them shared the 1945 Nobel Prize in medicine or physiology “for the discovery of penicillin and its curative value in a number of infectious diseases.” Interestingly, moldy preparations had been used since ancient times to treat infections(11).

The traditional use of Galega officinalis (goat’s rue or French lilac) in medieval Europe is explained by its rich content of the hypoglycemic substance guanidine. Although guanidine proved too toxic for clinical use, the alkyl diguanides synthalin A and synthalin B were introduced as oral anti-diabetic agents in Europe in the 1920s but were discontinued when insulin became more widely available. Experience with guanidine and diguanides prompted the development of biguanides and the current use of metformin(12).

The institutions that had supported these early efforts (pharmacies, university laboratories, or the chemical companies producing dyes) were not structured to handle the new research driven by chemistry but increasingly controlled by pharmacology and by clinical sciences. Out of pharmacies and chemical or dye companies, new institutions were created to support interdisciplinary drug research and development. A new way of finding, characterizing, and developing medicines led to the formation of a new industry. After the discovery of penicillin and subsequently of other antibiotics, many drug companies established departments of microbiology and fermentation units, which added to their technological scope(13).

Summary

· Human use of natural substances as medication, since ancient times, is just an example of animal self-medication.

· Both animal/plant extracts and inorganic substances were (and still are) used for treatments.

· Observations on the properties of herbs probably led to the concept of an “active principle” which reduced the complexity of herbs to just one compound that could be synthesized and modified.

· The dye industry played an essential role in the development of chemical research in the 18th and 19th centuries and ultimately evolved into today’s pharmaceutical industry.

· Compound screening and chemical structure modifications were key for the invention of novel drugs.

References

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