Mildred Rebstock: Profile of the Medicinal Chemist Who Synthesized Chloramphenicol

This year marks the 70th anniversary since Parke-Davis and Company announced the synthesis of chloramphenicol, the first naturally occurring antibiotic to be chemically generated in vitro for large-scale production. The effort was led by the chemist Mildred Rebstock, Ph.D., (1919 to 2011), who would turn 100 years old this year.

ABSTRACT

This year marks the 70th anniversary since Parke-Davis and Company announced the synthesis of chloramphenicol, the first naturally occurring antibiotic to be chemically generated in vitro for large-scale production. The effort was led by the chemist Mildred Rebstock, Ph.D., (1919 to 2011), who would turn 100 years old this year. Her accomplishment, at a time when very few chemists in the United States were women, was celebrated internationally. This commentary reviews her important contribution.

TEXT

Who were the giants of antibiotic discovery and development? Popular answers include various combinations of Ernst Chain, Gerhard Domagk, Paul Ehrlich, Alexander Fleming, Howard Florey, and Selman Waksman. These Nobel laureates ushered in the golden era of antibiotics during the middle 20th century. Their sulfa drugs, beta lactams, and aminoglycosides transformed human health, reigned in the threat of bacterial infections, and saved countless lives. Yet, significant advances made by women scientists of the era have remained underappreciated. Perhaps the best-known female investigator in early antibiotic research was the Nobel laureate Dorothy Hodgkin, Ph.D., an Oxford X-ray crystallographer, who, assisted by Barbara Rogers-Low and scientists at Imperial Chemical Industries, solved the molecular structure of penicillin (1). Here, I highlight the important contributions of another woman deserving of greater appreciation, Mildred Rebstock, Ph.D. (1919 to 2011) (Fig. 1).

FIG 1.

Mildred Rebstock, Ph.D. (1951). (Smithsonian Institution Archives [image no. SIA2009-2146], used with permission.)

Like Hodgkin, Rebstock made her discoveries and contributions in a male-dominated discipline during a male-dominated era. Rebstock led the scientific team that developed the first successful, large-scale synthesis of a naturally occurring antibiotic, chloramphenicol, 70 years ago. As the first broad-spectrum antibiotic to hit the market, chloramphenicol’s success and impact were immediate. Though its popular use was short-lived due to the emergence of unanticipated toxicities, chloramphenicol’s discovery and its synthesis by Rebstock and her team at Parke-Davis made an indelible impact on the golden age of antibiotics.

The discovery of chloramphenicol in the antibiotic era.

The first great era of antibiotic discovery occurred from 1940 to 1960, borne from the 1928 discovery and subsequent large-scale purification of penicillin (2). Although sulfonamide antibiotics had previously been synthesized in the 1930s (3, 4), those compounds were rooted in the azobenzene dye industry, and their synthesis was not directly related to naturally occurring compounds. It was really the discovery of the fungal-derived penicillin by Fleming (5) that ultimately triggered a gold rush of hunting for other naturally occurring compounds that were produced by one microorganism yet lethal to others (2). Literally hundreds of new lead compounds produced by naturally occurring microbes were identified during this era, with a handful eventually reaching clinical use in humans (2).

The fevered search for new compounds involved several pharmaceutical companies. Investigations directed by Parke-Davis and Company of Detroit, MI resulted in the isolation of chloramphenicol (originally trademarked as chloromycetin). In partnership with academic scientists, the efforts of Parke-Davis led to chloramphenicol’s initial isolation from an actinomycete bacterium in 1947 at Yale University by the botanist Paul R. Burkholder and colleagues (6). This mold-like bacterium was cultured from a soil sample collected in a mulched field near Caracas, Venezuela. That very same year, a University of Illinois team collaborating with Parke-Davis obtained chloramphenicol from an actinomycete taken from compost soil in the horticultural farm of the Illinois Agricultural Experiment Station at Urbana, though their report would not be published until 1948 (7). This discovery of chloramphenicol from a soil sample from Urbana, IL holds special relevance to Mildred Rebstock’s history.

