Miracle Cure

by William Rosen

  For a century, morphine would be the most profitable and popular medicinal product produced by Merck, but its real importance was giving the still-small company expertise in chemical manufacturing. The same techniques used for making consistent doses of morphine out of decidedly impure opium allowed Merck entrée into the business of manufacturing so-called fine chemicals: small-batch, high-value, and very pure compounds. His timing was excellent, as the giant chemical companies that emerged after William Henry Perkin’s discovery of the first aniline dyes became Merck’s largest customers, and a valuable source of knowledge about the most advanced nineteenth-century industrial chemistry. In 1889, the company’s first publishing venture, Merck’s Index, became the ultimate source of chemical information for a generation of scientists and engineers.

  Merck remained a maker of medicines as well. In 1887, the company opened its first office in the United States, as a marketing and sales department for the German parent, still known primarily for morphine; and, in 1891, as a subsidiary: Merck & Co., run by Georg Merck. The following year, Georg anglicized his name by adding an e to it, and welcomed his first child: George W. Merck.

  For the next twenty-five years, the company prospered. In 1900, it acquired 120 acres of swampland in Rahway, New Jersey, where it built a factory to produce bismuth—the active ingredient in Pepto-Bismol, invented as an antidiarrheal in 1901—cocaine, and morphine. Next door, another Merck subsidiary known as Rahway Coal Tar Products manufactured, among other things, carbolic acid, the antiseptic discovered by Joseph Lister four decades before. By 1917, Merck & Co. was recording sales of $8 million annually—roughly $96 million today—solid, but not earthshaking, considering that same year General Electric sales were nearly $200 million, and U.S. Steel $400 million.

  Of course, 1917 is the year that marked the entry of the United States into the First World War, with serious consequences for U.S. subsidiaries of German companies. Because Germany, particularly the I. G. Farben cartel, dominated manufacture of virtually all medicinal chemicals, supplies of critical compounds were at risk. The world’s entire supply of atropine, for example, an extract of belladonna that was one of the key medications in treating heart problems, was in the control of Germany and her allies. On April 17, 1917, the Medical Section of the Advisory Commission of the U.S. Council of National Defense convened a meeting attended by representatives of more than 250 companies, including Merck, to find alternatives.

  Meanwhile, anti-German hysteria led to a dozen new laws intended to limit the activity of “enemy agents,” such as German-owned corporations. The Trading with the Enemy Act, which went into effect in October 1917, was the most significant. One of its clauses provided for the selection of an Alien Property Custodian, a federal judge named A. Mitchell Palmer who immediately required that the German-owned chemical companies be “Americanized.” True to his word, he confiscated 80 percent of Merck, the eight thousand shares owned by the parent company in Hesse-Darmstadt—and only held them in trust after a plea from George W. Merck, Sr., who owned the other two thousand shares himself, and didn’t want his company sold out from under him.*

  At the moment the roof fell in, twenty-nine new researchers—chemists, pharmacists, and chemical engineers—had just been hired. They were just in time to help the company grow dramatically during the war years, which saw the Rahway plant triple in size—and to see George Merck outbid Monsanto and American Aniline to repurchase his company at auction, in 1919, for $3.75 million. Some of those researchers were still there in 1925, when George W. Merck, Jr., took over the firm.

  Biographers looking for a successful business leader with a virtually unblemished record for honorable behavior would probably stop searching immediately after coming across George Merck, Jr. Born in New York, he was raised in the comfortable New Jersey suburb of Llewellyn Park where, at least in family legend, he was so friendly with Thomas A. Edison’s two sons that he was permitted to haunt the great inventor’s lab and workshop. Supposedly, Edison called the Merck heir “Shorty,” though he was probably the last to do so. George, as an adult, was an imposing six foot five inches tall, athletic, and charismatic. When he graduated from Harvard as part of the class of 1915—a year early—the war in Europe prevented him from pursuing his earlier plan to attain a graduate degree in chemistry in Germany, and he instead joined the family firm, becoming a vice president by 1918, and, when his father fell ill in 1925, president.

