Ben Franklin and Open Heart Surgery Special Article Ben Franklin and Open Heart Surgery By Julius H. Comroe, Jr. and Robert D. Dripps • In 1966, President Lyndon Johnson said: "Presi- dents. . .need to show more interest in what the specific results of research are in their lifetime, and in their administration. A great deal of basic research has been done. . ., but I think the time has come to zero in on the targets by trying to get our knowledge fully applied. . . . We must make sure that no life saving discovery is locked up in the laboratory (italics added)." President Johnson's words popularized a new set of terms: research in the service of man (implying that there are two types of biomedical research, one that is in the service of man and another that is not), strategy for the cure of disease, targeted research, mission-oriented research, program- matic research, commission-directed research, contract supported research, and payoff research. And the President's remarks have been summa- rized as "research is fine, but results are better" and "we know all we need to know; now all we must do is to apply what we already know." His philoso- phy led to a sharp upsurge in contract-supported research and commission-initiated research. Most scientists are convinced that basic, un- directed research is essential to the prevention, diagnosis, and treatment of disease, and most scientists can support their convictions with dra- matic examples. (1) When Roentgen discovered X rays, it was not to enable a cardiologist to visualize the coronary arteries of a patient suffering from angina pectoris; he was studying a basic problem in physics to determine the electrical nature of mat- ter. (2) When Karl Landsteiner discovered blood From the Cardiovascular Research Institute, University of California, San Francisco, California 94143 and The University of Pennsylvania School of Medicine, Philadelphia, Pennsylva- nia 19174. This study was supported in part by grants from the Commonwealth Fund and the Burroughs-Wellcome Fund and Contract l-HO-1-2327 from the National Heart and Lung Institute. This article is based on the address by Julius H. Comroe, Jr. on accepting the Wiggers Award of the Circulation Group of the American Physiological Society, April 9, 1974. Dr. Dripps died October 30, 1973. Since this article is of great importance for the future of basic research, the Editor of Circulation Research urges its readers to have it reproduced and made available to their representa- tives in the Government and also to the public through appro- priate media. groups, it was not part of a program to make blood transfusions safe; he was investigating basic prob- lems in immunology. (3) When Coumand and Richards passed a catheter into the heart of man, it was not to develop a new method of diagnosing congenital or acquired heart disease. They were primarily pulmonary physiologists who wanted to learn more about a basic physiological problem of how blood and air are distributed to air sacs of lungs. To do that, they first needed to measure the oxygen content of mixed venous blood in the right atrium. (4) When Shackell developed the tech- nique of freeze-drying in 1909, it was not to preserve penicillin without loss of potency (there uias no penicillin) or to preserve plasma and its fractions (there were none in 1909). He was study- ing a basic problem of the water content of liver and muscle of steers and needed a better method to prevent loss of water during his measurements. (5) When Clarke, a collector and amateur breeder of butterflies, studied variations in the color of but- terfly wings, he had no idea that it would lead to the discovery of the Rh factor in human blood. (6) When Davies and Brink devised an electrode for measuring the partial pressure of oxygen (Po,) it was not to monitor blood oxygen in an intensive care unit; it was to measure oxygen consumption of resting and active sympathetic ganglia. Such "for instances" or anecdotes are fascinating but they would not convince an editor of a scientific journal that they prove the case for support of basic science (though these "for instances" would make interesting "Letters to the Editor"). Nor should "for instances" form a logical basis for a national science policy. In 1966, the position of the Johnson Administra- tion on basic research was bolstered by a study called Project Hindsight (1), commissioned by the Department of Defense. A team of scientists and engineers analyzed retrospectively how 20 impor- tant military weapons such as Polaris and Minute- man missiles, nuclear warheads, C-141 aircraft, the Mark 46 torpedo, and the M 102 howitzer came to be developed. Some of the conclusions of the study were that (a) the contributions of University research were minimal, (b) scientists contributed most effec- Circulation Research, Vol. 35, November 1974 661 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 6 6 2 COMROE. DRIPPS tively when their effort was mission oriented, and (c) the lag between initial discovery and final application was shortest when the scientist worked in areas targeted by his sponsor. Although the report stated that the study focused primarily on the