In the spring of 1941, as a junior surgical resident 2 years out of medical school, I scrubbed in on an operation at the MGH in which Edward Churchill removed the calcified pericardium (the envelope or sac surrounding the heart) in a young man with constrictive pericarditis. Pericarditis is a chronic disorder, sometimes due to tuberculosis, in which the pericardium becomes thickened, calcified, and stony hard. A pump such as the heart must be allowed to fill and swell before it can contract to eject its blood. The iron grip of constrictive pericarditis interferes with the heart’s normal distensibility, impairs its filling, and therefore reduces its output of blood. The operation to remove that calcified sac (known as pericardiectomy) is a tricky one because the heart muscle beneath the stony sheath is very thin.
In those days the use of blood transfusion was limited, and there was no such thing as a pump-oxygenator to take over and maintain the circulation if the heart was torn or damaged during the operation. When the operation goes well, the heart, released from this death grip, can distend with blood and pump it out to the arteries. The patient can gradually resume normal activities but, depending upon the duration of the constriction and its effect on the heart muscle itself, can rarely indulge in more strenuous work. Churchill was a careful, precise operator, and his patient got along very well.
Churchill was the first surgeon in the United States to perform pericardiectomy. Although a pioneer in cardiac surgery, his main interest was in lung surgery. He demonstrated that lobectomy (removal of one or more lobes of the lung) could be done safely, with a low mortality even in patients with chronic bronchial infection (bronchiectasis) or for lung cancer, and in certain cases of tuberculosis when the bronchial passages became narrowed.
Seven years after that operation of Dr. Churchill’s, in the fall of 1948, I was recruiting new staff to bring our department at the Brigham up to strength. I asked Dwight E. Harken to head up thoracic surgery. A few months earlier I had left behind me the impressive strength of the MGH in thoracic surgery. Now at the Brigham I found a total vacuum in that field. No one on the staff was doing thoracic and cardiac operations regularly, attending the relevant meetings, or making an academic commitment in this area. Harken had already gained a reputation and had developed a bustling practice in thoracic surgery in the Boston area. He did his work largely at the Boston City and Mount Auburn Hospitals. In addition—and most unusual for the late 1940s—Harken was already becoming known as a cardiac surgeon. During the war he had removed 145 bullets and shell fragments from the hearts of wounded soldiers in 134 operations with no deaths. Several of these metallic objects lay free within one of the four major chambers of the heart. He removed them by opening the heart, a procedure he had probably performed more frequently and more successfully than anyone else in the world at that time.
Despite this impressive record as a cardiac surgeon and the fact that during the previous 6 months he had operated on two patients for disease of the heart valves, it was Dwight’s skill in thoracic surgery (i.e., operations involving the lungs and chest) that led me to seek him out for our staff. We had many patients with lung disease who needed surgical care and many residents and students who needed instruction in this field. While he more than fulfilled our needs for a chief of thoracic surgery (and very promptly), Dwight Harken’s main interests continued to be in the development of heart surgery.
The previous June (1948) Harken had carried out his first success-
ful operation to relieve narrowing (stenosis) of the mitral valve, one of the four major valves of the heart. The name “mitral” was adopted by the early anatomists because the valve resembles the two portions of a bishop’s miter, or hat. This valve is located in the channel between the left atrium (which receives blood from the lungs under low pressure) and the left ventricle (which pumps blood out through the aorta to the rest of the body under high pressure). When the mitral valve closes normally with each beat, as it should, blood can flow in one direction only, vital to proper function of the heart. Narrowing of the mitral valve is almost always produced by rheumatic heart disease in childhood.
While I was well aware of Harken’s interests, neither he nor I could have foreseen the number of patients with mitral stenosis who would seek his help over the next few years. By 1955 he had operated on over 1,000 such patients, most of them at the Brigham, and had become universally regarded as one of the world’s foremost cardiac surgeons. It was through my long acquaintance with these two men—Edward Churchill, my professor, and Dwight Harken, my staff member—that I came to have intimate contact with and continuing enthusiasm for cardiac surgery. I was never a cardiac surgeon myself.
Churchill and Harken stood in sharp contrast to each other and were of different generations (Harken in his middle 30s and Churchill in his 50s). While colleagues on the faculty and in the same field, they were never close personal collaborators. Both were middlewesterners, Churchill from Chenoa, Illinois, and Harken from Osceola, Iowa. Churchill was not given to talkativeness and at times could be somewhat withdrawn and austere, bearing a rather lofty if not Olympian demeanor. By contrast, Harken was informal, forward, red-haired, and appropriately flamboyant. He was given to speaking out boldly, lecturing frequently, and seeking to interest cardiologists in his work, as well as the students, residents, internists, and the many visitors who trailed behind him on rounds. While Harken admired Churchill’s wisdom and skill, Churchill was at times rather critical, not only of Harken but of any plans for surgery within the chambers of the heart.