Mildred Rebstock, Ph.D.

Mildred Rebstock was born in Elkhart, IN on 29 November 1919 to parents Redna and Adolph on the heels of the First World War. She and her two younger brothers grew up during the Great Depression. At the age of 10, Mildred showed an interest in science, creating a chemistry “work shop” in the basement of her family home and enlisting her younger siblings as assistants (8). She graduated from Elkhart High School in 1938 and continued her education at North Central College in Naperville, IL from which she graduated with a B.A. degree with High Honors (1942). She had chosen North Central College because two cousins had attended and because of her affiliation with an Evangelical Church. “My first memory of North Central is when my parents brought me a few days early and I was really homesick,” she recalled later in life (9). She then earned a M.A. (1943) and a Ph.D. (1945) in Chemistry at the University of Illinois in Urbana, where her studies focused on the organic chemistry of ascorbic acid (10, 11). That the very Streptomyces organisms from which chloramphenicol was isolated were plucked from the soil so near to where Rebstock learned synthetic chemistry and earned her doctoral degree is a remarkable coincidence, at the very least. It is interesting to speculate that Parke-Davis’s collaboration with the University of Illinois faculty somehow catalyzed Rebstock’s hire at that company in 1945.

After earning her doctorate, Rebstock was hired into the Research Department at Parke-Davis, under the direction of Leon Sweet (12). Her initial research was focused on deriving new antibiotics from the streptomycin molecule (13), a naturally derived antibiotic that had garnered significant attention since its discovery by Schatz and Waksman in 1944 (14). In 1947, chloramphenicol was discovered. The drug was found to have a broad spectrum of activity, as it was the first clinically useful drug for the treatment of a range of difficult-to-treat bacterial infections, such as rickettsial diseases (e.g., Rocky Mountain spotted fever, murine typhus, and rickettsialpox), scrub typhus (Orientia tsutsugamushi), and typhoid fever (Salmonella enterica serotype Typhi). The clinical utility was obvious and Parke-Davis and Company was interested in scaling up production and identifying more potent derivatives. Thus, Rebstock was reassigned to the Parke-Davis chloramphenicol research project (15) (Fig. 2).

FIG 2.

Left to right: Eugene H. Payne and Mildred Catherine Rebstock (1919 to 2011). Payne was the first person to use chloromycetin on humans and Rebstock, the leader of the Parke-Davis Research Laboratories team, was the first person to synthesize the drug. (Smithsonian Institution Archives [image no. SIA2009-1338], used with permission.)

The chloramphenicol synthesis team was coordinated by Harry M. Crooks, Jr. and also included John Controulis and Quentin R. Bartz (16). Initial efforts quickly paid off with the apparent synthesis of the drug by Controulis (17). However, the arrangement of the atoms in his synthesized product proved to be wrong and did not have the antimicrobial activity of the native drug (17). Thus, the job was handed off to Rebstock, who successfully generated the authentic, fully active compound (17). Substantiating this primary role for Rebstock, William Laurence, a reporter for The New York Times, wrote on 27 March 1949, “Credit for the achievement of being the first to synthesize an active form of chloromycetin goes to a woman scientist, 28-year-old Dr. Mildred Rebstock (16).” Time magazine in 1949 ran her photo with an article about the discovery, noting that “the achievement was due to teamwork. But a large part of the credit goes to pretty Dr. Mildred Rebstock, a 28-year-old research chemist. She chose the field because ‘I just liked that sort of thing better than some others.’” (18) The Times of India reported, “A woman scientist Dr. Mildred C. Rebstock was the first to synthesise [sic] active chloromycetin” (19).

Parke-Davis and Company publicly announced the synthesis of chloramphenicol on 26 March 1949, news that swiftly traversed the globe (16, 19–21). A headline in the London News declared, “A Victory over Typhus: Chloromycetin Synthesised [sic] for the First Time, by Dr. Mildred C. Rebstock” (Fig. 3) (21). It is noteworthy that, by the time of this public notice by Parke-Davis, clinical studies in humans using fully synthetic chloramphenicol had already been completed (22, 23), suggesting that the successful laboratory synthesis of chloramphenicol by Rebstock and colleagues preceded the 1949 announcement by some time. By the end of 1949, chloramphenicol (as chloromycetin) was released by Parke-Davis and Company to the medical profession, and within 3 years, the sales of this product alone totaled $120 million (24).

