Authors: James Forrester
The Heart Healers (31 page)
Until that moment I knew that Eduardo stood poised on the edge of a chasm, the netherworld of misty benevolent light that accompanies death, according to many who have been resuscitated. In the years before thrombolytic therapy we had spent years trying to develop a prognostic index of death in our newly arrived patients, based on factors like age, blood pressure, heart rate, body temperature, etc. But we found that the best index we had was what we called the Nora Index. Nora was a crusty CCU nurse with many years of experience. In the crude language doctors sometimes employed to insulate themselves from our 30% mortality rate of that era, the Nora Index was “when Nora says they’re gonna die, they’re gonna die.” Thrombolytic therapy changed all that. Eduardo’s Nora Index was off the charts when we began the infusion. He was undoubtedly sliding inexorably toward death until the clinging red worm was abruptly dissolved. When Eduardo’s ECG began to change, we were ready to repeat the coronary angiogram. I held my breath as I watched Eduardo’s coronary angiographic image appear on the TV monitor. In medicine we are trained not to jump, wave our arms, and cheer. But for me that instant felt, still feels today, like an explosive release of unanticipated pure joy, like the moment when injured Dodger Kirk Gibson hit his miracle home run in the 1988 World Series. Who says you cannot cheer at a transcendent moment like that? The red worm had disappeared! I had seen a miracle in my own lifetime. Blood flowed briskly down Eduardo’s previously obstructed vessel. We had aborted Eduardo’s acute myocardial infarction.
When he collapsed in his kitchen, Eduardo’s risk of death had he been unable to get to a hospital was at least 50%. Now, lying on the table in that singular glorious moment he had about an 85% chance of walking out of the hospital, and returning to his life with his family and to his job. When he did I felt Eduardo probably had smoked his last cigarette. My experience is the patient who emerges intact from the emotional cataclysm of impending doom, as Eduardo had, undergoes a foxhole conversion. In the face of imminent death, he becomes a true believer … in Eduardo’s case, in lifestyle change.
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WE HAD OUR
glorious, mind-bending answer: infusion of streptokinase into coronary arteries aborts a heart attack in progress. But wait: in medicine, great answers always raise new questions. If time is muscle, was not infusion directly into the coronary artery colossally inefficient? It took us at least an hour to mobilize the cath lab if a patient arrived in the middle of the night. Then each little step—scrub, drape, gown, anesthetize the groin—took more time before we finally directed a catheter into a patient’s coronary artery to begin the infusion. And with each minute more heart muscle was dying. As our lab and others reported spectacular angiographic results, the question became inescapable. What about saving at least an hour, maybe more, by circumventing the cath lab? Could we start an intravenous infusion of streptokinase at the moment the patient burst through the emergency room door? It would quite clearly be a trade-off between an increased risk of bleeding due to a much higher dose of streptokinase and a decrease in the time required to restore coronary flow. By the mid-1980s we were ready for the first large-scale randomized trial of intravenous streptokinase. The landmark trial came from Italy, conducted by the Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico, nicknamed GISSI for obvious reasons. The group reported that intravenous streptokinase worked best when given early after the onset of symptoms. When GISSI reported that their survival advantage was maintained at one-year follow-up, intravenous thrombolytic therapy was anointed as the standard for treatment of a heart attack.
In the 1950s, when future president Lyndon Johnson sustained his first heart attack at age forty-six, we had no effective therapy at all. By the time of Johnson’s final fatal massive heart attack on his ranch in the early 1970s we could have offered CCUs to control his arrhythmias and his heart failure, but we still had no effective therapy for his acute myocardial infarction. Now in the 1980s we had delivered another staggering blow to the ravages of CAD. We had discovered the cause of heart attack, and knowing its cause, we had devised spectacularly effective therapy. Average citizen Eduardo Flores had just received vastly more effectively therapy than that available to the president of the United States just a decade earlier.