physical and engineering sciences, and that only a small fraction of the technological advances analyzed could have occurred without the discov- ery of nuclear fission in 1939 and without the organized body of knowledge that had accumulated in physics and mathematics by the 1930's and, although only a summary was published in 1966 and a full report has not yet been published 8 years later, this brief "interim report" had a great impact on Congress and on the Office of Management and Budget, because it was a study and not another "for instance." Medical and other scientists countered Project Hindsight with some carefully prepared case stud- ies. Shannon (2) wrote one on the development of polio vaccine (1966); Visscher (3) wrote one on the development of rubella vaccine (1967); Deutsch et al (4) analyzed advances in the social sciences (1971); and Holton (5) traced research in one aspect of physics (shock waves) in 1973. The National Science Foundation commissioned two studies: a 1969 study by the Illinois Institute of Technology (6) that included only one case report on a biomedical advance—how oral contraceptives came about, and a 1973 study by Battelle Labora- tories (7) that also included an analysis of only one biomedical advance—the cardiac pacemaker. And in 1974 Kone and Jordan edited The Greatest Adventure: Basic Research that Shapes Our Lives (8). But a continuing weakness in all of these studies or stories was that the authors analyzed "for instances" that they themselves had selected. So it seemed to us that we, as scientists—despite strong personal conviction—have little objective data on how lifesaving advances in medicine and surgery have come about, and it's time to collect it. We became convinced that it was more important for us to do research on research, on the process of discovery, than it was for us to continue with our ongoing research or other interests. We soon learned that research on research is more difficult than conventional laboratory research, takes a much longer time, and presents unusual problems in achieving objectivity. And we learned that an initial research project in this field, as in other fields, leads to many projects. So, we're far from finished, and we have no Results to present and no Conclusions to draw at this time. But we would like to present the the design and the goals of our main project, invite your criticism, advice, and help, and tell you some interesting things that we have learned (that won't ever fit into the Results or Conclusions of our final report). A. Design of the Project We wanted to learn how clinical advances came about that directly prevented disease, cured or arrested disease, or decreased suffering and pro- longed useful life. We believed that it was essential to avoid using the anecdotal approach, which inevitably leads to bias. Therefore, we decided to look at a large field, and we selected "Advances in cardiovascular and pulmonary medicine and sur- gery since 1945". To avoid stacking the cards to favor the contributions of basic research, we asked physicians and surgeons to pick the most impor- tant clinical advances since 1945 that directly benefited their patients. Here are their "Top Ten" (Table 1). At this time, we will discuss only one of the top ten, open heart surgery, because it headed the list of almost every voter. However, the discussion that follows applies equally well to each of the other nine advances. The public knows about open heart surgery. To the public, it is the dramatic achievement, the pinnacle of surgery, comparable to the conquest of Mt. Everest (Fig. 1). There are two ways the cardiac surgeon could have reached the top of Mt. Everest. The first is one giant leap from sea level to the pinnacle. The second is a less dramatic walk up the back of the mountain (Fig. 2), up steps laboriously chiseled out by thousands of workers in many branches of science (physical, biological and clinical) over tens or hundreds of years. Stated very briefly, our main project has three goals. (1) We want to find out whether the cardiac surgeon took a giant leap up the front of the mountain or whether he walked up the back. (2) If he walked up the back to or almost to the top, we TABLE 1 The "Top Ten" Open heart surgery Cardiac resuscitation, defibrillation, cardioversion, pacing Intensive cardiovascular and respiratory care Chemotherapy and antibiotics Vascular surgery Medical treatment of coronary insufficiency Oral diuretics New diagnostic methods Drug treatment of hypertension Prevention of poliomyelitis Circulation Research, Vol. 35, November 1974 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 BEN FRANKLIN AND OPEN HEART SURGERY 6 6 3 CARDIAC SURGEOH FIGURE 1 One giant leap to the pinnacle? FIGURE 2 Or Sid he climb the steps up the back of the mountain? want to learn who built the steps and why? Was Cardiac Surgery their target? (3) We want to tell the public and especially the makers of public policy how he got there. (1) A Giant Leap?