Over half of the therapeutic antibiotics used  today were discovered in a brief 20-year period.

A fortuitous discovery in the 1940s led to a  global rush for miracle medicines in the soil.

That wondrous method ended in the late 1960s.  And unfortunately we have yet to find another.

In today's video, let us look back  at the golden age of antibiotics when  

people spanned the globe for the next big drug.

## Beginnings

In 1928, Alexander Fleming  famously noticed that a spot  

of mold was killing bacteria  in one of his Petri dishes.

It is important to note however,  that it has long been known that  

chemicals in molds can kill or inhibit bacteria.  

Like really long known. The ancient Egyptians  applied moldy bread to help burns, for instance.

And Joseph Lister in the 1800s knew that the mold  Penicillium glaucum can somehow inhibit bacterial  

growth. The physicist John Tyndall wrote a paper  about the effects of mold in tubes of bacteria.

Drugs have even been found and sold with strong  anti-bacterial properties. In the early 1900s,  

the Nobel winning physician and scientist  Paul Ehrlich discovered Salvarsan.

Derived from the poison arsenic, Salvarsan was  the first drug found to be effective against  

syphilis - which then afflicted a sixth of  all Parisians and a tenth of all Londoners.

It also works against a few other  diseases. But the larger issue was  

the drug’s toxicity - severe enough  to potentially kill the patient too.

This leads to a key point about drugs. It is not  enough to be effective. It also can't be toxic.  

It must be able to reach a good concentration  inside the body after intake (bio-availability).  

And it must be stable enough to remain as  such in the body until the job is done.

## Fleming's Discovery

So anyway, after Fleming noticed  the bit of mold in his petri dish,  

he sought to isolate the material but failed.

So he published his findings the  following year. And nobody really  

cared. People acknowledged that mold  can kill or inhibit bacterial growth,  

but considered therapeutic use  at commercial scale impractical.

This changed in the late 1930s when a team of  scientists at Oxford University - Howard Florey,  

Norman Heatly and Ernst Chain - managed  to identify and extract the antibiotic.

They then ran a trial on mice that  was a phenomenal success. In 1940,  

they published their results. The drug later  hit the market in 1943 with great success,  

saving many lives and inspiring  a search for similar drugs.

## Waksman and Streptomycin

Our story now turns to an Ukrainian-born  American named Selman Waksman.

Waksman was then a professor at Rutgers  University and one of the best soil  

microbiologists of his day. One day in  1939, two pieces of news reaches him.

The first was that one of  his students, Rene Dubos,  

had isolated a new antibiotic at the  Rockefeller Institute. This antibiotic  

is now known as tyrothricin, used  for treating minor skin wounds.

Interestingly, Dubos found the drug  by systematically feeding colonies of  

pathological bacteria to mixed samples of soils.  

The idea being to find a chemical in  those soils that can kill that bacteria.

At the same time, Waksman hears that the  British had successfully isolated and purified  

penicillin - making it useful therapeutically.  Waksman put the two together and has an idea.

In an oral history, student Woodruff  Boyd recalls Waksman saying to him:

> "I know that my favorite  organism, the actinomyces,  

will do better [than Penicillin]. ... Drop  everything you're doing and start isolating  

some streptomyces and see if you can find an  antibiotic that's better than penicillin."

The actinomycetes are a family of  complex soil bacteria. Streptomyces  

refers to a genus within that family,  encompassing several hundred known species.

So Waksman and his team collected thousands of  

soil bacteria and cultured them on agar  plates seeded with pathogenic bacteria.

Team members would then visually scan  the plates for spots where the growth  

of that pathogenic bacteria seem  to have been inhibited - a sign  

of antibiotic activity. A simple  mechanism performed at great scale.

In 1940, this method yielded a new antibiotic  candidate called Actinomycin. Despite it being  

effective against a broad range of  bacteria including tuberculosis,  

the drug turned out to be too  toxic for therapeutic use.

