All products of the creative process are a reflection of the individual makeup of the inventors. A painting by Mark Rothko looks like a Rothko painting. A symphony by Wolfgang Amadeus Mozart does not sound like the works of other composers. A Harry Potter story is will never be confused with The Hardy Boys or Nancy Drew. Steve Jobs made sure that no one has trouble distinguishing an Apple computer from a PC. Beverly Sills, the opera soprano, was world renown not only because of her musical skills and technical mastery, but because her voice had a very distinctive and pleasant timbre.
It should not be surprising therefore that drugs, which are also products of human creativity and ingenuity, reflect the character of the people who discover them.
Soil microorganisms have been explored as sources for novel drugs ever since 1928, the year when Alexander Fleming took note of an odd fungal contaminant in one of his experiments that turned out to produce penicillin. Soon virtually all common soil microorganisms had been screened for the production of clinically valuable yielding the antibiotics we typically rely on today: penicillins, cephalosporins, tetracycline, erythromycin etc. But by the 1980’s new antibiotics were getting harder and harder to find and workers began pursuing the idea that microbes growing in exotic places and exotic ecosystems would likely be the best sources to produce unusual and novel therapeutic leads. To encourage their employees to prospect for such microbes, most pharmaceutical research laboratories instituted the practice of “soil days”. The idea was that, if employees who went to unusual places on their vacations were willing to collect a few dozen soil samples while there, these employees would be awarded a “soil day”, a free day of extra vacation time.
It was a great deal for both parties. Collecting the soil samples was trivial, basically bending down and scooping a tablespoon of dirt into a tiny zip lock bag. The employee got a vacation day for minimal work and the pharmaceutical company gained access to some exotic samples. I did it myself. One year, when my spouse and I went on a hiking trip to Switzerland, I took a soil kit with me and picked up samples whenever we stopped at what looked to be an interesting place. One day we were hiking along the shore of an alpine lake and I noticed a beach with very fine powdery off-white sand. It looked unusual so I bent down and scooped some up.
I didn’t think about this sample again until we were going through customs at Newark Airport. It’s against the law for individuals to bring food, farm products and soil samples into the United States, but you can import soils with a special permit. I was always scrupulous to make sure that I had my permit in the collecting kit before I left the country. So when the customs people looked at my luggage I had no worries, at least until the official started to look very suspiciously at my little bag of fine white powder. I whipped out my permit, but I think the customs man was not completely reassured until he saw that, along with my little bag of white powder, there were dozens of similar zip lock bags with contents ranging in appearance from simple garden dirt to dried mud and slimy pond muck. I also think my saying that I was hoping that one of these samples might lead to a novel treatment for AIDS-related infections helped. He let us in through customs and I went right to lab where we found that my samples, collected with much hope and expectation, produced zero.
In the mid-1980’s a Lederle Lab scientist was on vacation in Texas in and took a chalky soil sample from an area near the town of Kerrville that the locals call the “calichi pits”. Back in the lab a strain of the Actinomycete bacteria, Micromonospora echinospora, was isolated from this soil sample and was found to produce a novel antibiotic later named calicheamicin . Calicheamicin is fabulously potent. The good news was that only a couple of calicheamicin molecules could easily kill a cancer cell (almost totally unheard of in efficacy and a thousand times more potent than some of the best clinical antitumor drugs, like adriamycin). The bad news was that only a couple of calicheamicin molecules could also easily kill a normal cell. In fact, calicheamicin kills everything it touches: bacteria, fungi and viruses, eukaryotic cells, and eukaryotic organisms like mice and people.
Studies on calicheamicin by George Ellestad and Nada Zein, who among other scientists at Lederle Laboratories*, showed why calicheamicin was so fabulously potent: it had a highly unusual mode of action . Calicheamicin acts as a “chemical nuclease”. Calicheamicin is similar to an enzyme (it’s really a chemical catalyst); it is able to repeatedly bind to DNA and make double-strand breaks. Exposure to just a few molecules of calichaemicin can chop an entire genome into hamburger. But this finding also raised a question: how is the Actinomycete bacterium that produces calicheamicin is able to resist its toxicity? That question was answered by studies in the early 2000’s , which showed that Micromonospora echinospora produces a protective protein called CalC. Calichaemicin tightly binds to CalC, which leads to the destruction of both the CalC protein and the bound calichaemicin. As a result, any molecules of calichaemicin that remain within the producing organism are rapidly destroyed before they can do any damage.
The therapeutic goal for calicheamicin was therefore to devise some sort of guided missile that could selectively deliver lethal calicheamicin to cancer cells. This was a proven concept. One hundred years earlier the German scientist, Paul Ehrlich, had devised the world’s first effective treatment for syphilis by attaching toxic arsenic to a Treponema pallidum binding dye: missile and warhead.
But one hundred years later scientists were able to come up with a better missile than an aniline dye. The obvious modern missile was going to be some type of highly selective monoclonal antibody. The problem was that the monoclonal antibody carrier had to be designed so as not to release any toxic calicheamicin until it reached the cancer cell. Then, upon reaching the cancer cell, it had to dump its entire toxic payload. Not easy. It took ten years of hard work to get there, resulting in the development of gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth) . The gemtuzumab ozogamicin antibody binds CD33, a myeloid-specific cell surface protein that targets the calicheamicin for the treatment of acute myeloid leukemia (AML). But frustrating everyone involved, gemtuzumab ozogamicin did not turn out to be the magic bullet. Ten years post-launch gemtuzumab ozogamicin was removed from the market in the United States at the request of the U.S. Food and Drug Administration (FDA). After years of clinical experience, the FDA concluded that the drug was still too toxic, although it is still being used in Japan and studies continue to support the re-approval of this agent .