—Our approach had to be retrospective. We started with the fact of open heart surgery and worked back, always asking the same question in one form or another: What had to be learned before the next step could follow? For the final step, the question was: What had to be learned before the operation could become a rou- tinely successful procedure? Most surgeons would answer that the laboratory was an absolute require- ment, but what they really mean is the surgical dog laboratory where surgeons practice and perfect their skills. These techniques are, of course, impor- tant, but what we need to know is: What knowledge had to be acquired before open heart surgery could become a routinely successful procedure? One absolute requirement was the development of a pump-oxygenator to keep the patient alive while his own heart was being repaired. The pump-oxygenator was developed by a surgeon, John Gibbon. For 15 years it was a product of mission-oriented research, and then, for the last few years, of engineering and development. But now our question becomes: What had to be learned before Gibbon could even think of building a pump-oxygenator, let alone construct a dependable device? It is crucial that the public and maybe also medical students, physicians, and surgeons realize Circulation Research, Vol. 35, November 1974 that the pump-oxygenator was itself possible only because of many earlier discoveries. One of the necessary earlier discoveries was that of two anticoagulants: citrate, which was discov- ered immediately following the basic discovery of the role of calcium in blood coagulation, and heparin, which was discovered during a basic physiological investigation of blood clotting. Gib- bon didn't begin his work on pump-oxygenators until 1934—the year that pure, potent heparin became available. This timing was not a coinci- dence; the most elegant pump that could be devised by engineers was doomed to fail unless the blood it pumped remained liquid. Another neces- sary earlier discovery was that of blood groups by Landsteiner; this led to blood typing, then to safe blood transfusions and now to safe blood for use in pump-oxygenators. A third earlier discovery un- covered basic knowledge of red blood cells, their life span in the body and how to preserve them outside the body; this led to the ability to store blood for use in emergencies, then to blood banks for routine convenient use, and now to adequate supplies of compatible blood for use in the pump-oxygenator. A fourth yielded basic information on the diffu- sion and exchange of Oa and CO2 that provided an essential base for the construction of artificial oxygenators. A fifth was the synthesis of new plastic materials, which began in chemistry labora- tories in 1905. Ultimately, this permitted the development of plastic tubes, bags, and valves, D ow nloaded from http://ahajournals.org by on A pril 5, 2021 6 6 4 COMROE, DRIPPS which are absolute requirements for a pump and valves that will damage blood little or not at all, and of an artificial lung that will permit proper pas- sage of oxygen and carbon dioxide. But successful open heart surgery requires more than the use of a pump-oxygenator. So our question now becomes: What had to be learned to permit the cardiac surgeon to open the thorax, stop the heart, open the heart, restart the heart, and care for the patient to ensure full and speedy recovery? (a) Physiologists had to learn about the existence and function of the heart's conducting system and the normal rhythm of the heart. Cardiologists had to study abnormal rhythms, especially ventricular fibrillation, which, if not reversed, leads to death in a few minutes. These studies led to the technique of electrical defibrillation and to other devices now used to detect serious arrhythmias, to reverse them ("cardioversion"), or to control them (cardiac pacemaker), (b) Physiologically trained anesthe- tists had to develop closed-circuit anesthesia and learn to use muscle-relaxing agents that allowed careful, delicate, painstaking repair of cardiac tis- sues to replace lightning-fast slashing and stitching that was the hallmark of early cardiac surgeons, (c) Physiologists had to learn about control of respira- tion and mechanical properties of lungs, how to ventilate lungs when the thorax was open, and how to measure blood oxygen (O2), carbon dioxide (CO2), and acidity (pH). Only then could there be precise oxygenation of the patient's blood and proper removal of CO2 during the operation and later in the intensive care unit (which itself was based on years of fundamental physiological re- search on the heart, lungs, and circulation), (d) A German physicist, Roentgen, had to discover X rays, a Dutch physiologist, Einthoven, had to devise a sensitive instrument to record the elec- trocardiogram (ECG), and a French and an Ameri- can physiologist had to develop the technique of cardiac catheterization, all essential to accurate preoperative diagnosis. (The history of cardiac surgery includes many optimistic starts followed by abrupt stops. These stops were usually due to the death of a patient because an inaccurate preopera- tive diagnosis forced the surgeon to face an unsus- pected lesion that he was not prepared to deal with, (e) Physiologists and clinicians had to study the survival times of completely bloodless organs at normal and low body temperatures, so that cardiac