The Accidental Genius

"A veces, Fortuna guía a buen puerto un bajel privado de piloto".

William Shakespeare, “Cimbelino”

What exactly is “inspiration”? What is “genius”? Wherein lies the secret ember that transforms the world?

Beyond funding and a stable society, science requires no small amount of randomness. It’s widely known that some of our finest scientific discoveries have been the result of pure, unadulterated, blind luck, something I personally find reassuring.

Let’s review some of the funniest, finest, freest mistakes and coincidences in the history of medicine. It’s a treat - enjoy!

The French disease

“A result due, at least in large part, to luck.”

Paul Ehrlich

Syphilis, “The French Disease” (actually originated in pre-Columbian America) ranked among the world’s major health burdens for over four centuries. In the 18th century, for example, 20% of Londoners aged 15-34 had been treated for syphilis, and the long list of historical figures believed to have endured the disease includes Baudelaire, Schubert, Schopenhauer and Nietzsche, to name but a few (yes, all men).

In the early 1900s, Paul Ehrlich and Sahachiro Hata were researching potential Zauberkugel (“magic bullets”), compounds that would kill an infection without killing the host – a tiny but important detail that wasn’t quite a priority in syphilis treatment before then.

After unsuccessfully testing 605 chemical compounds (mostly arsenic-based, and mostly randomly generated), compound 606 was injected to a syphilis-infected rabbit on August 31, 1909. The next day, all syphilis bacteria were dead, and within weeks the rabbit’s ulcers healed. Compound 606 was arsphenamine, soon dubbed Salvarsan, “the arsenic that saves”; clinical trials followed on humans with immediate and spectacular results (including a few dead patients, a circumstance that didn’t seem to be quite as dramatic back then).

By late 1910, Salvarsan was on the market and quickly became the most widely prescribed drug in the world – the first true blockbuster drug. The return on investment was enormous: for the cost of a few years’ scientist’s salary, a tiny Rockefeller grant (€400,000 in today’s money), and some lab supplies, Salvarsan brought in £150,000 a year (€25 million today) by 1911, and made up one-third of Hoechst’s pharma revenue.

To grasp Salvarsan’s impact, consider what came before. For centuries, syphilis was treated with mercury in various ghastly forms – as one historian noted, “a night with Venus; a lifetime with mercury”. Patients endured mercury rubs, steam baths (often suffocating in the process), even toxic mercury-laced tonics – all horrifying and ineffective.

Salvarsan became the first modern antimicrobial drug and proved that synthetic chemistry could cure diseases.

The Italian bombing

"They realized that this horrible compound, a chemical weapon, could kill cancer cells; not because they were looking for it, but because nature showed them where to look."

Vincent DeVita

On December 2, 1943, German bombers pounded the port of Bari, turned into a major logistic hub by the Allied advance into Italy. Several ships were sunk, among them the USS John Harvey, which exploded spectacularly, releasing clouds of oil and smoke into the air.

After the attack, scores of sailors showed unusual symptoms: their skins were covered in burns and blisters, they could hardly breathe, and some died in the next few days. Upon examination, the culprit was found to be none other than Nitrogen Mustard, a variation on the classic chemical warfare agent Mustard Gas (and no, the Germans didn’t gas-bomb Bari: the lethal agent was stocked in the USS John Harvey as a, erm, “deterrent”).

But the incident brough a singular discovery: 3-4 days after the attack, the sailors’ white blood cell count took a sharp dive, and autopsies revealed depleted bone marrows. Instead of boosting the immune system to fight infections, the body had deactivated it in response to Nitrogen Mustard.

That corroborated results from early trials carried out (in secret) by Yale pharmacologists Louis Goodman and Alfred Gilman back in 1942, which had resulted in the spectacular recovery of a terminal lymphoma patient known only as “JD”. Although the cancer returned weeks later (resistance set in), this was the first ever demonstration that a chemical drug could treat cancer in a person.

After the Bari attack, US military doctors recognized the potential of the discovery: if this chemical agent targeted immune cells, which are characteristically fast-dividing, could it be used to selectively kill cancer cells, which are also fast-dividers?

Further trials were carried out in secret (mustard gas was classified) and were finally published in a 1946 paper showing significant tumor regressions in 67 patients. By 1949, the compound mechlorethamine (nitrogen mustard) was approved as the first chemotherapy drug. Thus, a chemical weapon became a chemical therapy.

The impact of chemotherapy has been staggering: five-year survival rate for all cancers in the U.S. rose from ~35% in the 1950s to about 68% today, and cancers which were considered a death sentence, such as Pediatric Acute Leukemia or Hodgkin’s Lymphoma, now have survival rates of 90%.

As a cheap chemical that gives patients many years of healthy life, chemotherapy is one of the most cost-effective treatments ever: It is estimated that for every €1 spent on early chemotherapy development, the societal return likely exceeds €1,000, making chemotherapy more cost-effective to society than seat belts, handwashing or clean water.

The Australian salt

"It was a purely accidental finding...I was lucky."

