Mary was a child of seven or eight. Martin found her lips and fingertips blue, but in her face no flush. . . . He thanked the god of science for antitoxin and for the gas motor. It was, he decided, a Race with Death “I’m going to do it—going to pull it off and save that poor kid” he rejoiced.
—Sinclair Lewis, Arrowsmith, 1925(1)
Genzyme Corp. won approval from the Food and Drug Administration to sell the first treatment for Pompe disease, a rare and devastating enzyme-deficiency disorder that often causes extreme muscle damage and heart failure. The new treatment, called Myozyme®, will be extraordinarily expensive, likely costing around $200,000 a year. Genzyme, based in Cambridge, Mass., says it spent $500 million over eight years to develop the treatment.
—The Wall Street Journal, April 29, 2006(2)
John took a deep breath, looked around the room, and lifted his right hand to a switch and pressed the “on” button. He saw the switch open and the clear liquid [Myozyme®] begin dripping . . . Megan’s heart monitor began to beep and . . . soon everyone was laughing through their tears.
—Geeta Anand, The Cure, 2006(3)
IT’S NOT OFTEN THAT YOU SEE scientists in movies point to “glycobiology” or “phosphorylated glycans” on a blackboard, unless they’re fabricating avatars to destroy the world. But, along comes Extraordinary Measures, a film in which Indiana Jones—I mean Harrison Ford—puts down his hat and bullwhip to become a lovable curmudgeon and “another beloved American archetype: the renegade scientist.”(5) Reminds one of that first archetype of an American movie scientist, Martin Arrowsmith. However, Extraordinary Measures isn’t about one lovable scientist—curmudgeon or not—finding a magic medicine in one “Eureka!” moment. If you want that story, you’d better go back to Martin Arrowsmith and his bacteriophage. In his day, bench moved to bedside without venture capital.
In Extraordinary Measures, the dialogue may come from the playbook of storage diseases,(6) but the story is cast as a NASDAQ release. The movie begins with two cute kids afflicted with Pompe’s disease, a glycogen storage disease that cripples their muscles and heart; it ends with a cure dripping into their veins. The movie doesn’t tell us a lot about the science of Pompe’s disease: it certainly doesn’t describe the efforts of Rochelle Hirschhorn or Arnold Reuser(7) to clone the gene for acid maltase, the enzyme that’s missing or mutated in Pompe’s. We don’t hear about Elizabeth Neufeld and Roscoe Brady,(8,9) who traced how enzymes can get into lysosomes in the first place and how acid maltase can be replaced. And we’re not treated to the story told by Christian de Duve in his 1974 Nobel Prize lecture:
What we did not suspect in the beginning was that the failure of lysosomal enzymes to act at their normal site could also cause serious diseases. This fact was brought home to us in a rather surprising fashion by Géry Hers, who in 1962 diagnosed glycogen storage disease type II as being due to a severe deficiency of a lysosomal enzyme.(10)
Extraordinary Measures is based on The Wall Street Journal reporter Geeta Anand’s book, The Cure: How a Father Raised $100 Million—and Bucked the Medical Establishment—in a Quest to Save His Children.(3) Plus or minus some tear-jerking moments, the film is as true to Anand’s book as a popular film can get, although the book is as close to science as a financial journalist can get. Both tell us that the road to a cure is paved with venture capital and that in this game, one hundred million bucks is Jacks-to-Open. Ford plays a fictional physician/scientist named Robert Stonehill, roughly modeled on William Canfield, a glycobiologist, formerly of the University of Oklahoma. In the movie, Stonehill is tracked down to a fictional lab in the boondocks by John Crowley, a go-getting entrepreneur.(11) Actually, Crowley did not “buck the medical establishment”; in real-life, Crowley met Canfield at an NIH meeting in 1998, called to include every figure in the Pompe’s disease medical “establishment.”(12)
Crowley, a pharma executive, then with Bristol-Myers Squibb, was out to develop, at any cost and with any effort, the newest treatment for his two children who were afflicted with Pompe’s disease. At that NIH meeting, he learned that Canfield had formulated a novel polyphosphorylated glycan adduct of the acid maltase. Crowley bought the notion that Canfield’s enzyme might gain far easier entry into the glycogen-stuffed lysosomes of Pompe’s disease than any other. But setting up animal models of Pompe’s disease was expensive; new labs and equipment were needed. A new biotech company was the answer, and Novazyme became its name.