Needed: A Tremendous Dose of Luck
Among the members of the calicheamicin team, George Ellestad was a very special kind of person. George’s hobby was trekking in the Himalayas in Nepal. (No, none of the soil samples he brought back from Nepal ever produced a drug). He was a natural scientific leader but avoided any and all formal scientific management roles. He was a pure bench scientist. When George spoke up at meetings he was so authoritative that everyone would immediately focus and listen carefully to him, listen much more carefully than they would listen to the big management bosses who also spoke at these meetings. People would mistakenly characterize George as a high-level manager. “No”, he would insist, “I’m just high bench”. George is one of these unsung heroes of industrial science – someone who was effective way beyond his rank but not adequately formally recognized.
His colleague, Nada Zein was a passionate scientist whose lifelong goal was to pursue and discover the truth. She never let her career goals get in the way of that pursuit, exemplifying a quote from the famous 20th-century philosopher, Ludwig Wittgestein: “Ambition is the death of thought.” Nada was passionately thoughtful. I got to know Nada in no small part because she married a terrific chemist collaborator of mine named Doug Phillipson, with whom I had worked with in a previous job. If it seems like all drug hunters know one another, that’s because it’s true. We’re an amazingly small community.
Doug and I worked on a number of drug projects together, with me leading the biology and Doug leading the chemistry. We were also good friends outside the lab. Doug sold me his favorite car, a little white 1993 Mazda Miata, which he had meticulously kept in near brand new condition but could not financially justify taking with him when he moved from New Jersey to California in the late 1990’s. Over 20 years later the car is still running just fine. Doug was totally trustworthy both as a scientific collaborator and a used car salesman.
One project that Doug and I worked on together was the development of a novel antifungal drug. At the time the AIDS crisis was in full swing and, prior to the development of effective antiviral drugs, fungal infections were producing 70% of the morbidity in AIDS patients. Squibb** management felt that only one therapeutic approach was justified: to target the enzyme that was hit by the azole antifungals, drugs like miconazole (sold a Micatin Cream for vaginitis) that were first discovered in the late 1960s. And after years of toil by a large group of Squibb scientists, we finally found what management had asked for: lanomycin, a structurally novel antibiotic acting on the azole target. However, just as the discovery was made management abruptly reversed themselves and withdrew all support from our lanomycin lead. The Greek gods should have sentenced Sisyphus to a lifetime of drug hunting. Doug tried to keep the project going under the radar without management approval, but alas, with only minuscule resources lanomycin was never going to be turned into an FDA approved drug. (Ultimately the pneumocandin antifungals, compounds with a novel anti-cell wall mechanism of action, turned out to be the answer.)
Nada pursued a number of scientific initiatives after her work on calicheamicin, moving from Lederle to the Genomics Institute of the Novartis Research Foundation in La Jolla, California. At the Novartis Foundation in La Jolla she was seeking to mate drug ligands to receptors but soon came to the conclusion that this goal would be elusive due to management and leadership issues in the pharmaceutical industry. So she decided instead to study for a master’s degree in social work and for years ever since has been working as a marriage counselor. Counter-intuitively it appears that it was easier for her to bind spouses together than drug ligands and their targets. Go know.
The discovery of new medicines is brought forward by the dreams, aspirations and creative spirit of all those involved. But despite all the great ideas and hard work you still need a tremendous dose of luck.
* Lederle Laboratories was purchased from American Cyanamid in 1994 by American Home Products Corp., and the Pearl River operation was renamed Wyeth-Ayerst. American Home Products renamed itself Wyeth in 2002 and became a piece of Pfizer in 2009. Today, the Pearl River campus is one of Pfizer’s five primary research sites and a central hub for Vaccine and BioTherapeutics research. The company also manufactures a number of oncology drugs at the Pearl River, including Mylotarg®.
** Squibb Corporation was founded in 1858 by Edward Robinson Squibb in Brooklyn, New York, New York. E.R Squibb was known as a vigorous advocate of quality control and high purity standards within the fledgling pharmaceutical industry of his time, at one point self-publishing an alternative to the U.S. Pharmacopeia (Squibb’s Ephemeris of Materia Medica) after he was unable to convince the American Medical Association to incorporate higher purity standards. References to the Materia Medica, Squibb products, and Edward Squibb’s own opinion on the utility and best method of preparation for various drugs are found in many medical papers and journals of the late 1800s. Squibb Corporation served as a major supplier of medical goods to the Union Army during the American Civil War, providing portable medical kits containing morphine, surgical anesthetics, and quinine for the treatment of malaria (which was endemic in most of the eastern United States at that time). Squibb merged in 1989 with Bristol-Myers (founded in 1887 by Hamilton College graduates William McLaren Bristol and John Ripley Myers) to form Bristol-Myers Squibb.
January 17, 2017 | Corresponding Author: Donald R. Kirsch | DOI: 10.14229/jadc.2017.17.01.001
Disclosures: Donald R. Kirsch is the co-author of “The Drug Hunters: The Improbable Quest to Discover New Medicines.”
Received: January 15, 2017, | Published online January 17, 2017, | This article has been submitted for peer review by an independent editorial review board.
Last Editorial Review: January 17, 2017