Small note of interest. Much later,  Actinomycin was found to have anti-cancer  

abilities and a variant of it is used  for chemotherapy today. Eff cancer.

Despite this setback, the discovery  encouraged Waksman and his corporate  

partner Merck enough to expand their efforts.  The screening continued - eventually leading  

to the discovery of a new drug  called Streptomycin in 1943.

Streptomycin is widely acknowledged as the  second great antibiotic after penicillin  

itself. And the first shown to be effective  against the dreaded disease tuberculosis.

Soon afterwards, a dispute emerged on who deserved  credit. One of Waksman's students - Albert  

Schatz - had been the one who ran the actual  experiment to uncover the Streptomycin drug.  

He later sued for co-authorship credit and  a financial stake in the drug’s royalties.

Most of the royalties went to a  foundation. But Waksman took a  

20% share and earned from it what  is now about $4.5 million a year.

In the settlement, that 20% split was  amended. Waksman would get 10% of the  

royalties. Schatz received 3% share plus  co-discovery credit on the drug's patent.

Elizabeth Bugie Gregory, who  independently verified the results  

and so was listed as a co-author  on the first streptomycin paper,  

also received a 0.2% share. The remaining was  evenly dispersed amongst the lab's members.

## A Systematic Search In 1952, Waksman won a Nobel Prize in Medicine.

Debate and ethical discussions remain  over whether Schatz should have shared  

the Nobel too. But Waksman’s Nobel  Prize citation hints at what I find  

to have been most significant about  Waksman's work, historically speaking.

The citation noted that while  penicillin’s discovery was by pure  

chance. Streptomycin’s discovery  on the other hand came about via  

a sophisticated method that was  targeted and scalable. I quote:

> In contrast to the discovery of penicillin  by Professor Fleming which was largely due  

to a matter of chance, the isolation  of streptomycin has been the result of  

a long-term, systematic and assiduous  research by a large group of workers.

So the big deal wasn't necessarily the  discovery of the drug itself, though that  

was certainly important. Rather, it was Waksman  producing a systematic search methodology.

From then on, antibiotics discovery would  be a team effort, no longer dominated by  

the solitary figure in the lab. It already  was kind of the case with streptomycin.

The antibiotic was found in two strains  of bacteria. The strain more effective  

at producing the drug came out of  a chicken's throat. A student named  

Doris Jones Ralston swabbed and cultivated  the sample before handing it to Schatz.

Does she deserve credit too? This was  Waksman's point. Schatz spent a total  

of three months in Waksman's lab performing the  same protocols as everyone else. If anything,  

Bugie probably deserves more  of a share than what she got.

Was he right? I shall leave that to your  own determination. Regardless of whatever,  

my readings of the accounts of Waksman's actions  find him to have acted like an ungenerous a-hole.

## The Special Soils As mentioned, Streptomycin is produced by

a species within the Streptomyces  genus of the actinomycetes family.

The 700 species in this genus  have provided two-thirds of  

the naturally occurring antibiotics used today.  

What about these soils and bacteria that make  them so conducive for producing new drugs?

There has been much debate over the  years about this. One early idea was  

the "Great War" theory. Soils host hundreds  of millions of bacteria, protozoa, algae,  

and fungi - creating an intense competition  for scarce resources like space or nutrients.

So early on, people surmised that soil  bacteria evolved these antibiotics to  

defeat rivals in vicious combat for those  resources. That view has somewhat evolved  

over the years. Studies have shown that  antibiotics serve multiple purposes.

For instance, antibiotics at low doses  seem to be used as signals. Signs that  

things are changing in the neighborhood  and that nearby bacteria have to start  

preparing. Or they can be a signal to rivals  that this particular area is occupied.

But it is true that in high stakes  situations - like during competition  

for a spot in a local nutritious  niche in the soil - the bacteria  

can ramp up the antibiotic  dose to defend its position.

## The Great Antibiotic Race

Anyway. Waksman's discovery set  off the Great Antibiotic Race.