Extraordinary Measures presents a realistically filmed pageant of any start-up biotech, the ups and downs of compound after compound synthesized and tested in the dish, the dog-and-pony shows to lure the first investors, the tense presentations before “mezzanine-round” venture capitalists. In the movie, as in real life, Novazyme succeeded. Based entirely on preclinical data, Canfield and Crowley persuaded a large, top-ten biotech company, Genzyme of Cambridge, Massachusetts, to buy out Novazyme for something north of $137 million. Canfield told his local paper, “It was one of the largest biotech transactions in 2001. It was an unusually high value for a pre-clinic [sic] company. We had been in operation for only 27 months. This wasn’t typical; do not try this at home.”(13)
In the event, as with many such acquisitions, it’s by no means clear whether The Cure led to the cure. Certainly the drug that flowed into the child’s vein in the film, and into hundreds of real-life children, was not Canfield’s enzyme. Genzyme had set four independent groups the task of finding which of four enzyme preps would work best in several preclinical models. Only one of these was the Novazyme version. By 2002, after reviewing the results of “The Mother of All Experiments,” Genzyme was ready to go into clinical trials with the winner of the contest. It was not The Cure but the real cure, Myozyme®, a formulation developed internally at Genzyme. Almost a decade later, it’s hard to tell whether the Canfield/Crowley effort spurred or delayed the development of Myozyme®. Buying Novazyme was costly, but the move forestalled any future competition with Genzyme’s other lysosomal enzyme products.(14)
And now for the kicker: When Myozyme® was approved by the FDA, Henri Termeer, the Dutch CEO of Genzyme, was proud to announce that the drug was developed, not only with scientists at Duke University (Yuan-Tsong Chen, Priya Kishnani et al.) but especially with A. J. J. Reuser, A. T. Van der Ploeg et al., of Erasmus Medical Center in Rotterdam.(15) Rotterdam, indeed!
Joannes Cassianus Pompe (1901–1945) would have been pleased at the contribution of his native land to the treatment of a disease that he was the first to describe. Pompe, a native of Utrecht, received his MD from the University of Amsterdam and after a short stint in pathology at Nijmegen, returned to Amsterdam in 1939, where he moved up the academic ladder. He had presented his doctoral thesis on “Cardiomegalia glycogenica (glycogenic cardiomegaly)” in 1936,(16) but perhaps because of the rarity of the condition—and of peace in Europe—there was no follow-up. After the German occupation of Holland in 1940, Pompe became an active member of the Dutch resistance.(17) Eventually, the Germans found a secret radio transmitter in his pathology laboratory and imprisoned him on February 25, 1945. As bad luck would have it, other members of the resistance blew up a railroad line in nearby St. Pancras. In keeping with Nazi practice, he and 19 other prisoners—uncharged and untried—were shot in retaliation. [Mit 19 weiteren Personen erschossen bei einer Vergeltungsmaßnahme nach dem Anschlag auf eine Bahnlinie. Zwei Wochen später wurden die Niederlande befreit].(18) Pompe was executed two short weeks before Holland was liberated. Sixty years later, thanks to science and NASDAQ, a cure for Pompe’s disease was dripping into the veins of children in the Netherlands.
The moral of Extraordinary Measures was foretold by Henry James in The Golden Bowl: “For what was science but the absence of prejudice backed by the presence of money?”(19) The moral we can draw from Pompe’s biography is that a single observation, by a single scientist, can have a profound impact. It’s a gift, so to speak, that’s ours for the taking.
Nowhere is the story of the single scientist making a single discovery better told than in the 1925 novel and 1931 film Arrowsmith by Sinclair Lewis, who won the Nobel Prize in literature in 1930. Years ago, every medical student in the country was attracted to it; lately, a good number of my students have been led to read Arrowsmith, after someone told them that the name of the rock group “Aerosmith” was taken from a “doctor book.” They’ve found it quaint, dated and totally inspiring. The character of Martin Arrowsmith was prompted by the “Microbe Hunters the late Paul de Kruif wrote about: Koch, Pasteur and Ehrlich.” Lewis has Martin resolve that if he had to be “a small town doctor he would be such a small town doctor as Robert Koch.”(1) However, unlike Aerosmith’s grungy millionaires, Martin leaves riches, not for rags but for science; his picaresque career blends the biographies of Paul de Kruif and Lewis’s father: research in a bacteriology lab in Michigan, a small-town doctor’s life in Wisconsin, basic experimental work at the Rockefeller Institute, and the temptations of money and the flesh. Martin works at the fictional McGurk Institute on bacterial reproduction with a Dr. Gottlieb (Jacques Loeb) and has the Eureka! moment.
