Experiment Eleven (4 page)

In 1924, Waksman took six months off from Rutgers to go to Europe on a “
grand scientific tour
” with his wife and their four-year-old son, Byron. It was the first of five European tours that he would make with his wife
before the outbreak of World War Two. In 1924, the main attraction was a conference on soil science in Rome organized by Jacob Lipman, who allowed Waksman to continue to be paid his small Rutgers salary but gave him no expenses for the trip. Despite his tight budget, Waksman packed in a hectic schedule of visits to major soil microbiology laboratories in Britain, France, Germany, Sweden, and Holland. In Paris he met and struck up a thirty-year friendship with the Russian pioneer of soil microbiology, Sergei Winogradsky, now an émigré in Paris. And in Holland he visited Martinus Beijernick, who made his reputation by discovering viruses in 1898 and went on to find bacteria that make nitrogen available to plants. According to Waksman, Beijernick greeted him with the words “
You are the actinomyces man
.” Waksman also went to Moscow and even his hometown, Novaya Priluka, in Ukraine. There he witnessed the ravages of the revolution and the civil war and saw again the little house where he was born. “It looked like a
hole of a troglodyte
,” he wrote later. He returned to America determined to write source books to fill the gaps in the literature of soil science.

“I was
primarily a soil microbiologist
,” he wrote, “studying soils and composts, peat bogs and manure piles ... concerned with products of microbes that are used in green plants.” He “scarcely dreamed of becoming profoundly involved in problems dealing with human health.” He was “
too busy
completing [his] work on the distribution of different groups of microorganism in the soil, their role in the decomposition of organic matter and formation of humus.” His studies resulted in several major works that said almost nothing about the possible medical application of his fighting microbes.

In a 360-page book,
Enzymes
, published in 1926, he devoted only one paragraph to antagonistic bacteria. In his 894-page tome
The Principles of Soil Microbiology
, he wrote only two pages on “
antagonism and symbiosis
among microorganisms.” On another page, he mentioned the “inhibitive effects” of fungi and actinomycetes. In a
smaller book
,
The Soil and the Microbe
, written with Starkey, now Waksman's deputy, in 1931, they discussed the role of microbes in the life cycle of soil organisms. But he wrote only one sentence about bacteria fighting among themselves.

In his lectures and scientific papers, he would remind his students and readers that the soil was a complex system, our knowledge of it limited,
our methods crude, and we were still unable to understand how it works. In the basement lab, his students followed “a semi-military regime,” often working weekends during the depression years because they had no money to spend. They wrote brief descriptions of each day's projects in five-by-seven-inch lab notebooks, which Waksman reviewed at the beginning of each week. One student recalled what was known as the “book parade.” “Waksman would spot Harry and say, ‘Let me see your book.' Waksman would glance at it and add, ‘Tell Dave to bring his book.' Harry, disarmed, would go down to the basement lab and pass the word. Dave would submit his book and come back to order another student up to the office. The books were returned when Waksman spotted an error, or something unclear, but he never accused anyone of being a slob and all partings were amiable. The book parade seemed to me
a little Teutonic
.” Waksman rarely visited his students in the basement lab, even then. But once a year he held a spring cleaning, which he obviously enjoyed. All drawers and cabinets had to be open for inspection, and Waksman would walk in followed by his assistant, who carried a laundry basket. The student wrote, “If he found equipment lying on the bench, or chipped, or unlabelled, he would say, ‘Vat's this for?' in his Russian accent (which he never lost) and if there was any doubt, he would tell his assistant, ‘
Throw it in the basket
.'”

In those days, Waksman's students were still not looking for medical applications. “The soil and the microbe,” Waksman wrote, “await the investigator [who] is not looking for practical gains but for explaining the obscure and observing the unknown. The application will doubtless come.” Undoubtedly, Waksman missed a great opportunity. Had he pursued what he had observed with Pasteur's “prepared mind,” he, not Alexander Fleming, might have been the first to discover an antibiotic.