Over the next twenty years, pharmaceutical  companies scoured the globe for soils to  

produce the next great antibiotic. The  Waksman team at Rutgers screened hundreds  

of thousands of microbes drawn from these soils.

Some samples came from far away. The thinking  was that the rarer and more exotic the locale,  

the more likely to find something new.  Employees taking trips or vacations abroad  

were encouraged to bring sampling bags  with them so they can bring soils back.

This certainly worked at times. The antibiotic  

Erythromycin came from a soil  sample in the Philippines.

The first broad-spectrum oral  antibiotic chloramphenicol came  

from a soil sample collected in 1947  near the city of Caracas in Venezuela.

The Italian company Lepetit discovered the  antibiotic rifamycin from a sample collected  

in the French city of Saint-Raphaël  by a vacationing employee. Rifamycin  

derivatives are still used to treat  traveler's diarrhea and tuberculosis.

And most famously, the antibiotic Vancomycin  was discovered in 1952 in a soil sample from  

the forests of remote Tengeng, Borneo  collected by a Christian missionary.

But plenty came from the companies' own  backyard. A member of the drug company  

Pfizer discovered a drug called Oxytetracycline in  

a soil sample collected just outside  their lab in Terra Haute, Indiana.

It would be marketed as Terramycin -  named after where the original sample  

came from. The drug's success transformed  Pfizer from a mildly successful producer  

of citric commodities for the food  industry into a pharmaceutical giant.

After collecting the samples, a streak  of the unknown actinomycete would be  

put in a standard petri dish. The  pharmaceutical companies employed  

experienced soil microbiologists to  identify such actinomycete by eye.

And then various pathological bacteria and fungi  would be put at right angles to the actinomycete  

streak. The bacteria to be tested usually  was whatever was the main concern of the day.

After a few days, a technician would evaluate the  petri dish for signs of antimicrobial activity.  

Meaning whether the growth of the pathological  bacteria had been impeded in some way or form.

And remember, since this was the late 1940s  and 1950s, there were no automated systems  

or Tesla Optimus robots to handle  this. It had to be all done by hand.

The hit rate for these screening  programs was extremely low.  

Eli Lilly studied over a million  isolates over 30 years. Out of  

that million, Vancomycin was one of just three  antibiotics eventually brought to the market.

And Pfizer screened over a  hundred thousand candidates,  

but Terramycin would be the only  antibiotic from that program to  

make it to market. Most turned out  to be duplicates or were too toxic.

## The Golden Era Ends

In the 15 years after 1943, Streptomyces  produced basically one new useful drug each year.

The number of new drug discoveries likely  peaked in the late 1950s. Afterwards,  

researchers started finding the same drugs over  and over again - despite persistent efforts.

Between 1947 and 1956, there were  606 papers published proclaiming  

the discovery of a new antibiotic.  163 turned out to be duplicates.

Between 1957 and 1967, the number of  duplicates surged to 253. A quarter of  

all previously discovered drugs were  then "rediscovered" at least once.

Some like streptothricin - a  toxin produced by 10% of all  

soil microbes - were rediscovered as  many as 19 times. By the late 1960s,  

it became clear that the soil  mass-screening model had run its course.

This was a major problem because  antibiotic-resistant bacteria were  

already emerging in the 1950s.  Particularly in hospitals,  

where that emergence was quite rapid - driven  by microbes like Staphylococcus aureus.

One hospital in 1951 had just 4.8% of its  cases resistant to tetracycline and aureomycin.

Two years later, that had risen to 78%.

One troubling case in September 1952  saw no strains of bacteria resistant  

to the aforementioned erythromycin. A month later,  

those resistant strains began to emerge.  And by January, they were all resistant.

In response, doctors turned to  multi-drug therapies starting in  

1953 - hoping that combinations can  hit bacteria from multiple sides and  

limit their evolution towards resistance.  But such a thing only worked for so long.