  Although it would be reasonable to assume that his rapid promotions were a function of his name rather than his talent, from the start he did his best to correct any misapprehension about his abilities. In 1927, still in serious debt from the purchase from the Alien Property Custodian, George engineered a merger with another fine chemical manufacturer, the Powers-Weightman-Rosengarten Company of Philadelphia (Adolph Rosengarten, Merck’s largest nonfamily stockholder, was ready to retire), and in 1929 made the far more momentous decision to build, on the Rahway property, a research laboratory. At its dedication on April 25, 1933, more than five hundred spectators heard Sir Henry Dale, the future president of England’s Royal Society (and the same man who would try and fail to interest British pharmaceutical companies in the penicillin innovations under way at the Dunn School a decade later), give a speech on “Academic and Industrial Research in the Field of Therapeutics.” And they heard George Merck assert, “We have faith that in this new laboratory . . . science will be advanced, knowledge increased, and human life will win a greater freedom from suffering and disease.”

  This corporate gamble on the future of scientific medicine wasn’t unique to Merck. The onetime Abbott Alkaloidal Company, renamed Abbott Laboratories in 1914, opened a 53,000-square-foot Chicago research facility in 1938 (interiors by the design genius Raymond Loewy). That same year, in October, the Squibb Institute for Medical Research was dedicated in New Brunswick. In Indianapolis, Eli Lilly opened Lilly Research Laboratories in 1934. A year later, DuPont opened the Haskell Lab of Industrial Toxicology in Newark, Delaware.

  But the Merck Institute for Therapeutic Research was the first, and by most measures, the most innovative. In conscious imitation of the academic-industrial conveyor belt that had served the German chemical companies so brilliantly, Merck hired the Viennese pharmacologist Hans Molitor as the institute’s first director, and recruited Randolph Major from Princeton to join Alfred Newton Richards—Howard Florey’s erstwhile mentor from the University of Pennsylvania—in Rahway.* He invested in more than just personnel; the institute’s annual research budget increased from $146,000 in 1933 to nearly $1 million by the beginning of the 1940s.

  If George Merck’s goal was that “science will be advanced, knowledge increased,” he could scarcely have been disappointed. In 1937, Major persuaded the brilliant Max Tishler—in the words of a colleague, “Max was born with an energy level that was like an avalanche and a brain that was incandescent”—to leave Harvard for Rahway. During the institute’s first five years, its researchers published thirty papers in peer-reviewed journals; from 1939 to 1941, the number was closer to fifty. Not included in that number is a nonetheless revealing article that the president himself published in 1935, in the journal Industrial and Engineering Chemistry. Entitled “The Chemical Industry and Medicine,” it contains the lines, “to do research worthy of the name, to do research which will bring to industry true recognition of its contribution to the advance of knowledge, industry must have at its disposal genuinely creative minds so placed and so protected that the mental powers of thought, study, and imagination can concentrate on problems of great difficulty. For even to see the problems clearly is of itself a major task.”

  When Heatley arrived in Rahway in 1942, the lab, under Major, was still primarily doing research on vitamins, which then accounted for more than 10 percent of the company’s sales. In 1936, Joseph Cline of Merck and Robert Williams of Bell Labs had succeeded in synthesizing vitamin B1 for the first time, and by 1940 Karl Folkers, late of Yale, had iso
lated and synthesized both vitamin B6 and pantothenic acid. Max Tishler had been explicitly recruited to work on vitamins by Randolph Major himself, who told him, “We made up our minds that we’re going to specialize in research in the field of vitamins. We’re going to isolate every vitamin; we’re going to determine their structures . . . synthesize them, and make them available.” Tishler didn’t waste any time; by 1938 he had discovered a new way to synthesize vitamin B2 in order to perform an end run around patents owned by I. G. Farben and Hoffmann-La Roche, neither of which would license them to Merck.