John Cade

John Cade, an Australian psychiatrist, conducted his pivotal experiments in mental health in an old pantry at Bundoora Repatriation Mental Hospital in Victoria. He had no formal research grant and barely any equipment. He had also just spent three years in a Japanese POW (Prisoner Of War) camp during World War II, probably the closest experience to hell that Man has created.

Cade’s observations in Changi prison suggested a connection between urine and a chemical compound that caused mental disorders. On that theory, he started injecting guinea pigs with urine from bipolar patients, reasoning that if mania was due to a toxin, their urine might be more toxic. Indeed, urine from manic patients killed guinea pigs faster than normal urine.

But as part of his chemical tinkering, Cade started using lithium as an inert solvent to stabilize uric acid – or so he thought: suddenly, guinea pigs became unusually calm. By pure luck, the tenacious Cade had stumbled upon the first effective chemical treatment for mental disorders: Lithium salt. After testing it on himself to confirm it was safe, he gave it to his most severely manic patients, and the results were stunning. A particularly troublesome patient “settled down within three weeks and was able to leave hospital 12 weeks later” – essentially cured of mania.

Cade published his findings in 1949, reporting the first time ever that a psychiatric illness was successfully treated with a pill. Such a paradigm shift didn’t find many adopters at first: the psychiatric profession was rather happy performing gruesome lobotomies, lithium had just caused some deaths while being tested as a cardiac therapy, and, worst of all, as a naturally occurring element lithium can’t be patented, making it commercially unattractive. Despite all that (it was banned in the USA until 1970), it eventually became the seed of modern pharmaceutical psychiatry.

The importance of Cade’s discovery is clear if you picture the 1950’s approach to mental health. Patients with bipolar disorder were often confined to asylums, where doctors managed mania with heavy sedatives, electroshocks, straitjackets, and in severe cases, lobotomies. By today’s standards of psychiatric well-being, a 1950’s asylum would fare only slightly better than an Iraqi war prison.

But don't worry: ending your days in one of these nightmare centers is no longer a possibility, in part, thanks to the unexpected connection between a random salt and brain chemistry.

The Scottish vacation

One sometimes finds what one is not looking for

-Alexander Fleming

Scottish bacteriologist Alexander Fleming returned from holidays in September 1928 to find that mold had grown on bacterial culture plates left on a stove. And, around the mold colony, bacteria were dead, creating an infection-free zone. Fleming had discovered the first antibiotic in history; he identified the mold as Penicillium notatum and called its secretions "mold juice," later penicillin.

This discovery was pure chance: if Fleming had not been messy, and if the climate had not been just right (cool enough for mold growth), it would not have happened. But it did happen, and it became the most famous mold growth in history.

In fact, he was not even looking for a pharmaceutical, which is why penicillin did not become an overnight success: the compound was unstable, Fleming was not a chemist, and almost nothing happened for a decade.

But the second push this story needed came on September 2nd 1939, when Germany invaded Poland and started World War II. In view of the amount of people that were about to get seriously hurt, Howard Florey and Ernst Chain at Oxford University decided to revisit Fleming’s discovery and purify penicillin. The US and UK governments pumped serious money into the development: about 10 billion dollars in today’s money, over a thousand times more than the previous record investment in a drug development program (insulin).

In early 1941, the first human ever was treated with antibiotics - a policeman dying of a septicemia (from a rose-thorn scratch). After getting penicillin injections, the patient’s condition dramatically improved, although he did die later, when the researchers eventually ran out of the still experimental drug.

So… yes, death by flower scratch. That was life before antibiotics; common bacterial infections had no effective treatment, and were the leading cause of death in 1930. Things we consider trivial today, like an ear infection (my youngest son has had 15-20 of these), could be lethal. Once penicillin, a true wonder drug, became available in the mid-1940s, survival rates from infections skyrocketed.

And the lords of war got returns on their investment: by D-Day (June 1944) enough penicillin had been produced to treat all the Allied wounded; it is estimated that this saved up to 12-15% of soldiers who would otherwise have died from infected wounds. For those of us who have not seen war, the upside has also been enormous; the estimated economic benefit of antibiotics (lives saved and productivity gained) is in the order of trillions of euros.

The Swiss trip

"I didn't choose LSD; LSD found and called me."

Albert Hofmann

In 1938, Albert Hofmann, a chemist at Sandoz Laboratories in Switzerland, was working on alkaloid derivatives from Ergot, a type of fungus. His goal was to find new analeptic drugs – stimulants for respiration and circulation.

The 25th compound Hofmann synthesized in that series of experiments ("LSD-25") was intended to be a respiratory and circulatory stimulant, but the effects were simply insufficient. LSD-25 was shelved as a failed compound and sat in a drawer for five years, until Hofmann decided to go back for it "on a hunch" that he might have missed something. And boy had he missed something!

In April 1943 he accidentally absorbed a tiny amount (perhaps through the skin) and experienced "strange sensations". Intrigued, a few days later he deliberately took 250 micrograms thinking it would be a tiny dose (it wasn't), and duly went on the world's first acid trip while cycling home on April 19, 1943.