## Hamao Umezawa

One of the scientists facing  this growing resistance was  

Hamao Umezawa (梅澤濱夫), born the  fourth in a line of doctors.

Near the end of World War II, Umezawa led  a team of biologists to help Japan be the  

third country in the world to domestically  produce penicillin - a critical resource in  

the days following the war. He then  pivoted to discovering new drugs.

Umezawa at first followed Waksman's methods  of mass screening soil-dwelling actinomycete  

bacteria. But as resistance to drugs  like streptomycin became more common,  

he shifted his screening targets  to addressing this resistance.

He was rewarded with the antibiotic kanamycin,  which initially defeated streptomycin-resistant  

tuberculosis. Kanamycin became Japan's first  exportable antibiotic, and the drug's royalties  

help fund work at the Institute of  Microbiological Chemistry in the coming years.

When Waksman's methods started to lose their  effectiveness in the late 1960s and early 1970s,  

Umezawa retooled. Studying Kanamycin resistance,  

he notices bacteria producing two enzymes  that disrupt the drug's effectiveness.

So he synthesizes a new drug that works  like Kanamycin but evades those enzymes  

by removing a specific hydroxyl group - dibekacin.

When the bugs became resistant to that one too,  he creates arbekacin - which attaches a special  

side chain to dibekacin to make it effective  again. Throughout his illustrious career,  

Umezawa produced nearly seventy  antibiotics targeting bacteria.

At the same time, he realizes that  antibiotics can inhibit the growth of  

cancer cells too. His work discovers  nearly 40 anticancer antibiotics,  

including Bleomycin - used for Hodgkin’s  Lymphoma and testicular cancer.

In the latter, Bleomycin makes one leg  of a three-way therapy called BEP that  

turned testicular cancer from a  near-certain death sentence to  

a highly curable situation. Literal game changer.

Umezawa passed away in 1986 after a life  well lived. In terms of sheer number  

of drugs discovered, he stands above  perhaps even the great Selman Waksman.

## Semi-synthesis

When the soils finally ran dry, drug chemists like  Umezawa turned to the "semi-synthetic" method.

This worked by modifying or improving known  molecules called scaffolds to create new drugs.  

So you take a natural drug molecule,  strip it down to its effective core,  

and then add new side chains to give it a twist.

Candidates are then screened for factors like  improved bio-availability, effectiveness against  

resistance, or safety. I already discussed Umezawa  producing variants to evade Kanamycin-resistance.

Another example of this is the adding  of hydrogen to streptomycin to create  

dihydrostreptomycin, a more  chemically stable variant.

Semi-synthesis was very successful  - crucial in maintaining antibiotic  

effectiveness even as resistance  continues to expand. It has turned  

the original penicillin into its own  whole class of drugs called beta-lactams.

And today, beta-lactams make up 60%  of all the drugs used for treatment  

and 65% of the approximately  $15 billion antibiotic market.

But these new methods cannot help  accelerate the discovery of new  

classes of antibiotics. The number of which  coming to the medical market has slowed to a  

crawl. Several were actually discovered  all the way back in the golden age.

## Conclusion

The soils were so effective in producing  new antibiotics because it combined high  

microbe population density with  fierce competition for food and  

resources. And collecting  soil samples were simple.

Is there another treasure trove like it out there?  

Researchers have suggested a variety of  different environments: Within sponges,  

marine invertebrates, and insects. Lichens,  gut bacteria have also been suggested.

But perhaps first the economic incentives for  finding new antibiotics must change. In the 1980s,  

there were twenty pharmaceutical companies  working on discovering new antibiotics.

That has since dwindled to only  a handful. The economic incentive  

for a new antibiotic has somewhat  diminished because it is a cheap cure  

and getting a drug to market takes  years and many millions of dollars.

But the demand from patients persists.  Two million Americans are infected by  

antibiotic-resistant diseases  each year. An estimated 20,000  

will lose their lives to it. The  need for new drugs is urgent.