All the great families of antibacterial therapies—the sulfa drugs, beta-lactams (like penicillin), chloramphenicol, tetracycline, erythromycin, streptomycin, and the cephalosporins—appeared in a span of less than ten years. Alexis de Tocqueville described the 1848 conflict as occurring in a “society that was cut in two: Those who had nothing united in common envy, and those who had anything united in common terror When an organism—you, perhaps—encounters a microbe with evil intent, a dozen different proteins that are always circulating in the bloodstream send out a chemical alarm that activates another group of proteins known collectively as the cytokines. These molecules are folded in distinctive ways, permitting them to attach themselves to a pathogen, and hang on while sending off another alarm, summoning cell-based immune defenders like white blood cells. Meanwhile, other cell-based defenders, Ehrlich’s mastzelle, release chemicals like the histamines, which turn up the body’s thermostat, causing what is known as the inflammatory response: fever. Specialized forces include cell-based troops like the B-lymphocytes manufactured in the bone marrow that create highly specific antibodies that hold on to the surface of invading cells; the T-lymphocytes that can destroy invaders by punching a hole in the invader’s membrane; and macrophages that can swallow and destroy them. Side-chain theory proposed that the membranes that enclosed the cells of multicellular animals were extremely complex chemical machines, each of whose components—Ehrlich’s side chains—has an affinity for a particular nutrient needed by the cell. Normally, each side chain is a kind of combination lock that opens when it encounters a needed protein. If any foreign substances—bacteria, viruses, or toxins—fit the same lock, metabolic activity is blocked. The cell responds by producing similar side chains as replacements, but overdoes it—in Ehrlich’s words, “nature is prodigal.” The extra side chains are then sloughed off into the cell’s surrounding fluid; and each of them, by definition, possesses precisely the shape to combine with the invading antigen. It is as if the cell had produced a finely machined gear that fits perfectly with its pathogenic match: antigens that latch onto the invaders and produce all the actions of the immune response—chemical signaling, inflammation, and everything else. The reason that Prontosil worked only in vivo and not in vitro—in a living animal and not a test tube—was finally clear: Living animals produced enzymes that separated the dye from sulfanilamide. British chemists Donald Woods and Paul Fildes had discovered the mechanism by which sulfa drugs do their magic. Sulfa inhibits an enzyme essential for the production of the B vitamin required for folate production in bacteria. Sulfanilamide essentially tricks bacterial enzymes into latching onto it, rather than the correct compound, para-aminobenzoic acid, or PABA (which is why sulfa remained limited in its effectiveness; not all bacteria use PABA). Penicillin (and related compounds) chemically weakens the cell walls of the bacteria as it splits—this is why penicillin only acts on bacteria when they’re dividing—but only for Gram-positive bacteria that are unprotected by the lipopolysaccharide outer membrane: staph and strep, but not typhus.* And not animal cells, which have membranes but not walls, and are therefore safe from the actions of penicillin. Glaxo, founded in New Zealand in 1880, had expanded into the United Kingdom less as a pharmaceutical company than as a manufacturer and processor of milk fortified with vitamin D;* by the 1930s, they were the country’s largest producer of nutrition products. Beecham’s Pills were Britain’s most popular laxative, and the foundation of Beecham Limited. ...Burroughs Wellcome, then Britain’s most technologically sophisticated pharmaceutical company. The company had been founded by two American expatriates, Henry S. Wellcome and Silas M. Burroughs, graduates of the Philadelphia College of Pharmacy, who had decamped to London and opened for business in 1880 Pfizer, a chemical company headquartered in the Williamsburg section of Brooklyn, that made most of its income from producing the preservative and flavoring compound citric acid, also had a small interest in medicines. So did E. R. Squibb, another Brooklyn-based company and a major producer of surgical drugs like ether As they were applied to medical innovations, patents were even more controversial. While mechanical inventors were unapologetically commercial in their goals, medicine—in theory, at least—was subject to a higher law, one that required that its work be performed for the greater good. Patenting of medicines, in consequence, had been forbidden in France from the time of Napoleon forward, and in Germany the nation’s first patent law, which was passed shortly after the modern state appeared in the 1880s, prohibited them for decades. American medical researchers had a very specific objection to medical patents, dating from 1923, when Harry Steenbock, a professor of biochemistry at the University of Wisconsin, discovered that exposing the sterols in fatty foods like milk to ultraviolet light enriched them with vitamin D, and therefore made milk into a defense against the then-widespread deficiency disease, rickets.