  All that was about to change, not just at Merck, but at other American pharmaceutical firms that had invested millions in research laboratories they were eager to employ on products with more commercial potential than vitamins and antiseptics. In February 1942, Merck signed a research-sharing agreement with E. R. Squibb, the company founded in 1858 by a former U.S. Navy surgeon, Dr. Edward R. Squibb, largely to produce surgical anesthetics. His timing was, in its way, impeccable; the Civil War broke out only two years later, and so increased the nation’s annual quota of amputations and other surgical procedures by at least an order of magnitude. Union surgeons carried thousands of the fully stocked wooden medicine chests known as Squibb Panniers from Antietam to Appomattox: a kit of medicinal compounds including anesthetics like ether (which would remain the company’s signature product for more than forty years), quinine for malaria, and, of course, whiskey.

  By the beginning of 1942, the company had been owned and managed by a former Merck executive, Theodore Weicker,* for more than thirty years; and if there had been any bad blood over his leaving the firm—Weicker had sold his share of Merck’s U.S. division in 1903, and, backed by his wealthy industrialist father-in-law, Lowell Palmer, transformed himself from a colleague into a competitor—it had long since been diluted by time, and the national emergency. The Merck-Squibb agreement contemplated joint ownership of any inventions that might appear, not just between the two companies, but including “other firms who have made definite contributions to the solution of the problem.”

  For most of 1942, the “other firm” that mattered the most was Chas. Pfizer & Co., Inc., of Brooklyn, New York.

  Like Merck, Pfizer was a German transplant, though one with a longer history in America. Beginning in the 1840s, a huge wave of German immigrants arrived in the New World, some of them politically motivated—the failed 1848 revolution made thousands into political refugees—but mostly for economic reasons. More than 1.4 million German-speaking immigrants arrived in the United States between 1840 and 1860, and with them came an enormous amount of technical knowledge that its carriers were ready to commercialize. Two of them, Charles Pfizer, an apprentice apothecary, and his cousin Charles Erhart, a confectioner, left the town of Ludwigsburg in the still-independent Kingdom of Württemberg sometime in the 1840s. In 1849, they opened a business office, and later, with a $2,500 loan from Pfizer’s father, their first chemical factory, at the corner of Bartlett and Tompkins in the Williamsburg section of Brooklyn.

  The cousins’ first product combined their chemical training with their skills in candy making, packaging the bitter compound known as santonin—an antiparasitic, or, more precisely, an anthelminthic: a drug used for killing, or at least discouraging, intestinal roundworms—in a toffee-flavored sugar cone. But while flavored santonin remained its most important medical product for more than sixty years, and the company produced disinfectants like iodine, chloroform, and calomel—the highly dubious mercuric compound used to treat both constipation and syphilis—its real business was, like Merck decades later, fine chemicals: tartaric acid (used as the leavening agent in baking powder, and as a flavoring), camphor, and especially citric acid.

  It was citric acid that made the company both profitable and perhaps the world’s most experienced at the process of deep fermentation. This, in turn, made them ideal to expand on the innovations that Moyer, Heatley, and Coghill had developed in Peoria. Late in 1941, the company had borrowed the same aerated flasks used at its SUCIAC plant to manufacture citric acid and put them to work making penicillin. Yields were still highly variable—from 20 penicillin units per cc to none at all—and tiny, but enough to provide testable quantities to the same team at Columbia University that had requested samples from Ernst Chain back in 1940: Henry Dawson, Karl Meyer, a chemist, and Gladys Hobby, a microbiologist, all part of a group of scientists studying hemolytic streptococci. Others were investigating as well. Alexander Hollaender, a researcher at the National Institutes of Health and one of the founders of the field of radiation biology, assembled a team at Cold Spring Harbor lab to find a mutated version of the Penicillium mold using radiation. Researchers at the University of Minnesota and the University of Wisconsin were enlisted to bombard them with X-rays; the team at Madison had a pilot plant for deep fermentation, and had been researching irradiation in milk to improve vitamin D content since the 1920s. They were so successful that they ended up developing a new variety of the mold, known as Q-176, which produced more than 2,000 units of penicillin per cc. This improved on Pfizer’s yields dramatically, and matched the best number produced by Moyer and Heatley in Peoria. (The original Oxford number, lest we forget, was barely 2 units per cc.)

