In the previous tutorial we turned to the
birth of microbiology, but immediately prior, we told the story of how the young British chemist
William Perkin, while trying to prepare quinine, accidentally started the artificial dye
revolution, which sparked the birth of huge dyestuff conglomerates in Germany. And as we
mentioned, toward the end of the 19th century, these dyestuff companies switched their focus,
and gave rise to the first modern pharmaceutical companies, some of which are still around today.
One future giant was the company Farbwerke Höchst, founded in 1863 in the town of Höchst,
which is now part of Frankfurt, Germany. The company became a huge player in the dye
business through the second half of the 19th century, growing its workforce to over 2,000
workers and scientists. Near the end of the century, as the dye business became saturated,
the company moved into synthetic drugs, and over the years 1888 and 89, it introduced to the
market two analgesics, antipyrine and amidopyrine. These were the first synthetic drugs to
be developed to treat fever and pain. The chemistry is quite simple, consisting of two
trivial chemical steps, but this turn to synthetic chemistry as opposed to exclusively utilizing
natural products was decisive and represents the paradigm shift that led to the modern pharma
industry. The new drugs were supplied as tablets, since around 1860, machinery that could compress
powders into tablets had been developed in France. This practice of combining the drug with inactive
substances called excipients and compressing the powerdered mixture into a tablet had been slowly
perfected, and was then available worldwide. Another important area of research was the
field of anaesthetics. It is difficult to imagine that throughout most of human history,
there was little to no relief from pain, and even surgeries were typically performed
without applying any kind of anaesthesia. Historically, only a handful of substances with
anaesthetic properties had been stumbled upon. The power of poppy extracts was apparently discovered
by the Sumerians 6,000 years ago. The great Indian surgeon Sushruta introduced anaesthesia
via hemp smoke, or cannabis, around 600 BCE. Mixtures of alcohol and other herbal extracts
were used in Rome. These herbs included opium, mandrake, henbane, and hemlock. These were allowed
to be used to alleviate the pain of crucifixion. During the 19th century cocaine was commonly used,
after the Inca discovered the properties of coca leaves in the 14th century. And ether was also
commonly used, after Paracelsus introduced it in the 16th century. This was often mixed with
chloroform, which produced some very nasty side effects. Laughing gas, or nitrous oxide, was
also effective but of short duration. None of these procedures was completely effective
and free of side effects. Not surprisingly, chemists turned to organic synthesis to prepare
better substances, and modern anaesthetics are now all synthetic. Höchst introduced
Novocain, also called Procaine, in 1905. Surgeons preferred to stick with cocaine, but
Novocain turned out to be extremely successful for dental procedures, which finally became painless.
Höchst grew to become a huge company. In 1913, the year when the company celebrated its 50th
birthday, there were 9,000 workers at the Höchst site in Frankfurt, and the company reached a
turnover of $100 Million. It had factories all over Europe, including Russia, France and the
UK. The Höchst site grew over the years to a size of over 60,000 workers, including a large
division devoted to research and development. Another extremely successful German giant was
Bayer. It was also founded in 1863 near Wuppertal, much like other companies, in order to enter
the immensely profitable dye business. Its history somewhat parallels that of Höchst. Around
1880, Bayer also entered the pharma business, and introduced phenacetin, an analgesic, which
competed with the Höchst products as the first synthetic analgesics devoid of addictive
properties. In 1880 the company already employed over 1,000 workers and had an R&D
department with dozens of organic chemists. This was essentially unheard of outside
of Germany. The company got so big that it eventually created its own city, the modern
Leverkusen, which currently has 160,000 residents. Bayer is most famous for the drug Aspirin,
which was introduced to the market in 1898. This drug is described in detail over in the
pharmacology series, but to cover the basics, the drug has anti-inflammatory properties, and its
mechanism of action was not elucidated until 1971, by Nobel-Prize winning
British biochemist John Vane. The drug is still widely used today for its
diverse biochemical and medicinal properties, and has been called “the wonder drug”. This is rather
astounding, given its structural simplicity. The lead for this structure comes from willow
extracts, later known to contain salicylates. The synthetic version, aspirin, also
commonly called acetylsalicylic acid, is a more active and safer version with
respect to the extracts it is inspired from. Aspirin is currently the most utilized drug in
the world, on a tonnage basis, with a volume of 40,000 metric tons, or 40 million kg per year,
an amount equivalent to 50-120 billion pills. In many countries, including Germany, Aspirin is
still Bayer’s brand name, and acetylsalicylic acid is the generic name, whereas in other countries,
like the US, aspirin has become the generic name of the drug because of procedural
complications with the trademark office. In the same year that it launched aspirin, 1898, Bayer launched a simple derivative of morphine
named heroin, as a cough suppressant. It was available over the counter, and it remained so
for decades, until people started to realize the addictive properties of the drug. We
will discuss the history of heroin later. Other important, and later controversial, market
introductions were in the field of hypnotics. The first barbiturates appeared on the market
around the turn of the century. Barbituric acid was first prepared by German chemist Adolf von
Baeyer in 1864 by reacting two compounds called diethyl malonate and urea. The story goes that
the chemists went out to celebrate the discovery at a tavern where an artillery garrison was
also celebrating the feast of Saint Barbara, their patron saint, hence the name of the new
substance, an amalgam of Barbara and urea. The new substance had no biological properties, however,
and it took a few decades until chemists decided to make some modifications to the molecule, which
produced drugs with important hypnotic properties. Indeed in 1904, Bayer marketed barbital with
the trade name of Veronal. The substance quickly replaced the most common treatment against
insomnia, bromide, and enjoyed wild success all over the world. However, its continued
use triggered tolerance, and insomniacs needed larger and larger doses to achieve the desired
effects. The effective dose was around 600 to 1,000 milligrams per day, and the drug could be
lethal at 3.5 grams per day. It was inevitable that people would abuse the drug. Deaths were
not uncommon, including some very famous people, and in addition Veronal became a preferred
tool to commit suicide, as the death was painless. Barbiturates are past their heyday
and no longer commonly prescribed. However, hundreds of people still die each year from
barbiturate abuse, whether accidental or planned. Another German Pharma giant that should be
mentioned is E. Merck. This is a Pharma company which did not originate from the dye business.
The company started as a pharmacy in Darmstadt, in 1668, and evolved into a modern pharma
company by sticking to the natural product business. It made a name for itself by marketing
several important alkaloids, including morphine. Among its key products was Oxycodone, marketed
as Eukodal, a synthetic opioid and powerful painkiller, which recently has become well
known for its devastating addictive potential. Merck established production and R&D
sites in many countries, including the US, and specifically in Rahway, NJ, whereas
other German companies thrived by exporting their new drugs to the growing US market.
As one might imagine, World War I changed the situation dramatically, and signaled the
end of the supremacy of the German chemical and pharmaceutical companies over the rest of the
world. Allied countries, including the US and UK, stopped importing German products, and local
branches of German companies were closed down. The US revoked all German patents, and local
producers could start making and selling German products, which enabled the fledgling US
and UK pharma industries to quickly grow. The US branch of the German company Merck was broken off
from the mother company, and Merck became de facto a US company, later to be renamed Merck, Sharp
and Dohme, and this separation from the original owner, E. Merck Darmstadt, became permanent.
The end of World War I saw the German economy in shambles, with some of its best pharma
companies having lost patent protection worldwide for their most important products.
At the same time, the victory in the war was a great boost for the US pharma industry, which
would emerge in the coming decades as the most innovative and productive worldwide. However, the
pharma industry in Germany was not quite dead. As we will see in the next chapter, the antibiotic
revolution actually started, as usual, in Germany.