When I was ready to propose Harken’s appointment to the Dean and to the Harvard Corporation, I needed the approval of Churchill and the two other senior professors (Gross at the Children’s Hospital and Fine
at the Beth Israel Hospital) to ensure an appropriate title. Churchill was down on mitral surgery. In this, as in one or two other judgments about the future of cardiac surgery, he was still swayed by the notion expressed by cardiologists at the turn of the century and in the 1920s that even if the narrowed valve were widened, rheumatic damage to the heart muscle itself in cases of mitral stenosis would prevent rehabilitation. He had been a young surgeon 20 years earlier when Elliott Cutler in Boston and Henry Souttar in London had attempted to open the narrowed mitral valve surgically and had failed. He was convinced that merely opening up the valve orifice would be in vain; the heart muscle would never recover. Churchill, my revered professor, a man of profound surgical and philosophical wisdom, appears now so clearly to have been in error in this judgment.
In contrast, Harken had the faith, the enthusiasm, and the ingrained optimism of the true pioneer. He was not worried about heart muscle damage because early in his work he showed that this concern was not borne out. Many of his patients—and I saw many of them with him—thrived beautifully after operation. Before the operation their skin was bluish and they had difficulty breathing because their lungs were filling with fluid. Their hands and feet, legs and arms were often shriveled up for lack of blood supply or swollen with edema; unable to work, they could not climb stairs and were often totally bedridden. After the operation, they could walk and exercise for the first time in years. As their hearts resumed more normal output of blood and provided nourishment to body cells, they pinked up and gained weight and could climb or even run up stairs. This was remarkable testimony to the buoyancy of the heart muscle as well as the human spirit. Mitral stenosis truly was a point defect, a focal, surgically accessible disorder, the repair of which rectifies many of the other bodily troubles it engenders. A narrowed mitral valve was just that: a logjam in the flow of blood through the heart. Open up the logjam, the river flows again. Cardiac output and health are restored.
The role of Edward Churchill in heart surgery was not confined to his pioneering operations on the lungs and pericardium nor to his skepticism about mitral valve surgery. His most notable contribution to cardiac surgery came about almost inadvertently, unbeknownst even to him at first. The story of the origin of the pump-oxygenator is a fascinat-
ing one. Although development of this machine moved forward with his departmental support, it never attracted his enthusiasm.
In June 1930, 10 years before that pericardiectomy, 15 years before Dwight Harken’s early valve surgery, and only 6 years after Cutler’s failed attempts to operate on the mitral valve, a young surgeon of Philadelphia came to the MGH to work as a research fellow with Churchill. John H. Gibbon, Jr., son of a famous Philadelphia surgeon, arrived to study surgery of the lungs. While working in the laboratory at the MGH, he met Miss Mary Hopkinson, one of Churchill’s laboratory technicians. John and Maylie (as she came to be known) worked together throughout that first year, became engaged, were soon married, and continued to work together over several decades to accomplish one of the greatest engineering feats of this century.
In February 1931, Churchill assigned Gibbon the task of monitoring an extremely ill patient who had suffered several pulmonary emboli (clots that passed from the leg veins to the lungs). Gibbon’s job was to sit with her and measure her pulse and blood pressure (vital signs) every few minutes to keep close track of her condition. Churchill’s idea was that if she threw off another big embolus (manifested by a sudden deterioration in these vital signs, particularly a fall in blood pressure), he would open the artery leading from the heart to the lung for a few seconds to remove the obstructing clots, which would otherwise be fatal within minutes. In this particular case, her vital signs did deteriorate, a clot did come to the lungs, and she lay at death’s door. Although the operation was attempted, the patient died (as did all others who underwent this operation until 30 years later, in the 1960s).
In assisting on this case, the young Gibbon had plenty of time to reflect and consider other, better ways of doing this operation. He began to develop the concept of a machine that could accept all the blood as it returned to the heart via the great veins (several quarts per minute), remove its burden of carbon dioxide, add oxygen, and then pump the oxygenated blood back into an artery under high pressure. If this could be done safely, even if for only 3 to 5 minutes, clots could be surgically
removed and patients might survive. His dream of an artificial heart and lung to tide over the critical period while the heart was open was to become a reality only because of the dogged persistence of Jack and Maylie Gibbon. It took 22 years. And then it opened up not only the heart but a whole new world of surgical care.
