Hazen, Elizabeth Lee and Rachel Fuller Brown

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Hazen, Elizabeth Lee and Rachel Fuller Brown

American scientists who discovered and patented nystatin, the first highly active antifungal agent to be found safe and effective for use in humans, and assigned all royalties to the Brown-Hazen Fund to expand research and experimentation in biology.

Rachel Fuller Brown (1898–1980). Born Rachel Fuller Brown on November 23, 1898, in Springfield,Massachusetts; died on January 14, 1980, in St. Peter's Hospital, Albany, New York; daughter of George Hamilton Brown (a real estate and insurance agent) and Annie (Fuller) Brown; attended public elementary school, St. Louis, Missouri, and later grades at Central High, Springfield, Massachusetts; received A.B. in chemistry and history from Mount Holyoke, 1920, and, subsequently, an M.S. and Ph.D from the University of Chicago; lived with Dorothy Wakerley; never married; no children.

Awards:

Squibb Award in Chemotherapy (1955); elected fellow of the New York Academy of Science (1957); honorary Doctor of Science from Hobart and William Smith Colleges in Geneva, New York (1969); Rhoda Benham Award of Medical Mycology Society of the Americas (1972); honorary Doctor of Science from Mount Holyoke (1972); Chemical Pioneer Award (1975).

Following work at the University of Chicago, became a chemist at the Division of Laboratories and Research in Albany, New York; developed simple tests for standardizing antisera used in treatment of pneumonia, vaccines and purification of antigens (1926–48); improved precipitation tests used to diagnose syphilis; paired with mycologist, Elizabeth Lee Hazen, to find antifungal agents (1948); with Hazen, discovered nystatin (1950); assigned rights and royalties of nystatin to establish the Brown-Hazen Fund (1951); with Hazen, discovered the antibacterial agents, phalamycin (1953) and capacidin (1959).

Selected publications:

Government: The Future Role of Women in Science and the World (1980); (with E.L. Hazen) Activation of antifungal extracts of actinomycetes by ultrafiltration through gradocol membranes (1949); (with A.B. Wadsworth) A Specific Antigenic Carbohydrate of Type I Pneumococcus (1931).

Elizabeth Lee Hazen (1883–1975). Name variations: Lee. Pronunciation: HAY-zen. Born Elizabeth Lee Hazen on August 24, 1883, in Coahoma County, Mississippi; died on June 24, 1975, at the Mount St. Vincent Hospital, Seattle; daughter of William Edgar Hazen (a cotton farmer) and Maggie (Harper) Hazen, both of whom died before she was three years old; raised by her Uncle Robert (Lep) Hazen and Aunt Laura (Crawford) Hazen; attended local Lula School; received B.S. in science and dressmaking certificate from Mississippi Industrial Institute and College at Columbus (currently the Mississippi University for Women), 1910; attended University of Tennessee and University of Virginia; received M.A. in biology from Columbia University, 1923; Ph.D. in microbiology, 1929; never married; no children.

Awards:

Squibb Award in Chemotherapy (1955); honorary Doctor of Science from Hobart and William Smith Colleges, Geneva, New York (1968); Rhoda Benham Award of Medical Mycology Society of the Americas (1972); Chemical Pioneer Award (1975).

Served as a technician in the Army diagnostic lab at Camp Sheridan, Alabama (1918–19); became assistant director of Clinical and Bacteriology Laboratory of Cook Hospital, Fairmont, West Virginia (1919–23); appointed resident bacteriologist at Presbyterian Hospital (1928); was a member of the teaching staff at College of Physicians and Surgeons, Columbia University (1929); took charge of bacterial diagnosis lab at New York State Department of Health, Division of Laboratories and Research (1931); paired with chemist, Rachel Fuller Brown, to find antifungal agents (1948); with Brown, discovered nystatin (1950); with Brown, applied for patent and assigned rights and royalties of nystatin to establish the Brown-Hazen Fund (1951); with Brown, discovered the antibacterial agent, phalamycin (1953);with Brown, discovered capacidin, an antifungal agent (1959).

Selected publications:

General and Local Immunity to Ricin (1927); Unsuccessful Attempts to Cure or Prevent Tuberculosis in Guinea Pigs with Dreyer's Defatted Antigen (1928); (with A. Schatz) Distribution of soil microorganisms antagonistic to fungi pathogenic for man (1948); (with R.F. Brown) Activation of anti-fungal extracts of actinomycetes by ultrafiltration through gradocol membranes (1949); (with Frank Reed) Laboratory Identification of Pathologic Fungi Simplified (1955).

The early part of the 20th century heralded an exciting era of important discoveries in the medical battle against infectious diseases. Alexander Fleming discovered penicillin. A few years later, Selman Waksman provided streptomycin, a broad-spectrum antibiotic that was effective against a wide array of bacterial diseases. But as research scientists began to win the battle against bacteria, another deadly collection of pathogens gained strength, the Mycota or fungi.