* Although Steenbock, who had patented the process in his own name, reportedly turned down a million dollars from the Quaker Oats Company for its use, he did transfer the patent rights to a newly established nonprofit organization, the Wisconsin Alumni Research Foundation (WARF). By 1940, WARF was charging milk manufacturers for the use of the technology, and had pocketed royalties well in excess of $7.5 million (the number today is well in excess of $1 billion). in 1942, Merck was the oldest continuously operating drug firm in the world; though as we have seen, this may be damning with faint praise. The company had been producing and selling medicinal compounds since 1668, when Friedrich Jacob Merck acquired the Engel-Apotheke, an apothecary in the Landgraviate of Hesse-Darmstadt 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. 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. Even with the results of the Fourier analysis of the X-ray crystallography, the molecular structure of penicillin remained controversial. beta-lactam ring is a fairly simple chemical feature: a square formed by three atoms of carbon, one of them connected to a doubly bound atom of oxygen; and one of nitrogen, connected directly to the oxygenated carbon atom. Because two of the carbon atoms and the oxygen are bonded together at one angle, and the third carbon is attached to the square at a different angle, the square it forms is constantly under tension—imagine trying to build a square out of struts that are bending away from one another. This gives the ring both its instability—which had frustrated everyone from Fleming to Chain—but also its effectiveness. As early as 1940, researchers from Florey’s team at the Dunn had been observing penicillin’s activity against pathogenic bacteria, and reported that it didn’t kill them or dissolve them immediately; rather that the microbes exposed to penicillin went through the same first stage of mitotic division as other bacteria—elongation—but instead of dividing, they just kept elongating (sometimes ten or twenty times their normal length) until they exploded. Now, they knew why. All that strain from the different attachment angles made the beta-lactam ring vulnerable to breakage, and the bond that typically broke first—between the oxygenated carbon and the nitrogen atom—ended up adhering the oxygenated carbon to the enzyme needed to create the substance used to make the cell walls of Gram-positive bacteria, the ones that are unprotected by the lipopolysaccharide outer membrane. When the enzyme was locked up by the now-open beta-lactam ring, it couldn’t produce a sufficient quantity of the key component of cell walls, so when the cells divided, the new walls were, metaphorically, missing a lot of bricks, and even more mortar. Unsurprisingly, such walls eventually collapse. The penicillin project had created an entire industry, and built what would become some of the most profitable companies in history: not merely the American participants in the penicillin project, but also British firms like Glaxo, France’s Rhône-Poulenc, and even Swiss companies like CIBA-Geigy and Sandoz For a long time, the accepted wisdom was that tuberculosis emerged around the same time that humans discovered agriculture and started forming settled communities, during the so-called Neolithic Demographic Transition, or NDT, which began some ten to twelve thousand years ago. large number of crowd diseases started as zoonoses: animal diseases that were able to jump to human hosts. The pathogen had originated in Africa, somewhere between forty and seventy thousand years ago. unlike most pathogens, including the strep bacterium M. tuberculosis doesn’t produce toxins. Instead, the microbe is ridiculously efficient at hijacking the host’s own defenses and transforming them into deadly attackers. Any time the host’s immune alarm bells go off, it summons macrophages, the oversized white blood cells, to the site of infection. The macrophages, whose job it is to engulf and digest foreign objects, form cavities: vacuoles known as phagosomes that surround the invading pathogens. Once surrounded, the macrophage then connects the phagosome to the lysosome, a chemical wood chipper that uses more than fifty different enzymes, toxic peptides, and reactive oxygen and nitrogen compounds that can, in theory, turn any organic molecule into mush. When they attempt this with M. tuberculosis, however, things don’t work out as planned. The bacterium secretes a protein that modifies the phagosome membrane so it can’t fuse with the lysosome. Thus protected, it is able to transform the macrophage from an execution chamber to a comfortable home—one with a well-stocked larder, since another of the pathogen’s talents is the ability to shift from dining on mostly carbohydrates (which is what it eats when grown in a Petri dish) to consuming fatty acids, particularly the cholesterol that is a common component of human cell membranes. It’s the replication that matters. Within three to eight weeks after breathing an aerosol containing a few hundred M. tuberculosis bacteria, the host’s lymphatic system carries them to the alveoli of the lungs: the tiny air sacs where carbon dioxide is exchanged for oxygen. As M. tuberculosis forms its colonies inside macrophages, they create lesions: calcified areas of the lung and lymph node. Some burst; others form a granuloma—a picket fence of macrophages—around the colony. Within three months, the interior of the granuloma necrotizes, that is, undergoes cellular death. Some of the deaths occur within the lungs, leading to the painful inflammation known as pleurisy, which can last for months. Other infested areas, known as