surgeons would know the safe time limits for an operation with the heart stopped, (f) Physiologists had to learn how to stop the heart beat chemically or electrically. Ultimately this knowledge permit- ted cardiac surgeons to stop a human heart and have a bloodless, motionless heart on which to operate, with assurance that this heart would beat again when the surgeon was ready and that its beat would be normal and vigorous, (g) A new type of scientist, the microbiologist, had to discover bacte- ria (which first had to await the discovery of the microscope), and many scientists had to do basic research on specific infections, asepsis, antiseptics, chemotherapy, and antibiotics. It seems certain, therefore, that the cardiac surgeon did not reach the pinnacle in one giant leap but climbed the steps carved by thousands of earlier workers up the back of the mountain. (2) Who Built the Steps and Why?—Table 2 lists 25 bodies of knowledge that had to be devel- oped to permit just one clinical advance—uni- formly successful open heart surgery. For all ten clinical advances listed in Table 1, we have iden- tified about 150 essential bodies of knowledge. But each of these 150 is only a heading of a word or two. Under each heading (e.g., electrocardiography in Table 2) is a long history of scientific progress from earliest concepts to full and effective use (for example, ECG) as a routine diagnostic test. TABLE 2 Twenty-Five Bodies of Knowledge Essential for the Full Devel- opment of Open Heart Surgery Anatomic and clinical diagnosis Physiological diagnosis: electrocardiography Physiological diagnosis: cardiac catheterization Radiologic diagnosis: selective angiocardiography Transfusion, blood groups and typing, blood preservation, components of blood and plasma Nutrition, intravenous feeding Preoperative care Assessment of cardiac, pulmonary, renal, hepatic, and brain function Asepsis Monitoring ECG, blood pressure, heart rate, blood 0 , , CCs and pH, and EEG Anesthesia and neuromuscular blocking agents Hypothermia and survival of ischemic organs Ventilation of open thorax Anticoagulants Pump oxygenator Elective cardiac arrest, defibrillation Fluid and electrolytes, acid-base balance Surgical instruments and materials Surgical techniques and operations Relief of pain General principles of intensive care Chemotherapy and antibiotics Management of postoperative complications Management of heart failure Wound healing Circulation Research, Vol. 35, November 1974 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 BEN FRANKLIN AND OPEN HEART SURGERY 6 6 5 With the generous help of consultants, we have identified about 3,000 scientific reports judged to be necessary for the development of the 150 bodies of knowledge. Of these, we plan to analyze in de- tail the 500 individual research reports judged by consultants to be the most important, most deci- sive, and most crucial for the full development of the ten clinical advances. From this analysis, we will learn how and why each study was done, how each led to the next step, how many studies were undirected and produced knowledge now essential but initially unrelated to its present clinical use, how many studies were mission oriented specifically to prevent or cure one disease, how many were reports of advances in engineering that created or improved needed instruments, apparatus, or techniques, and how many key, decisive studies were designed by commissions or supported by contracts. (3) Tell the Public and the Makers of Public Policy What We Have Learned.—The public us- ually knows only the final product of research and development, because it is easy to identify and publicize. And, as a rule, the public tends to link the name of one man with one discovery, e.g., the radio with Marconi or the airplane with Wright. What the public does not know is that tens, hundreds, and thousands of studies, stretching back over decades or centuries, contributed to any one step up the mountain. For example, Table 2 lists the word electrocardiography. The public knows ECG, but it does not connect the ECG with studies by Benjamin Franklin, the colonies' fore- most scientist, who learned in 1752 that naturally occurring lightning and electricity stored in a battery (initially a Leyden jar) are one and the same; or with studies by Galvani and Volta, whose curiosity about "animal electricity" in the late 1700's led to the science of electrophysiology and also to the intensely practical development of the storage battery; or with studies by Keith, Flack, His, Tawara, and Purkinje, who learned how the impulse that sparks the heart beat originates in the sinoatrial node and spreads to the atria and the ventricles; or with studies by Waller and Ein- thoven, who developed the ECG at the end of the nineteenth century; or with work by Sir Thomas Lewis, who used the ECG extensively as a physio- logical and diagnostic tool to learn much of what we know of normal and abnormal rhythms of the human heart, or with research by Wilson, who used the ECG in 1930 to diagnose myocardial infarction. Another problem with public understanding of science is that some of the great advances have Circulation Research, Vol. 35, November 