Prior to clot-dissolving therapy I was forced to stand by watching as heart muscle died during a heart attack. Now we understood the cause of heart attack. We had a highly specific, effective therapy. CCUs had an immediate effect on mortality rate in patients hospitalized with myocardial infarction. By saving heart muscle during heart attack we had reduced the long-term risk of heart failure. In the prior decade, our early CCUs had almost halved the hospital mortality rate for acute myocardial infarction; now our newfound ability to dissolve clots in coronary arteries had reduced it by half again. In 2013 I reminisced about the treatment of heart attacks as we had helped it evolve with Dr. Eugene Braunwald, my generation’s most recognized cardiologist. Pithy as always, Gene captured the essence of this story in a single sentence: “Jim, the coronary care unit is the most important advance in the treatment of acute myocardial infarction.”
And now it is time for us to take a break from medicine to ask a deeper, more fundamental question. Why did these amazing advances, and the equally astonishing breakthroughs still on the horizon, occur in such a short period of time? Why did they occur when they did, where they did? The unrecognized answer to these two questions is central to both today’s health care and more broadly, to the future of the U.S. economy.
America demands invention and innovation to succeed.
—KIT BOND, FORMER U.S. SENATOR FROM MISSOURI
OPEN HEART SURGERY,
coronary angiography, and the emergence of the CCU set the stage for the modern cardiology’s final assault on CAD. But along the way our attack was joined by an additional warrior with tremendous power and resources. Industry entered the battlefield, and with it came what I call The Merger. It was the merger of industry with academia.
From my perspective The Merger came about as an unintended consequence of two unrelated and little noticed events in the 1970s. The first event was a then-confidential change in policy within the National Institutes of Health (NIH). Dr. Claude Lenfant was then director of the National Heart, Lung, and Blood Institute (NHLBI), one of the major subunits of the NIH, and source of most heart disease research funding in the United States. An urbane, nattily dressed, rather formal intellectual with a disarming French accent, Claude was both an accomplished scientist and savvy politician. So when Claude spoke about Washington’s medical politics, I had learned to expect an indirect message, to focus on his subtext. I was now director of one of the NHLBI’s nine huge multimillion-dollar flagship research programs, called Specialized Centers of Research (SCOR) in Ischemic Heart Disease. Every five years the nation’s leading heart centers competed intensely for these nine grants, which were awarded only after on-site grilling by a group (usually about ten) of the nation’s leading heart researchers. With many millions of dollars at stake, I spent months rehearsing each member of my team for their two-day visit. The SCOR programs were devoted predominantly to clinical patient-oriented research, and my program had competed very effectively by pioneering advances like the balloon catheter and clot lysis in acute myocardial infarction.
At the annual meeting of his nine SCOR directors Claude delivered an oblique confidential warning. A major NIH change in research funding policy was afoot. The NIH was planning to allocate a much greater percentage of its funds to the support of basic research, while encouraging industry to share the cost burden of clinical research, particularly trials of new drugs and devices. If industry funded clinical research, a far greater percentage of the NIH budget could be devoted to the tremendously promising research programs in cellular and molecular science. The NIH vision was that much more research would be accomplished at the same cost to the taxpayer. As the director of the only nonuniversity SCOR among the nine programs, I had little access to large basic science laboratories of medical schools like Harvard and Johns Hopkins. This was a potentially devastating blow to my patient-oriented, bench-to-bedside clinical research program, but I could not deny the logic of the NIH policy decision. Individual companies should pay for multimillion-dollar randomized trials of new devices and drugs since they stood to profit from those that we proved were effective.
All of us missed what now seems like an obvious corollary of this at first little noticed event … an unintended consequence. Until that change in policy we physician-investigators were the ones who conceived and designed clinical research. Our scientific peers judged the merit of our proposals. But with industry paying for the trials that determined whether their new drug or device was effective, the power to design trials and to select investigators to conduct the trials passed from scientists to corporate executives. The massive influx of corporate money accelerated drug and device development, and led to randomized trials that never would have been possible within the NIH budget. The principal negative aspect of the NIH policy decision—industry’s control of the design and conduct of much of the important clinical research—was not recognized in these early years. But years later, critics would say that was the moment the fox strolled into the henhouse.
