Miracle Cure

by William Rosen

  The human microbiome—the microorganisms in a particular environment—is largely composed of harmless or beneficial microbes, but it is also a perfect reservoir for spreading the genes for every imaginable form of antibiotic resistance.

  There are any number of reasons for the explosive growth in the number and virulence of antibiotic-resistant bacteria—as late as the 1990s, fewer than 15 percent of hospital-acquired infections were resistant to antibiotic treatment; acute-care hospitals today routinely report rates of 60 percent or more. The widespread use of subtherapeutic antibiotic treatment on livestock is unquestionably one of them. Overuse of antibiotics in animal feed leads to the creation and spread of antibiotic-resistant bacteria in poultry and meat consumed by the public.

  Another driver of resistance is directly attributable to seven decades of overenthusiastic writing of prescriptions. Despite attempts to convince physicians to restrict the overuse of antibiotics from 1946 forward, the fact that antibiotics are so safe for any individual patient has persuaded hundreds of thousands of doctors to prescribe them for conditions for which they are almost always useless. A 1956 survey of doctors in North Carolina found that two-thirds of them, when presented with acute bronchitis—almost certainly a viral disease—prescribed antibiotics “indiscriminately to all patients. . . .” More than fifty years later, in 2010, 70 percent of emergency room doctors and 80 percent of primary care doctors were still prescribing antibiotic treatment for the disease. Patients bear some responsibility, too. Antibiotic prescriptions typically call for ten days of treatment in order to improve the odds that all the pathogenic bacteria causing the infection have been killed; since many antibiotics work by disrupting bacterial cell walls during cell division, and not all bacteria are dividing at the same time, it’s critical to maintain a concentration of antibiotics until the entire pathogenic population has been exposed to them. In industrialized countries, though, up to 40 percent of patients fail to comply with the instructions they’re given along with antibiotics; feeling better after a few days, they stop taking their medicine, thereby sparing the strongest and most resistant bacteria.

  Part of the solution to antibiotic resistance is behavioral change. The Centers for Disease Control and Prevention have established “stewardship” programs intended to promote more judicious use of antibiotics, especially in hospitals, where 20 to 50 percent of prescriptions remain either inappropriate or unnecessary. Better and faster diagnostic tests can make it easier to distinguish the bacterial diseases that require antibiotics from the viral infections that don’t.

  Just as clearly, though, is the need for improving the incentives for developing new antibiotics, which is the logic behind GAIN. They’ve been a long time coming. 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.

  It’s not only that pharmaceutical companies aren’t discovering new antibiotics. The old ones are disappearing, too. From 1938 to 2013, only 155 antibacterial compounds received FDA approval. Because of resistance, toxicity, and replacement by a newer-generation derivative, only 96 antibiotics remain available today. The decline isn’t helped by the eagerness with which pharmaceutical firms are exiting the field. In 1988, thirty-two independent companies were actively researching antibiotics; during the 1990s, the number of companies that had received FDA approval for an antibiotic declined almost every year. It now stands at eleven, the lowest number since 1961. Some of this is the result of mergers, but not all. Though twenty-eight companies remain of the thirty-two operating in 1988, seventeen have left the field of antibacterial development altogether. Antibiotics built virtually every modern pharmaceutical company, but are now barely a rounding error in the industry’s balance sheet.

  If the current trend lines in the battle against infectious disease—every day, more resistance; every year, fewer new antibiotics—continue unchanged, the future takes on a distinctly scary cast: a world in which every puncture wound, or skin rash, or cough carries the risk of death from an unkillable, unstoppable bacterial pathogen. It wouldn’t be precisely like the one that greeted George Washington on the last day of his life. It would be worse. Victims of bacterial infections in a completely antibiotic-resistant world would know precisely what was killing them. And would be utterly impotent to do anything about it.

  Fortunately, those trend lines aren’t set in stone. The Harvard-wide Program on Antibiotic Resistance (HWPAR) is developing novel methods for fighting bacterial pathogens, ones that don’t actually kill bacteria, or even halt their reproduction, but degrade the structures that make the bacterium dangerous. A compound that attacks the toxins produced as part of the bacterial infection is the anti-infective warfare equivalent of defusing the enemy’s artillery shells, rather than bombing the cannon themselves. Other researchers are developing ways to attack the source of antibiotic resistance: inhibiting the formation of the enzymes that penicillin-resistant bacteria use to disrupt the beta-lactam ring, for example. Michael Fischbach, at the University of California, San Francisco health campus, has discovered more than three thousand molecules within the human microbiome—the trillions of microorganisms that peacefully coexist inside our own bodies—that show antibiotic potential. Even better: Instead of relying on patience to await microbial innovation, Dr. Fischbach wrote a software program that could teach itself to recognize the patterns of successful antibiotic production in hundreds of existing microbial gene clusters.