But he was not a physician, like Fleming, and Rutgers had no medical department. In his daily life, Waksman was not exposed to faculty discussions about the therapeutic value of “magic bullets” like salvarsan, or the sulfa drugs that followed. In 1932, the German doctor Gerhard Domagk, working at the giant chemical company I. G. Farben, found a bright-red dye that cured mice infected with pathogenic streptococci. This new compound, named Prontosil, was good for fighting a wide range of bacterial infections and later gave rise to the sulfonamides, or sulfa drugs, which had a major impact on the treatment of infectious diseases. (The life of Winston
Churchill was saved by a sulfonamide when he developed pneumonia after the Tehran Conference with Stalin and Roosevelt at the end of November 1943.)

Yet Waksman still lacked funding to expand his research. In America, medical research, like other scientific research, suffered from a lack of public assistance. In the 1920s and '30s, the National Institutes of Health and the National Science Foundation did not exist. Waksman relied on his wits to attract support. He was a good salesman, a scientist-entrepreneur who never seemed short of industry sponsors.

He helped tanners find enzymes for
defatting hides;
brewers, enzymes to clarify beer. He convinced the local mushroom industry that providing funds to investigate a compost mix of alfalfa, peanut shells, and tobacco stalks was a better bet than relying on horse dung from the declining stables of the Philadelphia police department. These links with industry provided rare funding during the depression years, and endeared Waksman's graduate students to him for providing them with beer and mushroom tastings. There were some unexpected delights. On one famous evening in the college auditorium, female models paraded in then-daring off-the-shoulder evening dresses with fringes of miniature orchids bred in Dr. Waksman's Department of Soil Microbiology. The event was sponsored by a local businessman hoping to sell the orchids at debutante balls.

A few independent foundations gave research grants, and in 1932, the National Tuberculosis Association funded Waksman to study the fate of TB germs in people and animals who died of TB and were buried in the soil. He assigned the task to
one of his graduate researchers
, who found that the tuberculosis bacteria were greatly reduced in some soils. But Waksman did not follow up this interesting result. Similar results were being obtained by other researchers, and Waksman thought they all seemed to lead nowhere. He was not “yet
prepared to take advantage
of these findings.”

In late 1935, Fred Beaudette, Rutgers's director of Poultry Pathology, brought Waksman a test tube containing a TB bacterium specific to poultry that had been destroyed by a fungus that had accidentally contaminated the tube. This was indeed a “happy accident” of the kind that Fleming had encountered seven years earlier with penicillin. Yet Waksman was still not ready to seize the opportunity, this time staring him in the face.

There was, of course, a perfectly good and understandable reason for
not wanting to test a microbe's ability to destroy pathogenic bacteria: the risk of catching the disease. In his writings, Waksman
never mentions this as a factor
, but it must have been on his mind. His underfunded laboratories were poorly equipped to protect the workers against infections, or even the hazards of handling dangerous chemicals. In the basement laboratory, protective clothing consisted of worn and torn white lab coats and some “very crusty, black, rubber lab aprons designed to catch splashes of hot acid.” These coats were “
hung on spikes
driven into the wall” when not in use.

BUT WAKSMAN COULD
not ignore the research coming out of Europe and Russia. In the mid-1930s, the Russians led the world on research into the antagonistic properties of Waksman's precious actinomycetes. By 1935, Russians had published four papers on the subject; Waksman had published none. A key Russian paper reported that actinomycetes were antagonistic to
Bacillus mycoides
, one of the standard bacteria tests for antibiotics. The paper concluded, “The question of interrelationships of soil microbes deserves profound research.” Waksman had an enormous advantage over his peers in America in being able to read these papers, not just the English summary that was always included but the whole paper, and some have speculated that the Russian research
started to turn his mind
toward the possibility of antibiotics, a suggestion he never acknowledged.

In 1936, at the Second International Congress for Microbiology in London, Alexander Fleming discussed the
antibacterial properties
of his penicillin, a debate which Waksman later listed as an important event in the evolution of his own thinking. One of Waksman's graduate students recalled that Fleming's discussion was when Waksman became “
seriously interested
” in antibiotic research.