1974 been around so long that they've become part of everyday life. Who today thinks of fire, or the wheel, or electricity, or the flush toilet as the product of truly creative minds? Who today still thinks of penicillin as a wonder drug? Now it's something—like toothpaste—that you buy at a drug store. The public has long forgotten that the discovery of penicillin first required the develop- ment of whole new sciences of microscopy, microbi- ology, infectious diseases, and pharmacology. Cardiac catheterization is now an everyday rou- tine test. Physicians and patients think of it only in terms of a patient lying on a hard table with a long plastic tube in his heart. What a cardiac catheteri- zation laboratory actually needs and uses besides a patient, a catheter, a cardiologist, and a nurse is shown in Figure 3. The public forgets or was never told that cardiac catheterization is not a procedure that stands alone; its use depends on many ad- vances in the basic sciences, in clinical investiga- tion, in engineering, and in industrial develop- ment. In 1969, Robert Berliner said: "Above all we have an enormous job of education to do. We need far more general understanding of how science pro- gresses, of the tortuous paths from distant, un- related points of departure that converge to bring us where we are. When the press conference is held to announce the current achievement, we need less emphasis on wild speculation about unforeseeable applications and far more on the roots in the past. We need emphasis not only on the giants on whose shoulders we have stood, but on the contributions of unsung investigators too numerous to mention. We should have the equivalent of a brief'commer- cial' before each therapeutic measure, each dose of vaccine, each effective drug: 'This is made possible by the research of Whozis and So and So; we trust you will find it effective and remember what research has done for you.' " B. Some Things We Have Learned (1) Physiologists can be proud of their contribu- tions to medical science. In the field of cardiac surgery, they showed how to ventilate the open thorax; how O, moved from air to lungs to blood to tissues; how to measure Po2, Pco2 and pH. Physiologists learned how to keep blood from clotting and how to preserve this liquid blood for several weeks. They learned how the heart beat spread from the sinoatrial node to the atria and the ventricles. They devised and used the first ECG. They first used the cathode-ray oscilloscope to measure electrical events in animals—an appara- D ow nloaded from http://ahajournals.org by on A pril 5, 2021 6 6 6 COMROE, DRIPPS C A T H E T E R S 1 Oocron and nylon weave 2 Rodioopoque cloth wovtn 3 Opoqu* synthetic extruded rubes for catheters 4 Double lumen, balloon ripped 5 Dotter-Lucas, Rashklnd, Swan-Ganx 6 Spring wire guide* 7 Courncnd-rype needle for percutaneous i m r t i w 8 Platinum rip catheters for Hj or ascorbate curves 9 Fbcing catheten 10 Ptionocardiographtc catheters 11 Catheter Hp pressure transducer 12 Fiber optic catheter R O E N T G E N O G R A P H I C E Q U I P M E N T 1 X-ray tub* 2 Electronics for pulling 3 Imoge intemifier 4 Television camera and monitor 5 Video tape recorder 6 Dlic-rypc video storage 7 Biplane cine camera 8 High contrast cine film 9 Projector for still and morion pictures 10 Timing of x-ray pulses and cine exposure 11 Lead sheets and aprons for protection E L E C T R O N I C I N S T R U M E N T S 1 Multichannel recorder 2 Transducers and amplifiers for ECG, blood pressure, phonocoJtfiogroph, poJarogroph and hecrt rate 3 CRO For monitorirtg A Frn tape recorder and tape 5 Therm!itor probe 6 Chri meter 7 Deraitoraerer 8 Defibrillotor 9 External and internal pacemaker STERILE E Q U I P M E N T 1 Steam sterilizer 2 Ethylene axide go* sterilization 3 Benzalkonium and cyanJde solution* 4 Sterile brushes, tapes, ere 5 Scrub and preparation solutions C A L C U L A T O t S 1 Slid. r u l . 2 Calculator 3 Corapurer D R U G S A N D C H E M I C A L S I 2 Local and general anesthetics 3 Oxygen (with robing, masks, valves, tanks) 4 Antiarrrryrhmic drugs 5 Indocyanine green for dye dilution curves 6 Radioocoque contrast media 7 Sterile solutions 8 Antibiotics 9 Heparln 10 Acetylchollne B I O C H E M I S T R Y L A B O I A T O I i Y 1 Macro and micro blood got onalyztn 2 Apparatus for rrwosurina blood pH, PcoI( Po? at body t«mp«rarur« 3 Gas anolyxef 4 Sp«ctropKotcMn«ter for measuring abnormol Hb 5 D«nsirom«tef 11 boproterenoj S P E C I A L I T E M S 1 MJcrosyringts 2 Pr«s*ura ln|«cror for ongiograpriy, rimed to match cardiac cycle 3 Respiratory valves and spiroowtTs 4 DougJas bogs for collecting gas 5 Go* sample collectors 6 Disposable syringes, sropcocb and plastic tubes 7 Surgical Instruments for macro and micro dissection 8 Constant wirhdrawal-infusion syringe FIGURE 3 Cardiac catheterization requires more than a catheter and a table. tus now essential for all monitoring in operating rooms and intensive care units. Physiologists learned how to measure blood pressure, cardiac output, blood flow and how to evaluate cardiovas- cular function. A physiologist, Carl Wiggers, in- troduced the concept of the vulnerable period of the ventricles