As an antibiotic attacks the bacteria in a patient's system, it also cleans the body, including the intestinal tract, of the normal bacteria that inhabit it. As a result, biological competition is reduced and an overgrowth of any other organism present takes place. As the number of available antibiotics increased in the 1930s and 1940s, so did the number of patients with fungi infections. Pathogenic fungi are responsible for a host of diseases ranging from relatively minor ones like ringworm and athlete's foot to coccidioidomycosis, which can become as malignant as cancer and lead to death. Fungi that attack the respiratory system, such as blastomycosis, histoplasmosis and cryptococcosis, mirror influenza in the early stage. If untreated they can cause gross damage. Until the discovery of nystatin (pronounced nye-state-in), by Brown and Hazen, there was no known antifungal drug that could be used to combat these diseases without harming the patient.

Rachel Fuller Brown had already been working as an organic chemist at the New York State Division of Laboratories and Research in Albany for several years when Elizabeth Lee Hazen was hired in 1931 to take charge of the division's bacterial diagnosis lab in Manhattan. Brown worked extensively with polysaccharides (carbohydrates) to develop simple tests that standardized the antisera used to treat pneumonia. During this time, she was also responsible for developing a simple screening procedure for identifying the presence of syphilis in blood samples. Later, working with a staff scientist analyzing soil microorganisms with antibacterial qualities, Brown became adept at isolating the specific substance in the microorganism having antibacterial properties. This skill was to prove invaluable during her work with Hazen.

Elizabeth Lee Hazen was a gifted scientific investigator and, while working at Columbia University during the 1920s, she solved quite a few mysteries. An outbreak of anthrax, a disease usually associated with cattle and horses, was traced by Hazen to the animal bristles being used in a New York brush factory. She was also responsible for pinpointing unexpected sources of tularemia (rabbit fever), an infectious disease of rodents that can be transmitted to humans through insect bites or by handling the flesh of infected animals. One of Hazen's most important early discoveries, however, was the first reported case of Clostridium botulinum, Type E, which she traced back to canned fish from Germany and Labrador.

The Division of Laboratories and Research had no mycologist on their staff when Hazen was hired. Her strong background in bacteriology and her innovative research abilities made her the perfect candidate to become one. Working with Rhoda Benham , a recognized authority on pathogenic fungi, Hazen learned mycology. She began an extensive collection of systemic fungi found in soil samples she either dug herself or had given to her by fellow researchers. Hazen's original objective had been to develop standard methods of examination for disease-causing fungi, and her collection of cultures was the first step in providing comparative data. In 1944, she returned to Columbia University to formally study mycology.

During the course of testing soil for various microorganisms, Hazen found some samples that contained streptomycetes with strong anti-fungal activity. Now all she needed was a chemist to isolate the active material. Gilbert Dalldorf, director of the division, believed that Rachel Brown's skill in isolating active principles would help Hazen, so he arranged for Hazen to meet with Brown in her Albany laboratory. For the many years of their collaboration, Hazen and Brown would continue to work 150 miles away from each other, Hazen in New York City and Brown in Albany.

Hazen concentrated her research investigations on two pathogenic fungi: Cryptococcus neoformans, the cause of a chronic disease that affects the lungs, skin, and the central nervous system, and Candida albicans (candidiasis), a commonly occurring fungi that can become lethal in patients receiving large doses of strong antibiotics. After gathering soil samples, Hazen would mix some of each with sterile saline and seed them on a nutrient base until any actinomycetes—the microorganisms most frequently having antifungal properties—grew to the stage where they could be seen and identified. The cultures that were the most promising were placed on another nutrient base growing test fungi. Their action against the fungi were then observed.

Brown's job was to find the active properties of those cultures that most strongly affected the growth of the test fungi, separate them from the mass, and refine them so that they could be further tested. In 1948, Brown identified two properties that showed great promise: Fraction N, which turned out to be very toxic to humans, and Fraction AN. Further tests showed that Fraction AN was effective against both Cryptococcus neoformans and Candida albicans, as well as 14 other fungi. Many more long months of tests and research were required until, in 1950, Brown and Hazen were able to report that the toxicity level of Fraction AN in guinea pigs, rats, and mice was very low. It still had not been tested in humans, but nystatin, as it eventually came to be called, appeared to be the antibiotic they were looking for. They reported their discovery to the National Academy of Sciences in October 1950. Nystatin would become one of the most effective agents against Candida and Aspergillus infections in the mouth, skin, vagina, and intestinal tract.

The Brown-Hazen method of producing nystatin was expensive, too expensive for commercial production. In addition, the Division of Laboratories and Research had no patent policy. The division recommended that Brown and Hazen turn to The Research Corporation—a nonprofit establishment with expertise in patenting and licensing inventions for colleges, universities, and research institutions. Under the terms of The Research Corporation's policy, Brown and Hazen were required to give all rights to their invention to the corporation, which would use any financial gains for philanthropic purposes.