Later in 1936, Waksman began to study the published papers on warrior microbes and wrote two papers for
Soil Science
, the journal started at Rutgers by Dr. Lipman. The first paper reviewed the current literature, including the four Russian papers. A measure of Waksman's absence from basic research in this area is that of the 107 papers he listed, only 2 were written by him.

In the second paper, also finished in 1936, Waksman and a graduate student, Jackson Foster, tested a fungus, a bacteria, and an actinomycete
from a Scottish peat bog. They were all capable of producing “
substances which are antagonistic
” to other soil microbes when grown in petri dishes containing artificial nutrients. In 1937, another Russian researcher found that antagonistic actinomycetes were “widely distributed” in different soils in the Soviet Union.
Of eighty cultures
isolated from various soils, forty-seven possessed antagonistic properties, but only twenty-seven were found to be capable of liberating toxic substances into the nutrient agar on a petri dish.

In 1938, Waksman was especially influenced by the work of one of his former students, René Dubos. A Frenchman who had qualified in agriculture and immigrated to America in 1924 after hearing Lipman speak at the conference on soil science in Rome, Dubos worked for his Ph.D. under Waksman at Rutgers. He discovered a soil microbe that produced an enzyme capable of breaking down cellulose, the key ingredient of plant stalks and tree bark, and turning it into plant food. Similar work was being carried out at the Rockefeller Institute for Medical Research, in New York City, where Dubos later moved. There, he eventually isolated a bacterial enzyme that destroyed the sugary coat of the bacteria that causes pneumonia. Unfortunately, the enzyme was too toxic to be used by humans suffering from pneumonia, but Dubos was sufficiently encouraged to begin the first systematic search for antibiotics in the soil.

In 1939, he found an antibacterial agent produced by a bacterium,
Bacillus brevis
, and named it tyrothricin. The Rockefeller biochemist Rollin Hotchkiss helped him recognize that it was made up of two compounds, tyrocidin and gramicidin. Tyrocidin was toxic to mice, but gramicidin cured experimental infections in mice, without side effects. Gramicidin was too toxic to be administered to humans intravenously, but it was effective when used on open wounds. The Russians produced their own version of Dubos's discovery, known as
gramicidin S
(for Soviet), and used it throughout World War Two as their main antibiotic.

That same year, the Russians struck again. Two researchers, N. A. Krassilnikov and A. I. Korenyako, again found that many species of actinomycetes produced antibiotics. The Russians concluded that “
one cannot escape the possibility
of using the bacterial factor of actinomycetes” to treat bacterial diseases. For the first time, they discovered two that were active, ever so slightly, against
Mycobacteria
, the group that causes tuberculosis. To
anyone searching for a cure for TB, it was a powerful clue that such an antibiotic might be found.

By late 1939—in the wake of pioneering research by the Russians, a major discovery by Dubos in New York, and the beginning of the war in Europe—Waksman, the soil microbiologist who had pledged his life to microbes that could be used in plants and industry, was finally ready to change the direction of his research to look for antibiotics to cure human diseases. All he needed was a sponsor.

Twelve miles down the railroad track
from the Rutgers campus is Rahway, New Jersey, once an old Indian settlement and a stop on the stagecoach run from New York to Philadelphia. Since 1903, Rahway has been the home of Merck & Co., then and now one of the most important pharmaceutical concerns in the country. Friedrich Jacob Merck opened the original family-owned apothecary, the Engel-Apotheke (Angel Pharmacy), in 1656 in Darmstadt, Germany. In 1827, the Merck company started producing morphine, codeine, and cocaine. By the 1890s, Merck was selling so many products in America that the family dispatched the twenty-four-year-old George Merck to set up shop there. He settled in Manhattan, bought 150 acres of Rahway, and later sent his son, George Jr., a blond, blue-eyed giant at six feet five inches, to Harvard. On George Sr.'s death in 1926, his son took over the business.