FIG 3.

Mildred Rebstock on the 16 April 1949 cover of the Illustrated London News. (Illustrated London News/Mary Evans Picture Library [picture no. 12478270], used with permission.)

An immediate celebration of Rebstock.

Following the news of chloramphenicol’s successful synthesis and deployment in humans, the world celebrated Rebstock’s contribution to this victory over infection. In the wake of this accomplishment, she was listed in “Who’s Who in American Women” (25) and was made an honorary member of the Lambda Kappa Sigma International Pharmaceutical Sorority (25). In 1949, she received the Anna and Eleanor Roosevelt Woman of the Day award (26). President Harry Truman presented her with the National Women’s Press Club Woman of the Year award in 1950 (Fig. 4) (27). In 1951, Rebstock was recognized as Outstanding Woman of the Year by the Soroptimist Club, with the Club President declaring, “Dr. Rebstock has become one of the outstanding woman scientists of our time. She is a graphic example of how far a young woman can go in science in a short time” (28). In 1952, she was named Woman of the Week by the ABC Radio Network (25). She was chosen as the Outstanding Alumna of North Central College in 1959 (25).

FIG 4.

President Harry S. Truman poses with six women picked by the Women's National Press Club as outstanding during the past year, 15 April 1950, during a rehearsal for the award ceremony in Washington. From left: Martha Graham, dance; Dorothy Fosdick, government; Pearl Wanamaker, education; the president's daughter Margaret; President Truman; first lady Bess Truman; Olivia de Havilland, theater; Mildred Rebstock, science; Claire McCardell, fashion. (AP Photo/Bill Chaplis; used with permission.)

In the years following World War II, women made up a very small minority (<10%) of scientists in the United States and merely 7% of chemists were women (29, 30). This point is underscored as follows within a report on women in science published in 1949: “The role of women in the sciences has been a minor one. A year or more after the close of World War II, with its extraordinary demand for scientifically trained women, less than 3% of the nonmedical personnel in the sciences in the United States were women (29).” Rebstock was keenly aware of challenges and opportunities for women in science. In a 1950 interview, Rebstock noted that “[…]women are proving themselves, and this is demonstrated by the fact that laboratories are not going back to their prewar practice of barring women scientific workers from employment” (31). However, statements in the press about Rebstock’s achievement, such as “The synthesis was achieved by pretty, 28-year-old Dr. Mildred C. Rebstock…” (17), illustrate biased attitudes objectifying women as physical specimens rather than as professional scientists.

Life after chloramphenicol.

Despite the great economic success of chloramphenicol for Parke-Davis, Rebstock was not promoted to research leader until 1959, evidence of the prevailing gender bias of the day (30). Further, she remained at that rank until her retirement in 1977, which she undertook to care for her ailing mother (30). Rebstock lived alone in Ann Arbor, MI and kept busy by gardening, being active in her church, and painting in water colors. She passed away at the age of 91 in 2011 (27). My family and I were fortunate to be the next-door neighbors of Rebstock from 2003 until her death. I will always remember her as a gentle, humble, and kind neighbor. After her death, her family gave to me a brown glass pill bottle of white capsules, with a hand-written label declaring “Chloromycetin 250 mg Recrystalized” that were stored in her home. I cannot help but imagine that these might have been among the first production run of fully synthesized drug. I keep them, along with a copy of the program from her memorial service, in my office as an homage to her great legacy (Fig. 5).

FIG 5.

A bottle of chloramphenicol labeled “CHLOROMYCETIN 250 mg Recrystalized” that was among Rebstock’s memorabilia at the time of her death. The program from her memorial service is on the right. Photograph taken by the author.

The views expressed in this article do not necessarily reflect the views of the journal or of ASM.