Martin’s great discovery, set in the 1920s, is the “X Principle,” bacteriophage, in real life discovered by Twort and d’Herelle(20,21) at the time of the Great War.
“I have observed a principle, which I shall temporarily call the X Principle, in pus from a staphylococcus infection, which checks the growth of several strains of staphylococcus, and which dissolves the staphylococci from the pus in question.”(22)
In due course, Martin finds that various bacteriophages can kill all sort of bacteria, staph, strep, even the Yersinia of plague. He rushes to inform the smarmy director of the McGurk Institute, a character modeled after Simon Flexner, that he has a discovery that will kill bacteria without harming the host.
Paul de Kruif, unacknowledged coauthor of Arrowsmith, had been dismissed by Flexner in 1923 from the Rockefeller Institute for falsified claims and publicity seeking. De Kruif had written a trendy exposé about the medical establishment for The Century magazine under the anonymous signature of K, M. D. But de Kruif was more than a self-destructive iconoclast. As a young researcher, he had performed experiments at the University of Michigan with Frederick G. Novy, which might have put him in a position to discover that DNA was the “transforming principle” of the rough-to-smooth transformation of pneumococcus, a line of investigation that eventually proved crucial to the flowering of DNA.(23) However, after Flexner put a stop to de Kruif’s career at Rockefeller,(24) revenge reared its head in the blustering caricature of Dr. Tubbs. Both Novy and Flexner had been on the U.S. Plague Commission that worked to combat outbreaks of plague in San Francisco (1900) and New Orleans (1914–1917).(25,26) Lewis, following de Kruif, has Tubbs exort to Arrowsmith:
“I’ve been thinking, Arrowsmith,” said Tubbs. . . . “As I understand it, you’ve been going along with what Dr. Gottlieb would call ‘fundamental research.’ I think it may now be time for you to use phage in practical healing. I want you to experiment with phage in pneumonia, plague, perhaps typhoid, and when your experiments get going . . . let’s really cure somebody . . . Go cure the plague!”
In the event, Martin and his wife Leora (played in the film by Ronald Coleman and Helen Hayes) travel to a Caribbean island to stop an outbreak of the bubonic plague by means of a specific bacteriophage that he has developed. He will also do a controlled trial, à la Gottlieb: half will get the phage; the other half, not. On that plague-ridden island, Martin’s Swedish colleague is killed by the epidemic that they have been fighting; his death is the heroic death of a Microbe Hunter. Leora is with Martin in the place referred to as Black Water, but when he goes to another island after a heated argument with the Governor General, he implores his wife to stay where she is, believing that it is for the best. One perceives the telltale cigarette on which Yersinia have been spilled; Leora has a cut finger, and she is infected. Too late with his phage, Martin finds that Leora has died, forsaken and alone. In 1931, The New York Times commented on the film:
The Screen: A Nobel Prize Novel: Mr. Colman [is] Martin Arrowsmith, the zealous young doctor and hopeful scientist . . . combating the bubonic plague in the West Indies. Life and death and Arrowsmith’s devotion to science are emphasized toward the end, the last scene being depicted in a most dignified way.(27)
Despondent over his wife’s death, Martin decides that the controlled trial he has planned would be inhumane; everyone on the island he can reach will be treated! Film and book end with Martin leaving the Institute and the big city to work at a small lab in the country. That’s where he would have needed a John Crowley to find him and NASDAQ to bring phage back to life.
The lack of controlled trials for phage therapy has bedeviled clinical and experimental work with bacteriophage.(28) However, phage is crawling back as a therapy, as Joshua Lederberg predicted in 1996.(29) The website Phage International lists 14 biotechnology companies exploiting bacteriophage for the treatments of topical and systemic infections,(30) but injected phages are rapidly cleared by the lysosomal apparatus in liver and spleen,(31) and therefore, claims for such treatments have always seemed spurious. Happily, intravenous preparations have recently been formulated that can escape clearance by our scavenger cells, and topical applications already abound.(32)
Since 1915, phage treatment has wanted only “the absence of prejudice backed by the presence of money.” Perhaps the next version of Arrowsmith will feature the CEO of a well-funded NASDAQ company (George Clooney in blazer and chinos?) announcing FDA approval of a bacteriophage treatment for one or another plague.