  And then there’s GAIN. The tweaks it incorporates into the economics of antibiotic development—reducing the time, and therefore the costs, of bringing a drug to market; extending the patent life of drugs—are already bearing fruit. During a single four-month period in 2014—an even better year than 2012, with forty-four new drugs accepted—the FDA approved three distinct antibiotics as “qualified infectious disease products” specifically for the treatment of acute skin infections caused by MRSA: Dalvance, from the Chicago-based Durata Therapeutics; Sivextro, from Cubist Pharmaceuticals; and Orbactiv, developed by the Medicines Company of Parsippany, New Jersey. None of the new drugs represent a revolutionary advance, but a new protocol for antibiotic resistance, one that attracts the attention of the pharmaceutical industry, is one of the most hopeful signs imaginable in the battle against infectious disease.

  —

  The story of antibiotics, and the more general fight against disease, has alternated between unbridled optimism and dark foreboding. Every triumphal discovery—from Paul Ehrlich’s arsenicals to Gerhard Domagk’s sulfanilamides to penicillin, streptomycin, and the broad-spectrum antibiotics—has been followed, sometimes in a matter of months, by a reminder that the enemy in this particular war may lose individual battles, but that the war against it is essentially eternal. Back in 1962, Ernst Chain bemoaned the adaptability of his old enemy, the staph bacterium, which “had again emerged as a dangerous disease against which he had no effective chemotherapeutic weapon.” Bacterial pathogens, it seemed to him, were so adaptable that humanity’s struggle against them was inevitably a losing game. The only plausible response to Chain’s depressing conclusion came from his friend, the MIT chemist John Sheehan—the first person to chemically synthesize penicillin—who reminded him that, while the war against infectious disease was almost certain to go on forever, humanity wasn’t any more easily defeated than the pathogens. “How about an expression of faith,” Sheehan asked, “in the adaptability of the chemist?”

  ACKNOWLEDGMENTS

  It seems to me that acknowledgments appear so much more frequently in works of nonfiction than of imagination because of the widely held belief—rightly or wrongly—that nonfiction tend
s to be the product of many contributors, not simply one. This is a fairly romantic notion about storytelling in general, but it carries great weight with me. The subjects covered in each of my previous books were a complete mystery to me when I began researching, editing, and writing about them. To the degree that they are slightly less mysterious to me now is mostly due to the generous help of predecessors and contemporaries who left such clear footprints (in the case of the former) or signposts (for the latter) along the way.

  The bibliography for this book contains hundreds of primary and secondary references. All were valuable, but a few of my predecessors were utterly essential for the writing of Miracle Cure, and the sheer number of times they are cited surely underlines this. Thanks to Eric Lax, Peter Pringle, Robert Root-Bernstein, Peter Temin, Robert Bud, Thomas Maeder, Eric Kandel, and Gwyn MacFarlane. The obituaries that appear in the series of Biographical Memoirs of Fellows of the Royal Society are indispensable for anyone trying to recreate any of the great scientific innovations of the mid-twentieth century.

  A more focused level of help was forthcoming from this book’s earliest days. Before Miracle Cure was even a proposal, David Jacobus, the founder of Jacobus Pharmaceutical Company, a man I’m privileged to call my friend, inspired me to find the theme of this project, which eventually took form as the title of Chapter Five: “To See the Problem Clearly.” My friend John Rosen read this manuscript at various points in its development and never failed to provide useful advice. Patti McKenna’s knowledge of Merck’s corporate archives, and Jeff Brand’s of Pfizer’s, were gifts of immeasurable value. Thomas Frusciano, university archivist at Rutgers’ special collections, is owed thanks as well (not least for reminding me, after researching previous books took me from Scotland to Istanbul, that an impressive amount of the history of the antibiotic revolution took place less than an hour from my home in Princeton, New Jersey).

  Two people in particular were vital to Miracle Cure in later stages of its gestation. No one in the world has done more to illuminate the history of pharmaceutical development than Mike Kinch, of the Institute for Public Health at Washington University, St. Louis (his actual title, as I write this, is associate vice chancellor and director, Center for Research Innovation in Business, and professor of radiation oncology, School of Medicine), and he has been extraordinarily generous in providing counsel and access to his research ever since he was managing the Center for Molecular Discovery at Yale. Julian West of Princeton University read the manuscript front to back and saved me from a frightening number of embarrassing chemical errors, and I am forever in his debt. As I hope is obvious, any remaining errors of fact are mine alone.

  At Viking, Melanie Tortoroli served, as always, as a model editor, combining a powerful sense of narrative rhythm with a diligent advocacy on behalf of both the book and its readers . . . that is to say, you. At hundreds of points, she persuaded me to unpack complicated material so as to make it clearer, and to expand it, where needed, so as to make it more persuasive. If at any time you found yourself wanting either less or more on subjects like X-ray crystallography or patent disputes, I assure you it was one of the places where I overruled her advice. Her assistant editor, Georgia Bodnar, was diligent and knowledgeable about both the book and the process of publishing it. The book’s copyeditor, Jane Cavolina, and its designers, Alissa Theodor and Nayar Cho (interior and jacket design, respectively) reminded me, yet again, of one of the most important and yet frequently ignored assets of what has become known as the “traditional” publishing model. Dozens of other members of the editorial and publishing team at Viking, led by Andrea Schulz and Brian Tart, guided the process with the imprint’s customary care and grace.