and so provided the scientific base for defibrillation, "cardioversion," and cardiac pacing. Equally important, many physiologists contri- buted to the scientific training of modern surgeons who then applied their training to solve clinical problems. John Gibbon spent three and a half years (1931-1934) practicing surgery half of the time and doing research with Eugene Landis the other half; this was just before Gibbon started work on the pump-oxygenator in 1934. Landis, with characteristic modesty, says that his contri- bution to Gibbon was "transmitting what he (Landis) had learned from Cuthbert Bazett, Mer- kel Jacobs, A. N. Richards, Thomas Lewis, and August Krogh." We add, what a wonderful way to start a career in surgical research! (2) Research on physiological problems has had important spin-offs to other fields. Studies on ani- mal locomotion by Muybridge in 1872 produced the first motion pictures (on glass plates); this develop- ment led to Edison's use in 1893 of a celluloid strip, which then became the basis of a huge motion picture industry. Research by earlier physiologists on the mechanism of the heart beat in frogs and turtles led Einthoven to devise a sensi- tive string galvanometer, which was then used in Holland for recording wireless signals from the Dutch East Indies, for sound ranging in World War I to detect the location of German guns on French battlefields, and for telemetry. The need to completely denervate the carotid arteries of the dog to study responses of denervated arteries to chemical agents led in 1960 to the technique of microvascular surgery and now to reconstruction of a ligated vas deferens. The Po2 electrode, developed entirely for neurophysiological use, is now widely used to measure pollution of streams. Studies on the water content of tissues by Shackell (1909) led him to develop the technique of freeze- dryirig, which now has many industrial applica- tions, the latest being a large instant coffee in- dustry. Research on blood groups for safe use of blood has had important spin-offs in such diverse Circulation Research, Vol. 35, November 1974 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 BEN FRANKLIN AND OPEN HEART SURGERY 6 6 7 fields as human genetics, determination of pater- nity, criminology, and anthropology. (3) Physiologists in their research have both benefited other disciplines and in turn benefited from them. There are many instances of dis- coveries bouncing back and forth from basic to applied sciences to the benefit of both. Studies on animal locomotion (basic) led to the motion picture industry (applied), later to biplane cineangiocar- diography for research (basic) and clinical diag- nosis (applied), and now to the study of the velocity of contraction of cardiac muscle (basic). The urgent need in World War II for a device to detect leaks in aviators' oxygen masks led a physiologist, John Lilly, to devise a nitrogen meter (applied), using knowledge developed in earlier research in physics (basic). The new meter was soon used to study distribution of gas to alveoli (basic) and a little later to test pulmonary function clinically in patients suspected of having cardiopulmonary dis- ease (applied). Now it is also being used to study the mechanism of airway closure (basic) with the expectation that a new test will result to permit earlier diagnosis (applied). Studies on the cause of irregularities in the capillarity of mercury (basic) led Heyrovsky to devise a dropping mercury test that in turn led to the polarograph, an instrument useful in detecting small quantities of metals (applied). This discovery led to the O2 electrode used to measure Po2 in autonomic ganglia (basic) and, in turn, to the blood Os electrode now used universally to monitor the ventilation of pa- tients in operating rooms and in intensive care units (applied) and to detect stream pollution (applied). (4) Scientists do their research for a wide variety of reasons. John Gibbon did his be- cause a patient died of pulmonary embolism; he wanted to devise an apparatus to bypass the lung and allow him to remove the embolus (he did not have open heart surgery in mind). Julius Jacob- son, the father of microvascular surgery, was asked by two fellow faculty members at Vermont if he could perform a guaranteed total denervation of the carotid arteries of the dog so that they could test the responses of completely denervated vascu- lar smooth muscle to drugs. The only certain way was for Jacobson to cut the artery in two and then stitch it together again. This procedure required use of a dissection microscope and led to the birth of microvascular surgery. Dennis Jackson, a physiologist who later turned pharmacologist, developed the first closed-circuit anesthetic equipment in 1915 to help the poor. Circulation Research, Vol. 35, November 1974 Jackson later discussed his motives: "The need for some cheap, easy and effective method for administering nitrous oxide was impressed upon me long ago when I was a medical student on Chicago's old West Side. There...poverty...mingled with the stench from the stockyards. Many patients came into the clinic for minor surgery. Nitrous oxide was the anesthetic of