Today we have a guest post from Chris Drudge (PhD, MPH). Chris is constantly working on his intensely-researched life science blog Rosin Cerate (www.rosincerate.com). It’s mostly about weird microbes, old drugs, and super poisons. You can follow him on Twitter (@RosinCerate).
Many bacteria make their living by getting inside us and chowing down on our cells. Although we have a rapid-acting and multifaceted immune system to defend us against microbial attack, it’s not always effective. Sometimes the system becomes compromised, while other times the invader is exceptionally well-equipped to evade our defences. To help our bodies deal with disease-causing bacteria, we’ve looked to nature for weapons. Our earliest efforts involved crude materials such as honey, plant extracts, clays, and cow bile. Smear it on a wound and hope for the best.
The 20th century ushered in two key advances in antibacterial (antibiotic) drug development. Firstly, we started to screen piles of synthetic compounds for their ability to inhibit microbial growth, yielding arsenic- and sulfur-containing drugs such as Salvarsan and Prontosil. Secondly, we looked more closely at the biologically active products of microbes themselves. The latter approach is responsible for nearly all of the medicines we currently use to fight bacterial infections.
The earliest microbe-derived antibacterials were some combination of toxic, poorly effective, and unstable. Then, in 1928, a blue-green mould turned up on Alexander Fleming’s lab bench, initiating a 20-year process that yielded a relatively inexpensive, safe, and effective means of combating bacteria. The resounding success of penicillin kicked off a global microbe collection spree. Throughout the 1950s and 60s, we built up an impressive pharmaceutical armament against bacteria. Yet, after enjoying steep declines in many bacterial illnesses, we now find ourselves facing an intense microbial comeback. In the last couple of decades bacteria have progressively drawn on their ancient metabolic flexibility and gene-mobilizing powers to share amongst themselves the means to shrug off the drugs we want to use to kill them.
One obvious approach to addressing the spectre of widespread antibacterial drug resistance is to discover and develop new antibacterial drugs. In an effort to access undiscovered drug-making microbes hidden in locations not yet surveyed by drug discovery labs, scientists have engaged non-scientists. Specifically, for the last couple of years now, research groups at two American universities, the University of Oklahoma (http://npdg.ou.edu/citizenscience) and The Rockefeller University in NYC (http://drugsfromdirt.org/), have been asking the public to mail them samples of soil. Most soils are teeming with microorganisms, including ones highly adept at making compounds capable of causing biological responses in other organisms. In other words, potential drugs. Antibacterials, antifungals, immunosuppressants, anticancer drugs, and even a drug used to treat type II diabetes have all been successfully developed from the products of soil microbes. Bringing the public on board has enabled the university research groups to collect and screen a large number of soil samples from a wide range of environments, boosting their chances of finding useful compounds.
Modern public-involving drug discovery initiatives have their roots in the antibacterial boom of the mid 20th century. Non-scientists enabled scientists to find several important microbe-derived drugs. While penicillin was discovered by Fleming in his lab at St Mary’s Hospital in London, the strain of Penicillium mould he worked with proved to be inadequate for the production of large amounts of the drug. Spurred by World War II, researchers at the newly established Northern Regional Research Laboratory (NRRL) in Peoria, Illinois, began looking for better Penicillium strains to scale up penicillin production. Increased public awareness of penicillin as a potential miracle drug (and boon to the war effort) led people to mail the NRRL their mouldy fruits and vegetables on the offhand chance they’d bear an adept microbial maker of penicillin. Amusingly, not everyone who contributed to this early citizen science effort had a good grasp of microbiology. One of the NRRL researchers recalled “an Arizona rancher who dispatched a lichen-encrusted rock, adding that he could send us tons of like material if this would speed the investigation” (Raper, 1952). In addition to contributions from the general public, soil samples were collected for the NRRL by military personnel from locations across the globe.
Even with a global effort in place, the best strain of penicillin-producing mould was ultimately obtained from the stem of a cantaloupe found at a fruit market in Peoria. Progeny of this strain (created in labs by zapping the mould with UV and X-rays to improve its penicillin production) are responsible for most of the penicillin ever made.
Seeking to replicate the success of penicillin, drug company scientists recruited their non-scientist coworkers and acquaintances to collect soil samples from around the world. The samples were then screened for drug-producing microbes. Exotic locales were particularly coveted, so recruits often did their collecting while on vacation. Oxytetracycline (Terramycin) was the product of an intense research project based on the acquisition of thousands of soil samples from around the world by the drug company Pfizer. Soils were collected by “foreign correspondents, explorers, travelers, and friends” (Kane et al., 1950) from wetlands, mountains, riverbanks, and more on several continents. After screening the samples, an oxytetracycline-making bacterium was found in soil dug up near a Pfizer facility in the USA, a decidedly boring place to find a new drug after a global search.
Vancomycin, a glycopeptide used to treat problematic infections caused by certain bacteria resistant to penicillin-like drugs, was discovered after an American chemist working for the drug company Eli Lilly contacted a missionary in Borneo and asked him to send some soil samples. The two were able to connect via mutual acquaintances due to their involvement in the Christian and Missionary Alliance church. At this time, Eli Lilly paid for all air freight charges to help ensure any missionaries they connected with (they had quite a network going at one point) would continue to mail them samples. A year later, a small vial of soil from beside a rainforest footpath yielded a vancomycin-producing bacterium.
To conclude, public participation in antibacterial drug discovery has a neat history stretching back to the rise of penicillin. Recruiting people to send in microbe-laced samples is a great way to fuel the process of drug discovery. Hopefully someone’s backyard will yield the next bacteria killer.
Kane JH, Finlay AC, Sobin BA. 1950. Antimicrobial agents from natural sources. Annals of the New York Academy of Sciences 53(2):226-228.
McGraw DJ. 1974. The antibiotic discovery era (1940-1960): Vancomycin as an example of the era. PhD Thesis, Oregon State University.
Raper KB. 1946. The development of improved penicillin-producing molds. Annals of the New York Academy of Sciences 48(2):41-56.
Raper KB. 1952. A decade of antibiotics in America. Mycologia 44(1):1-59.