  Eric Simonoff, of William Morris Endeavor, has been my literary agent ever since I started writing. He was my friend before and remains so today. When I read, in the acknowledgments for other books, that this agent or that one is the best thing going, I smile to myself in the sure knowledge that only Eric’s clients are actually privileged to write a line like that. For counsel, advocacy, and support, he may have the occasional equal, but I doubt it. Working with him has marked the most productive and enjoyable aspect of my entire professional life, and any description of all he has done for me would gain in implausibility in direct proportion to its accuracy.

  —

  Shortly after I began researching what would become Miracle Cure, I was diagnosed with a rare and highly aggressive form of cancer. I have, in consequence, acquired a debt of acknowledgment that I haven’t had to think about much in previous projects. Dr. David August, Dr. Rebecca Moss, Dr. Elizabeth Poplin, and RN Joyce Plaza literally kept me alive long enough to complete Miracle Cure. So, too, did the hundreds of different researchers and clinicians at Novartis, Astra Zeneca, Bristol-Myers Squibb, and Bayer. It is, perhaps, a little ironic that a book that documents the birth of the modern pharmaceutical firm should have been so dependent on the products of its maturity.

  For similar reasons, the traditional acknowledgment to family members for enduring the strains imposed by the writing life seems totally inadequate. The contribution of my wife, Jeanine, and my children—Alex, Emma, and Quillan—was above and beyond. As always, their thoughts have informed Miracle Cure, and there are innumerable grace notes they have shared with me. Seeking out both the images contained inside, and permission to reproduce them, was a job Jeanine cheerfully and professionally accepted.

  But, of course, that says nothing about their real place in my life. They are the reason that it has been my privilege to love, and be loved, by some of the best people I have ever known.

  William Rosen, April 2016

  NOTES

  PROLOGUE: “Five and a Half Grams”

  a bronchial infection he acquired: (Grizzard, 2002) The actual disease—San Joaquin Valley Fever—was a serious one, caused by the fungus known as Coccidiodes immitis. As a fungal disease, it wasn’t treatable by the penicillin that saved Anne Miller’s life. (Tager, 1976)

  ONE: “All the Worse for the Fishes”

  “who was used to bleeding the people”: (Grizzard, 2002)

  “Do you understand me?”: (Houting, 2011)

  “to strangle a dog”: (Hebert, 2009)

  One thing that didn’t kill: (Ellis, 2005)

  The Principles and Practices of Medicine: (Osler, 1923) The first edition of Osler’s classic was published in 1892, the last, posthumous one, four years after his death.

  cared for them in hospitals: (Miller, T. S., 1984)

  ulcerated gums and uncontrollable salivation: (Janik, 2014)

  “Take a purified yellow Wax”: (An American Physician, 1827)

  therapy known as “swinging”: (Belofsky, 2013)

  “as you would a noisy dog or cat”: (Janik, 2014)

  “Every physician of experience”: (Rosenberg, 1977)

  so-called Plague of Athens: (Nelson, 2014)

  “infection of imperceptible particles”: (Thagard, 1996)

  tuberculosis was responsible: (Jones, D. S., 2012)

  Swiss mathematician Daniel Bernoulli: (Nelson, 2014)

  “society [that] was cut in two”: (Tocqueville, 1987)

  Lavoisier described how sugar: (Barnett, 2003)

  “the riddle of alcoholic fermentation”: (Barnett, 2003)

  “I do not think,” he wrote: (Robbins, 2001)

  Joseph Andreas von Stifft opened: (Kandel, 2012)

  linked examination of living patients: (Kandel, 2012)

  earth’s 5 x 1030 bacteria: (Bratbak, 1985)

  “It is not surprising that microbes”: (Margulis, 1995)

  “neither the cause”: (Fitzgerald, 1923)

  “Pasteur began with”: (Koch, 1987)

  “the most successful researcher”: (Gradmann, 2001)

  “Hatred to Prussia. Vengeance”: (Robbins, 2001)

  new therapeutic technique for tuberculosis: (Gradmann, 2
001)

  The Private Science of Louis Pasteur: (Geison, 1995)

  12 million dollars today: Calculating the value of things over time is a notoriously tricky business, with half a dozen different methods in regular use. The simplest one just compounds increases in the Consumer Price Index over time, and gives us the $12 million figure. However, the price of labor has increased much more rapidly, and using the “income value” of the same 2.5 million gold francs—in 1888, each worth .29 grams of gold, while the U.S. dollar was pegged at 1.5 grams—produces the figure of $115 million. An even larger number, roughly $600 million, is the result of calculating those gold francs as their share of the French economy in 1888.

  a girl named Julie-Antoinette Poughon: (Geison, 1995) For those interested in debating the appropriate level of adulation for Pasteur, the December 21, 1995, and April 4, 1996, issues of The New York Review of Books contain an exchange between Gerard Geison and Max Perutz on The Private Science of Louis Pasteur.

  “Turning now to the question”: (Thagard, 1996)

  killed between 45 and 50 percent: (Godlee, 1918)