Gibbon and his new wife returned to Philadelphia to continue their joint project. Three years later, in 1934, they returned to the MGH and Churchill’s department to spend another fellowship year working on their concept. While Gibbon was grateful to Churchill for providing facilities and support for this important work, it was clear from Gibbon’s later tales that his boss always remained skeptical about the feasibility of an artificial pump-oxygenator as a temporary substitute for the heart and lung. Churchill was not alone in this skepticism. Undaunted, the Gibbons carried on and in 1937 published an article describing their work at the MGH, entitled “Artificial Maintenance of the Circulation during Experimental Occlusion of the Pulmonary Artery.”
Twenty years later, just months before the pump-oxygenator was first used successfully, a respected physiologist stated that a pump-oxygenator substitute for the heart and lungs would never be possible because all that pumping agitation and friction would destroy the red blood cells. As is so often the case with science, the aging expert was a naysayer and the youthful enthusiast proved him wrong.
Before telling the rest of the Gibbons’ story, we should look back at some of the other things that were going on in cardiac surgery at that time. Some of these remarkable developments were occurring close by, at the Children’s Hospital in Boston and on our own service at the Brigham, while others were to take place in Baltimore at Johns Hopkins. All were destined to change heart surgery and, later, be improved themselves as a result of the pump-oxygenator.
Several scholars of heart disease had predicted around the time of World War I that there were two point lesions in heart disease that invited surgical repair: narrowing of the mitral valve (described above) and persistence of the open (or patent) ductus arteriosus. The ductus is a large
artery that is open in the fetus when circulation of blood to the lungs is unnecessary because the mother’s blood supplies oxygen to the infant. While still in the uterus the fetus has no need for lungs and has no air to breathe anyway. The ductus bypasses the lung. Immediately after birth, as the infant cries and takes its first breath this blood vessel starts to close. But if the ductus fails to close and remains open, heart failure gradually ensues, followed by infection and death.
While a few visionaries such as Elliott Cutler recognized these surgical possibilities, the usual pronouncements (more frequently heard) were those of conservative surgical sages with negative opinions who believed it was not only impossible but even perhaps sacrilegious to operate on the human heart. Never mind the needs of patients or the attractiveness of subjecting these ideas to scientific scrutiny in the lab. It just never could be done. Nor should it be tried. God did not have that intent, they preached. Maybe someone should have reminded them that God had also been quoted as being opposed to relieving the pain of childbirth, almost 100 years before.
In 1924-1925 Elliott Cutler, then a junior faculty member at Harvard working at the Brigham under Harvey Cushing, was inspired to try to widen the opening of the narrowed mitral valve in patients with rheumatic heart disease. He carried out six such operations on patients dying of mitral stenosis. In most cases he used a long punch-hole instrument (he called it a valvulotome) that could be introduced through the thick wall of the left ventricle and advanced blindly (by feel) up to the mitral valve. Once there, it would be used to punch a hole in the valve to relieve the obstruction and let the blood flow through more easily. At the time of the first operation he performed, his special instrument was not yet ready, so he used a long narrow scalpel to pry open the adherent leaflets of the stenotic valve. This one patient was somewhat improved and lived over a year. Later patients, in whom the punch-instrument was used, died soon after the operation. Possibly his new punch-instrument was more damaging than the scalpel. While Cutler clearly perceived the potential damaging effect of the valvulotome, he did not see a possible significance in the survival of his first patient, in whom it was not used.
In 1925, Henry Souttar of London carried out an operation with the same purpose on a 19-year-old girl and was knighted for his work.
He approached the problem differently. He inserted his finger into the thin-walled auricle (or atrium) of the heart, placing sutures as a purse-string around the finger in the heart wall, and cinching them up tightly to prevent a leak. Then, feeling for the valve with his “entrapped” fingertip, he could dilate or even break apart the leaflets of the narrowed valve. His patient improved and lived for 5 years. Thus, of the seven patients who underwent mitral valve operations in the 1920s, one lived for over a year (Cutler’s first patient) and one lived for 5 years (Souttar’s). While these two operations could hardly be considered total failures, that idea somehow got rooted in the literature and in the mind of Dr. Churchill, who always referred to them as failures. Little or no attention was paid to the fact that the two survivors were patients in whom the narrowed leaflets were pried open and no valvular tissue was removed or severed.
In 1938, 13 years after Cutler’s attempts at mitral valve surgery, two efforts were made at the same time and in the same city—Boston—to close the patent ductus. One was by John Strieder aided by a cardiac physiologist, Ashton Graybiel, at the Boston City Hospital. While their first operation appeared to go well initially, they could not tie off the ductus completely as they had hoped. The patient died a few days later of acute gastric dilatation, a disorder that today would be readily diagnosed and successfully treated.