choice, the cost being fifty cents. But that fifty cents often meant that the patient could not eat for the next day or two Nitrous oxide was generally given without oxygen..." because added Oj cost twice as much and that meant no food for 4 days! Jay McLean, a University of California college student, wanted a career in academic surgery and determined in 1915 to leave the University of California at Berkeley to enter the Johns Hopkins School of Medicine even though he had not been accepted. On his arrival in Baltimore, the dean ac- cepted him for admission a year later. McLean asked Professor William Howell for a year of re- search in the physiology laboratory "to see if I could solve a problem by myself." Howell put him to work on brain cephalin (a clotting factor). Mc- Lean instead discovered heparin in liver. Charles and Scott (Toronto) decided to purify heparin in 1933, not because of demand for its use clinically but "because of the importance of heparin in certain physiological experiments." Hustin in Brussels in 1912 had a patient who died of car- bon monoxide (CO) poisoning. Hustin reasoned that he could have saved the patient's life if he could have bled him, removed the CO, added 0 , , and then reinjected the blood. But this procedure required blood that would not clot. He had spent a year in the physiology laboratory at the University of Brussels, unusual for a young physician, and had perfused organs with defibrinated blood. Be- cause defibrinated blood had some toxic effects, he experimented with the addition of citrate and so developed the first indirect blood transfusion. (Re- member that in the early 1900's the gTeat American surgeon, Crile, was transfusing blood directly from an artery of a donor to a vein of the recipient; the two vessels were sutured end to end for the dura- tion of the transfusion). Carrel (more of him later) developed vascular surgery because he wanted to study the individual metabolic requirements of each organ: he wanted to know what each organ needed for maximal survival and optimal function. Sometimes one cannot tell from reading his re- port why a scientist began his studies. Maybe he thought it unscientific to say why. Maybe an editor deleted his account. Maybe the scientist stumbled D ow nloaded from http://ahajournals.org by on A pril 5, 2021 668 COMROE. DRIPPS or blundered on his discovery and didn't want to say so. Maybe he was a young scientist reluctant to acknowledge his debt to others. Sometimes a scien- tist in later years tells us how he came to make his early discoveries. Gibbon did this for the pump- oxygenator; McLean did it for heparin; one phys- iologist does this each year in the prefatory chapter of Annual Reviews of Physiology. (5) We have also learned that the record has not been entirely good. True, X rays were put to physio- logical and clinical use almost instantly; Roentgen's first report was in December 1895 and within a few months, in 1896, there was already a new journal (Archives of the Roentgen Ray) and within a year a new society (The Roentgen Society) devoted com- pletely to the new rays. The electrocardiograph too was put to clinical use quickly after Einthoven's work. But many discoveries made and widely used in the laboratory (such as artificial or controlled ventilation, measurement of lung volume, ventricu- lar defibrillation and closed-chest cardiac mas- sage) were not quickly applied clinically. Vesalius demonstrated artificial ventilation in 1543, Hooke demonstrated it again in 1667, and physiologists used it in laboratory experiments in the nineteenth century, but it never crossed over to clinical medicine, even to ventilating the lungs of patients with an open chest, until 1915. Humphry Davy in 1800 prepared his own hydrogen, breathed it in and out, measured its concentration in the expired gas and calculated his lung volume. How- ever, his method was not used again until the 1940's and 1950's. In 1899, Prevost and Battelli produced ventricular fibrillation electrically and then de- fibrillated the same dogs with stronger shocks. Their work had no impact until 1930 when Howell trans- lated their paper into English for Donald Hooker and William Kouwenhoven who were then working on electric shock in Howell's physiology laboratory at Hopkins. Closed-chest cardiac massage has been widely used in physiology laboratories since 1878 to resuscitate cats and dogs, but it was not applied to man until 1960. Long lags also occurred before the full clinical use of heparin, hemodialysis, the cath- ode-ray oscilloscope, telemetry, and techniques of vascular surgery. One of the most remarkable of all lags was that in vascular surgery. Between 1902 and 1910, Alexis Carrel performed every feat and developed every technique known to vascular surgery today (ex- cept for using a dissection microscope and plastic tubes, neither of which had then been discovered), but his work was essentially lost until 1940. He reunited vessels intima to intima; he sutured artery to artery, vein to vein, artery to vein, end to end, side to side, and side to end. He used patch grafts, autografts, homografts, heterografts, rubber tubes, glass tubes, metal tubes, and absorbable