tubercles, break off from the lungs and travel via the bloodstream to other parts of the body, becoming the frequently fatal form of the disease that physicians know as extrapulmonary tuberculosis. When it settles in the skeletal system, it can cause excruciatingly painful lesions in bones and joints. When it lands in the central nervous system, as tubercular meningitis, it causes the swelling known as hydrocephalus; on the skin, where it’s known as lupus vulgaris, it leaves tender and disfiguring nodules. Subbarao, an Indian-born physician and physiologist, arrived in the United States as a penniless immigrant in 1923, he isolated the components of adenosine triphosphate, or ATP, the fuel for all cellular respiration. y fundamental discoveries about ATP, creatine, and of B12, but half a dozen chemical breakthroughs still in use today, including discovering how a mimic of folic acid known as antifolate could be used to combat leukemia Aureomycin had a single chlorine atom—generically chlortetracycline—that Terramycin lacked. Meanwhile, Terramycin (or oxytetracycline) had an oxygen atom that was missing from Aureomycin. 1929 - penicillin - streptomycin 1945 - lederle - aueromycin - first broad spectrum 1949 - pfizer - terramycin It is in no way a criticism of Pfizer’s research and production brilliance to say that, when it came to marketing, they were truly in a class by themselves. Their teacher was the legendary advertising executive Dr. Arthur M. Sackler. it was jukes' discovery that antibiotics accelerated the growth of meat-producing animals that has had, by far, the longest tail of consequence. it exposed untold quintillions of bacterial pathogens to antibiotics in doses too small to kill them. The result was the cultivation of some of the most robust bacteria the planet has encountered in the last billion years. an enzyme produced by Staphylococcus aureus—penicillinase—that cleaves the chemical bonds holding the beta-lactam ring together, and so degrades the antibiotic action of nearly an entire family of antibiotics.* Many antibiotics are what biologists call “hormetic”: beneficial in low doses, even promoting the creation of what are known as biofilms, matrices that hold bacterial cells together with a polymer “glue” and make them far more durable in the presence of both the animal immune system, and antibiotics themselves. Subtherapeutic doses of tetracycline help bacteria to form what is known as the type III secretion system, which is one of the key elements of any pathogen’s arsenal: a tiny hypodermic needle that Gram-negative bacteria—salmonella, chlamydia, even the organism responsible for bubonic plague—use to inject themselves into animals cells. Abelardo Aguilar, a Filipino physician employed by Eli Lilly, who found a promising soil sample in the country’s Iloilo province The sample contained S. erythreus: the source for erythromycin, the first of the macrolide antibiotics, compounds that were effective against the same Gram-positive pathogens as penicillin, though via a different mechanism: The macrolides act by inhibiting the way the pathogens make critical proteins, rather than by corroding their cell walls. 1900, a Parke-Davis chemist, the Japanese-born, Glasgow-educated Jokichi Takamine, isolated adrenaline (also known as epinephrine), which the company marketed as Adrenalin, a drug whose ability to constrict blood vessels made it invaluable to surgeons, especially eye surgeons. 1938, Parke-Davis introduced Dilantin, the first reliable treatment for epilepsy; in 1946, Benadryl, the first effective antihistamine Chloromycetin (or chloramphenicol) was greeted enthusiastically mostly because of its activity against insect-borne bacterial diseases, particularly typhus. 1951, chloramphenicol represented more than 36 percent of the total broad-spectrum business, and Parke-Davis had it all to itself. The Detroit-based company had become the largest pharmaceutical company in the world, with more than $55 million in annual sales from Chloromycetin alone. At the same moment that their ability to treat patients had improved immeasurably, doctors had become completely dependent on others for clinical information about those treatments. Virtually all of the time, the others were pharmaceutical companies. What really put Parke-Davis in the FDA’s crosshairs weren’t the gory newspaper headlines, or, for that matter, the NRC study. It was the company’s detail men. The etymology of “detail man” as a synonym for “pharmaceutical sales rep” can’t be reliably traced back much earlier than the 1920s. Though both patent medicine manufacturers and ethical pharmaceutical companies like Abbott, Squibb, and Parke-Davis employed salesmen from the 1850s on, their job was unambiguous: to generate direct sales. As such, they weren’t always what you might call welcome; in 1902, William Osler, one of the founders of Johns Hopkins and one of America’s most famous and honored physicians, described “the ‘drummer’ of the drug house” as a “dangerous enemy to the mental virility of the general practitioner.” Strychnine, the active ingredient in Parke-Davis’s Damiana et Phosphorus cum Nux, is such a powerful stimulant that Thomas Hicks won the 1904 Olympic marathon while taking doses of strychnine and egg whites during the race (and nearly died as a result). First was that reflexive prescription of antibiotics often hid the real disease from diagnosticians; during the ten days required for most antibiotic treatments, the patient would frequently grow worse, as