The second event that led to The Merger was a little noticed amendment to U.S. patent law in 1980, fathered by two leading senators of that era. Whereas the change in NIH funding policy for clinical trials affected predominantly the pharmaceutical industry, the patent amendment changed the device industry. At the time, the NIH controlled most medical research funding, and thus legitimately claimed patent rights on any invention developed with the use of their funds. The problem was that the federal government had no structure for developing a patented idea into a commercial product. Those of us involved in new device development saw our inventions being strangled by bureaucratic red tape. Birch Bayh (Democrat from Indiana) and Robert Dole (Republican from Kansas) forged a bipartisan solution. The Bayh-Dole amendment ceded the NIH patent rights to the involved academic institution. By eliminating government control, academia could patent an invention and then deal directly with industry to commercialize it. The rationale for the amendment was sound: American industry was losing out to international competitors who did not have to deal with the barriers presented by transfer of innovations from university laboratories to government and then to industry. Again, however, there was an unintended consequence. When industry became a source of grant money for academia, the once brittle hands-off relationship between academia and industry became intimate. Industry’s leverage in dealing with academic institutions and research physicians had made another quantum leap. The biotechnology industry was about to be born.
The influx of money from industry to academia was monumental. For instance, the year that the Bayh-Dole amendment passed, industry was investing $26 million in academic university research. Fifteen years later, this investment had increased nearly 100 times to $2.3 billion. This single factor was to be the tipping point in the war on CAD. The federal government had shown great wisdom: first, to provide seed money for innovation, then again when it stepped aside to allow industry to bring these fantastic technological innovations in both drugs and devices to practical daily use. A nation that had led the century through investment, education, productivity, and innovation was about to do it again. The new era would be driven by a partnership between physician-researchers, basic scientists, and industry. Forays in technologic innovation that could not have been begun or completed without huge financial investment now became possible. The first new industry to emerge would be biotechnology.
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AS WE GAINED
experience with streptokinase infusion, we became aware that it was far from being a perfect drug. The basic science community now asked, “Can we make a better thrombolytic agent?” In Europe, using cells from human melanoma cancers, Belgian scientist Dr. Désiré Collen purified an agent that was more specific for thrombus and caused less allergic reactions than streptokinase. It came to be called tissue plasminogen activator or t-PA. A start-up company in Northern California initiated collaboration with Collen’s group with the idea of producing commercial amounts of t-PA. Their plan was to use a new technology called genetic engineering.
Genentech had been founded in 1976 when young venture capitalist Robert Swanson called Stanford University scientist Dr. Herbert Boyer who, with his university colleague Dr. Stanley Cohen, was working in an emerging new field called recombinant DNA technology. Boyer agreed to a ten-minute meeting with Swanson. The meeting stretched into a three-hour lunch, and ultimately led to the formation of the first pharmaceutical biotechnology company. The company’s mission was to create genetically engineered medicines using recombinant DNA technology. They chose Genentech’s name, like Medtronic before it, by fusing the names of its principal disciplines: genetics, engineering, and technology.
Boyer joined Genentech, Cohen remained at Stanford. Boyer began by collaborating with scientists at the Beckman Research Institute. In 1977, as the United States launched its first space shuttle and John Travolta danced in
Saturday Night Fever,
they successfully inserted a human gene into a bacterial cell for the first time. Genes produce proteins, for instance enzymes that regulate the body’s systems. Although this first step resulted in no commercial product the achievement was a crucial proof of principle. If a human gene could be inserted into a bacterium, then millions of bacteria could be induced to act as little factories for the protein that gene produced. The next year Genentech scientists announced a jaw-dropping achievement that had great commercial potential. Using their new technology they succeeded in mass producing one of the world’s most familiar proteins: human insulin. On that day, the treatment of diabetes was forever changed. Heady with success, now they wanted another drug.