Sandoz did not shelve LSD: in the late 1940s and 1950s, they distributed it under the brand Delysid, free of charge, to psychiatrists and researchers to study its effects on mental illness. It was tested on recovering alcoholics, depression, anxiety, and a number of other mental conditions.

And the CIA being the CIA, they obviously used it for bizarre mind control experiments; my personal favorite is Operation Midnight Climaxin which CIA prostitutes spiked their clients with LSD while American spies watched the proceedings through two-way mirrors. Yes, really.

By the mid-1960s, LSD escaped the lab and hit the streets: millions of people were using it non-medically and, as soon as it became a mind-expanding gate to artistic and political freedom, it was made illegal - even though its mortality rate was exactly 0 deaths per million (that of OxyContin, a perfectly legal drug, is about 1,500 per million).

In recent years, the clinical potential of LSD has been reviewed, and in 2024 the FDA pre-approved an LSD therapy for anxiety, indicating a likely commercialization in the near future.

The Berlin patient

"It wasn't clear to us what was going to happen. It was a great and good surprise that it worked."

Dr. Gero Hütter

Today, it’s hard to understand just how terrifying AIDS was when it became an epidemic. Back in 1981, scores of young people were dying of what became widely called “the gay disease” (it was even officially called GRID, “Gay-Related Immune Deficiency”, before becoming AIDS). Nobody had the faintest idea of what was going on, and showing symptoms of the disease was a death sentence.

The virus (HIV) was identified in 1983, and the first antiretroviral therapy appeared in 1987, but the disease didn’t become controllable until the 21st century. No cure was in the horizon.

Enter Timothy Ray Brown, later known as the “Berlin Patient”, a young man who had been dealt really bad cards: he had leukemia and AIDS, and he was going to undergo a bone marrow transplant – a very dangerous medical procedure. The medical team, led by Dr. Gero Hütter, selected a bone marrow donor with a very rare genetic mutation known as CCR5-∆32, which renders white blood cells resistant to most HIV strains – and finding a tissue compatible donor was extremely lucky.

Although Hütter’s team did select that donor to try to confer Brown some resistance to AIDS, it was essentially a shot in the dark – and a very long shot indeed. But much to Hütter’s surprise (and Timothy’s delight), the patient not only recovered from leukemia but also appeared cured of HIV. “The Berlin patient” became, in 2007, the first human functionally cured of AIDS.

In 2019, a second patient, later dubbed the “London Patient,” underwent a similar transplant for lymphoma, with equally remarkable results: no detectable HIV after cessation of ART. These cases were not specifically designed to cure HIV, but the unintended result demonstrated that a cure was biologically possible, even if bone marrow replacement is not medically scalable (they’re risky and expensive, costing ~$350,000 and requiring full-body irradiation).

These results helped launchgene therapy strategies , such as CRISPR-mediated CCR5 editing, that could provide scalable, non-toxic cures. Since then, billions of dollars have been poured into HIV cure research, and a commercial gene-editing cure for AIDS is estimated to reach the market in 2032-35.

The American heart

“Our work involved some logic, some prediction, some direction, but a lot of serendipity. I like to think that’s the way basic science ought to be.”

Jackie Corbin

Originally designed for angina pectoris, sildenafil citrate failed to meet its objectives in phase II clinical trials, and was destined to become a $150 million fiasco. However, researchers noticed something odd: male participants were reluctant to return unused drugs, and some even asked for more - not quite standard behavior in trials for an experimental cardiovascular drug.

The dots were quickly connected: male participants were experimenting frequent, consistent and persistent erections; to everyone’s surprise, the ‘failed’ project had stumbled backwards into something huge (no pun intended). Pfizer had discovered a drug that could heal the single most important decision-maker of mankind: the male penis.

This time, the pivoting was straight and robust (no pun intended). Pfizer immediately repositioned sildenafil, and, by 1998, it was FDA-approved as Viagra, the first oral treatment for erectile dysfunction (ED). The market shot up (no pun intended), driven not only by efficacy but also by a massive publicity and destigmatization campaign, including an unforgettable ad with football legend Pelé.

Viagra peaked at $2 billion/year in global sales, and hit the streets as a recreational drug almost immediately. These days you can't hack a football match without being flooded with ads for generic Viagra; it is, in fact, the most counterfeited drug in the world, selling millions in the black market even if it's known to have caused severe side effects - including a few stiffs (ok, this pun was intended).

Bottom Line: we’re nothing, the universe has so much in store for us, and it’s comforting to see that knowledge, that thin but beautiful connection with creation, can still fall from the skies when we least expect it.

These stories underscore a vital point though: serendipity favors the funded mind. In each case, broad or curiosity-driven support (be it philanthropic, government, or just institutional freedom) allowed researchers to chase odd observations or hunches. The payoffs were disproportionately massive: millions of lives saved, entirely new fields of medicine created, and immeasurable human suffering averted.

As the forces of darkness and stupidity grab hold of governments and institutions, it’s important to remember that beauty and wisdom are the most deserving of society’s resources. If scientists (or artists) can’t get funded because “they have no practical application”, then we are instituting the rule of ignorance, which can only end in tragedy.

And we had our fill of that in the 1930s, didn’t we folks?