magne- sium tubes. He devised his own nontraumatic needles, clamps, and sutures. He performed a cor- onary bypass operation on a dog using a preserved carotid artery; the procedure required only 5 min- utes. He preserved vessels, tissues, and organs by refrigerating them in Locke solution. He sug- gested using a segment of a patient's vein to re- place a damaged artery. He transplanted thyroid, spleen, ovaries, limbs, and kidneys and so proved that, surgically, it was possible and easy to trans- plant organs. But he recognized that a homograft vessel served only as a framework for new cell growth. And as early as 1912, he stated: "But it is not yet known whether surgeons will ever be able to perform a homoplastic transplant with perma- nent success . . . it will only be through a more fun- damental study of the biological relationships existing between living tissues (... to recognize individuals, if such exist, between whom organs can be interchanged with impunity) that the prob- lems involved will come to be solved." We must ask why his work was not mentioned in the classic reports describing the "new" vascular surgical operations in the 1950's. Was Carrel's work published in a rarely read foreign language like Jansky's work on blood groups? No, he published in English. Did he work in unknown laboratories? No, he worked first at the University of Chicago and then at The Rockefeller Institute in New York City. Did he publish in journals never read by sur- geons? No, he published in Surgery, Gynecology and Obstetrics, Journal of the American Medical Association, and Annals of Surgery. Was his re- search held in low esteem? No, he won the Nobel Prize in 1912, the first American to receive the Nobel Prize in Medicine and Physiology. Such lags probably occur in every branch of science and in technology, not just in biomedical research. It is such lags between initial discovery and application to patient care that support the clamor for commission-directed research and con- tract-supported research and development (9). It is our responsibility to try to interest clinicians in our ongoing work and its possible applications to medicine, even though our attempts will not al- ways work. Wiggers (American Heart Journal, 1940) fibrillated and defibrillated the heart of the same dog 41 times and then "by lecture and demonstra- Circulntion Research, Vol. 35, November 1974 D ow nloaded from http://ahajournals.org by on A pril 5, 2021 BEN FRANKLIN AND OPEN HEART SURGERY 6 6 9 tion attempted to acquaint laboratory workers and surgeons with the procedure" of electrical defibril- lation, but he was without success until 1956. As you can see, research on research, like labora- tory research, leads to many more questions than the initial one. What accelerated discoveries? What held them back? Could the delays have been pre- vented? Why didn't a scientist follow through with his initial discovery? Was it lack of interest? Was it because he didn't appreciate the importance of his work to his field? Was it because he didn't appreciate the significance of his work to other fields? Why didn't he get his ideas to others who would follow up on them? (By sharing his ideas with others? By speculating to help those with less imagination?) What would modern policies govern- ing research have done to the research of 30-75 years ago? What would have been the effect of the Food and Drug Administration, the committee on human experimentation at each university, NIH study sections, NIH task forces, and of commis- sions? When might directed research have paid off? When might it have failed? References 1. SHERWIN CW, ISENSON RS: First Interim Report on Project Hindsight. Washington, D. C , Office of Director of De- fense Research and Engineering, June 30, 1966 (Revised October 13, 1966). 2. SHANNON JA: NIH: Present and potential contribution to application of biomedical knowledge. In Research in the Service of Man: Biomedical Knowledge, Development and Use. U.S. Senate, 90th Congress, 1st Session, Docu- ment No. 55, 1967, pp 72-85 3. VISSCHER MB: Applied science and medical progress. In Applied Science and Technological Progress. National Academy of Sciences Report, 1967, pp 185-206 4. DEUTSCH KW, PLATT J, SENGHASS D: Conditions favoring major advances in social science. Science 171:450-459, 1971 5. HOLTON G: Models for understanding the growth of research. In The Thematic Component in Scientific Thought. Grad J 9:397-430, 1973 6. Technology in Retrospect and Critical Events in Science. Prepared for the National Science Foundation by Illinois Institute of Technology Research Institute under Contract NSF-C535, December 15, 1968, and January 30, 1969 7. Interactions of Science and Technology in the Innovative Process: Some Cases Studies. Prepared for the National Science Foundation by Battelle Laboratories under Con- tract NSF-C667, March 19, 1973 8. KONE EH, JORDAN HJ, eds: The Greatest Adventure: Basic Research That Shapes Our Lives. New York, The Rockefel- ler University Press, 1974 9. COMROE JH JR: What's locked up? Am Rev Resp Dis 110:111- 114, 1974 Circulation Research, Vol. 35, November 1974 D ow nloaded from http://ahajournals.org by on A pril 5, 2021