The final agreement with the corporation stated that half of all royalties would go to the corporation for use in its own philanthropic activities. The other half, some $6.7 million over the next 20 years, was designated to be used to support the Brown-Hazen Fund, from which distributions would be made to "non-profit scientific and educational institutions and societies for the advancement and extension of technical and scientific investigation, research, and experimentation in the field of biologic and related sciences." In the early years, the Fund supported both fledgling and seasoned researchers. It especially encouraged grant applications from women working in the sciences. In later years, it was expanded to provide funds for biology departments to encourage undergraduates, and for several years it was the single largest source of nonfederal funding for research and training in medical mycology.

At the time The Research Corporation took on the handling of the patenting process for Brown and Hazen, only 1% of all patents in the U.S. had been awarded to women. The organization also found an inexpensive way to produce nystatin using peanut meal. E.R. Squibb & Sons, a pharmaceutical house already known for its interest in antibiotics, contacted the researchers, and a license agreement was signed that gave Squibb exclusive rights for five years to manufacture and sell nystatin.

The time is already past when an occasional woman scientist, such as Mme. Curie, was grudgingly recognized for her pioneering contributions to chemistry and physics.
—Rachel Fuller Brown

In 1954, Federal Drug Agency (FDA) approval was given for sale of Mycostatin (Squibb's name for nystatin) in oral dosage form. It was recommended for the treatment of intestinal candidiasis, a condition that occurred often in patients receiving intensive or long-term courses of antibiotics. Nystatin was subsequently sublicensed to most of the other major drug companies.

In 1966, when the Arno river flooded in Florence, another use was found for nystatin. Because it had no effect on any of the pigments used in paint, nystatin was used on salvaged works of art to retard the growth of fungus. Four years later, it was also used successfully to fight Dutch elm disease.

Although a total of $13.4 million in royalties were paid to The Research Corporation between 1955 and 1976, the only money either Brown or Hazen ever saw from the discovery was a $5,000 honorarium in 1955. It was presented with The Squibb Award in Chemotherapy for "conspicuous accomplishment in the advancement of chemotherapy through their discovery and evaluation of nystatin." Neither woman permitted the discovery of nystatin to make any significant change in her life. Both continued to work in their respective fields, discovering several more antibacterial agents for fungi. Both remained single but were committed to strong family and religious ties, as well as close friendships. Hazen, who continued to work as the head of Mycology at the Division of Laboratories and Research until she retired in 1958, kept her personal and professional life separate, refusing to talk about work when visiting friends or relatives. Personal time for this small, delicate, meticulous woman meant the theater, canasta, dabbling in the stock market or encouraging young relatives to enter college.

Brown, who remained at the division until her retirement in 1968, maintained a lifelong friendship with Dorothy Wakerley . They met while both were involved with St. Peter's Episcopal Church. Brown, a handsome and energetic woman, taught Sunday school for 40 years at St. Peter's and was the first woman to be elected to the vestry of the church. Over the years, Rachel Brown and Dorothy Wakerley "adopted" many Chinese visitors who came to the division to study. As the years passed, the Chinese visitors sent their daughters and sons, nieces and nephews, to live with Rachel and Dorothy while they attended U.S. colleges.

The crowning achievement for Rachel Brown and Elizabeth Hazen came in 1975 at a meeting of the American Institute for Chemists in Boston when they were presented with the Chemical Pioneer Award. This was most unusual for two reasons. First, the institute had to change its bylaws to recognize Hazen, who was not a chemist. Second, it was the first time the award had been given to women.

In addition to funding the work of researchers, between 1960 and 1969 ten grants totaling $355,000 were made from the Brown-Hazen Fund for upgrading biology departments in liberal arts colleges. The 1968 grant to Pacific-Lutheran University helped fund a cooperative effort of two departments: biology and chemistry. It marked the beginning of molecular and cellular biology at an institution that had previously only offered classical biology.

Both Brown and Hazen actively encouraged women to enter the sciences and personally campaigned to get women to apply for Brown-Hazen grants. Brown was continually frustrated in not finding many women interested in science, with the result that she became instrumental in beginning a summer program that provided practical education in biology at Vassar in 1969 and 1970. Funds for scholarships and fellowships given to Mount Holyoke, named for Brown, and those given to the Mississippi University for Women, in Hazen's name, were restricted to advancing the studies of women in science.

In 1980, five years after Elizabeth Hazen's death, Rachel Brown was a contributor to a special issue of The Chemist that focused on women in science. Her closing thoughts are a key to the path both she and Hazen took in their careers. She said that the woman scientist must "recognize her own potentials, believe in herself, and determine to give unstintingly of herself to her chosen career. Only then can she expect to achieve on a par with her male counterparts."