  In less than a year, the seemingly inexhaustible resources of the United States—Department of Agriculture laboratories, university biology departments, and especially the research facilities built by American drug companies in the 1930s—had increased the pace of innovation in penicillin research by an almost unimaginable amount.

  All this progress in the manufacture of the drug was well known to the brilliant but underfunded scientists at the Dunn School (to say nothing of St. Mary’s), who could only look on in amazement as the United States invested millions in exploiting their discoveries. But except for the occasional “wonder drug” article here or there, general awareness of penicillin’s potential for fighting infectious disease was very low in both the United Kingdom and the United States. Through 1942, the OSRD’s various subdivisions had authorized only twenty-two specialists in the entire United States to receive the drug at all, and even they were permitted to test it only on a very short list of infections—basically staph, strep, and pneumococci infections that didn’t respond to the sulfa drugs.

  In November 1942, the public’s obliviousness about penicillin came to an abrupt halt, in a gruesome fashion.

  The Cocoanut Grove, on Piedmont Street in Boston’s Back Bay neighborhood, had been a speakeasy through the years of Prohibition, and, after the repeal of the Volstead Act, the city’s most popular nightclub. On November 28—the Saturday of the Thanksgiving holiday weekend—more than a thousand partiers crowded into the club, which the Boston Fire Department had authorized for fewer than five hundred. Sometime after 10:00 P.M., one of the artificial palm trees used to decorate the club caught fire, and flames quickly spread to the club’s wall and ceiling decorations. In five minutes, the nightclub was an inferno of superheated air and toxic smoke. Panicked people were crushed at exit doors. Four hundred ninety-two people died.

  Hundreds more were victims of smoke inhalation and second- and third-degree burns. More than a hundred were brought to Massachusetts General Hospital, whose emergency physicians decided against debriding the burns—picking off particles of clothing or other foreign material; they were convinced that debriding would be more likely to remove what was left of the skin’s protection against invading bacteria. Instead, they hoped to fight infection using “chemotherapeutic agents administered internally.” Sulfa drugs were available, but only effective against a limited range of infections. It was an emergency, and it demanded an emergency response. Only days after the fire, Merck’s Rahway facility packaged a quantity of penicillin—not Anne Miller’s powder, but thirty-two liters of highly diluted broth—and transported it, complete with police escort, to Mass General.

  It’s hard to know whether the miracle medicine performed miraculously. The emergency
room physicians at Mass General and the other Boston hospitals used a variety of techniques in treating burn patients, and while dozens survived staph infections that would have been fatal only a few years before, there is no way of knowing for sure whether the broth from Merck was the reason. Victims were treated with protective dressings and given antibacterial treatments—including sulfa drugs—internally. That didn’t stop the December 2 issue of the Boston Globe from proclaiming penicillin “priceless,” and if anyone was disposed to argue the point, no record of it survives. What did survive was the belief that a wonder drug was, at most, only weeks away from widespread use. Before the Cocoanut Grove, the number of human beings that had been treated with penicillin was measured in the dozens. Alfred Newton Richards, chairman of the CMR had, as a matter of policy, restricted the amount of publicly available information on the new drug, offering updates only in vaguely worded press releases. His logic was obvious enough; given that the national priority was manufacturing enough penicillin for battlefield use, raising hopes about its availability to the nonuniformed public would be both cruel and a public relations nightmare. Chester Keefer of Boston University, the chairman of the Committee on Chemotherapeutics and Other Agents, was actively hostile to journalists, whom he believed would inevitably create expectations that could not be met. For months, all communiqués about the penicillin project had been run exclusively through the CMR press office. A single night in Boston and the secret was out. Time magazine’s February 8, 1943, issue said it all: “The wonder drug of 1943 may prove to be penicillin, obscured since its discovery in Britain in 1929, only now getting its thorough sickroom trial.”