the true cause of disease went unaddressed. Second, despite the generally well-tolerated character of most antibiotics, when millions of people are given them every day, thousands will exhibit symptoms of antibiotic poisoning—everything from vomiting to skin rashes. Third, antibiotics, as antagonists to all sorts of bacteria, often caused gastrointestinal upset by killing the “good” bacteria residing in the digestive tract. Pfizer had researched, developed, and manufactured Sigmamycin, the combination of 167 milligrams of tetracycline and 83 milligrams of oleandomycin (a close relative of erythromycin) that had been endorsed by the eight nonexistent doctors John Lear had exposed in his January article. For the Antitrust and Monopoly Subcommittee, what mattered weren’t high prices as such, but the suspicion that the prices were being artificially inflated by a conspiracy in restraint of free trade. Since the demand for drugs was determined not by patients, but by a physician’s prescription pad, the place to look for such a conspiracy was in the unique marketing practices of the pharmaceutical industry. “The drug industry,” as Kefauver put it, “is unusual in that he who buys does not order, and he who orders does not buy.” corticosteroid prednisone, an immunosuppressant used to treat diseases like colitis and multiple sclerosis, in which the symptoms are frequently caused by the immune system’s own inflammatory response. Francis C. Brown, the president of the Schering Corporation, which introduced the drug in 1955 under the name Meticorten, was blindsided by the initial line of questioning: Why, he was asked, was his company charging some seven hundred times more for a dose of prednisone than it cost to manufacture it? an application from Richardson-Merrell, Inc., a drug wholesaler in Cincinnati then best known for the menthol-infused petrolatum known as Vicks VapoRub. The drug for which the company had applied for U.S. marketing rights, to be called Kevadon, had achieved enormous popularity in western Europe as a sedative: one that was safer than barbiturates, and, in addition, was effective as an antinausea drug. The German pharmaceutical firm Chemie Grünenthal—a postwar company that got its start selling penicillin under the Allied occupation—had developed and sold it, first by prescription, then direct to consumers, as Contergan. In the United Kingdom, Distillers Limited marketed it as Distaval. Its generic name was thalidomide. until November 29, 1961, when Chemie Grünenthal sent Richardson-Merrell the first reports of phocomelia—“seal limb,” a birth defect that caused stunted arms and legs, fused fingers and thumbs, and death; mortality rates for the condition approached 50 percent A decade later, when Merck received FDA approval for the antiviral drug Indinavir, and a separate set of approvals were granted to drugs known as NRTIs (nucleoside reverse transcriptase inhibitors), the combination therapy known as HAART, for highly active antiretroviral therapy, transformed HIV from a death sentence to a chronic, and treatable, condition. The managers and shareholders of companies like Merck, Pfizer, and Eli Lilly didn’t require very sophisticated arithmetic to see a greater potential return from drugs that treated chronic ailments rather than acute infections. And they invested their research and validation assets accordingly. From 1962, when George Lesher of Sterling Winthrop* discovered the first of the quinolone antibiotics, until 2000 not a single new class of antibacterial drugs appeared How much easier to deal with bacteria that produce a single enzyme that inactivates penicillin* than with a hospital full of patients infected with MRSA (for methicillin-resistant S. aureus), which doesn’t just laugh at penicillin, but cephalosporin, ampicillin, and every other beta-lactam antibiotic? Or XDR TB (extensively drug-resistant tuberculosis), a bacillus that is unaffected by either isoniazid or rifampin, the more recent agents called fluoroquinolones, and at least one of these second-line drugs: capreomycin, kanamycin, or amikacin. In the thirty years after Proloprim appeared in 1969, not a single new class of antibiotics was licensed; every weapon against infectious disease was a derivative of an earlier one. And even since 2000, only two new classes have been approved for treatment: the oxazolidinones like Linezolid, which works by disrupting bacterial RNA translation, and Daptomycin, a cyclic lipopeptide that turns bacterial walls into Swiss cheese by literally changing their geometry. From the 1950s, synthesizing new compounds that were penicillinase resistant led to the discoveries of oxacillin, methicillin, and other drugs with a narrower spectrum of activity than the penicillin G that was first produced in 1945. One of the most important beta-lactam antibiotics, cephalosporin C, was isolated by Abraham himself in 1955, and its structure published in 1961 (and decisively demonstrated by Dorothy Crowfoot Hodgkin’s X-ray crystallography). Cephalosporin was not merely effective against bacteria that had mastered the trick of producing beta-lactamase, but was also patentable. Huge number of dangerous infections are caused by such anaerobic bacteria, not just gangrene, but tetanus and peritonitis. Anaerobes come in two basic flavors: obligate anaerobes like clostridia, for which oxygen is a poison; and facultative anaerobes, including staphylococci and streptococci, which are able to grow without oxygen, but can often use it if it is present.