The other effort to close the ductus was by Robert Gross, a junior member of the Harvard surgical faculty (working at both the Children’s Hospital and the Brigham), and his collaborating cardiologist, John Hubbard. Together they developed a plan to ligate (i.e., tie off) the open ductus. In August 1938, evidently ignorant of the work being carried out by Strieder only a few miles away, Gross successfully ligated the patent ductus in a child. Several more such patients were successfully treated within a few months.
Some weeks after one of Gross’s first attempts at ductus ligation, the child died of sudden massive hemorrhage when the ligature cut its way through the delicate wall of the artery. Gross swore that he would never again simply tie the ductus. Instead, using an elegant technique that required great skill, he would divide it completely and close the two short ends with sutures. As a student I watched one of these operations and, like all who saw them, was immensely impressed with the skill, dexterity,
and gentleness with which Gross handled this large, thin-walled blood vessel, which was carrying a large volume of blood at high pressure. Word of his success immediately earned Gross a well-deserved reputation and an international following. He had demonstrated that the heart and its nearby great vessels were not sacrosanct at all and could be repaired surgically. Following these operations on the blood vessels near the heart, it became clear that the heart itself would soon be opened with success. The surgical world was ready, but as the war approached and then intervened, it was not clear just how, when, or for what condition this advance would take place.
Just before the war Alfred Blalock at Johns Hopkins, along with his cardiologist colleague Helen Taussig (an expert in congenital heart disease), devised an operation to reroute (shunt) the blood in certain types of babies who were born with a severe heart deformity and whose skin was blue (cyanotic) from lack of oxygen. Total repair of this complex defect would not be attempted for another 10 years, but Blalock’s operation on the great vessels near the heart offered remarkable relief and new hope for patients with heart disease, especially children with congenital heart deformities, and gave them many good years of life.
Following the war, Dwight Harken returned from England fresh from the experience of his surgical successes in treating heart wounds. Immediately he took up his principal interest: surgery of the mitral valve. On June 9, 1948, 5 months before I asked him to join our staff at the Brigham, he performed his first mitral operation. After joining our staff he did several more. Of the first six patients, two lived flourishing lives after the operation and were relieved of their heart failure. To Harken’s surprise, it was discovered that 4 days prior to his first mitral valve repair, Charles Bailey of Philadelphia had carried out a similar operation. Bailey’s first two patients died, but the third lived for 23 years. As was the case with Gross and Strieder, here were two surgeons arriving at the same historic point at almost the same moment. Without getting into the epistemology of such coincidences, I should point out that such convergent evolution is a commonplace in science. When the time is ripe, more than one person is likely to pick the fruit. Credit should go to both because controversy over priority is damaging to the reputation of both parties and to the public’s respect for science and scientists.
After Harken’s mitral stenosis operations, four of his first six and six of his first 10 patients died. As he told the story, he became discouraged, went home, and told Mrs. Harken that he was through with cardiac surgery. Hearing of this, his medical collaborator, Laurence Ellis, visited Harken at home and convinced him to carry on. How right Ellis turned out to be! Of the next 15 patients operated upon for mitral stenosis, 14 lived. Soon the world of cardiology learned of this success, and matters developed rapidly, just as they had with the ductus operation. In 1964 Harken and Ellis reported a series of 1,571 such patients. In the group with medium-grade disability, the mortality was only 0.6%; in those most severely crippled, the operation was understandably more hazardous and was associated with a 17% mortality. Rehabilitation to normal living for patients with mitral stenosis had never been attainable before. Even the most conservative cardiologists who had cautiously withheld operation from their patients finally came to realize that by accepting this risk they might offer the possibility of a new life to many. One of the first cardiologists to demonstrate by physiologic measurement the drastic improvement in heart function in these patients was Lewis Dexter, who became another of Harken’s close collaborators.
Harken widened the valve as Souttar had, with his own index finger (able to feel and sense the valve anatomy) inside the heart. There was no cut made that removed tissue from the valves themselves.
Most of the patients with mitral stenosis were operated on at the Brigham, with Harken working as a member of our staff, teaching students and residents. Leroy Vandam was in charge of anesthesia. As mentioned above, I had asked Vandam, who had been at the University of Pennsylvania, to come and join our department in 1954. He picked up the anesthetic care of the cardiac surgical patients at that time and standardized their anesthesia with a minimum of risk, as he had likewise done for transplantation. Lewis Dexter ran the Cath Lab for study of these patients. Several of the Brigham cardiologists, including Samuel Levine, Bernard Lown, Richard Gorlin, and James Dalen, worked with Harken in this increasingly massive undertaking. With their support, medical conservatism gradually yielded to the seeming radicalism of surgical procedures for valvular disease—operations now accepted everywhere as routine and, once mitral stenosis is established, the sooner the better.
At our weekly staff meetings (described in Chapters 10 and 12) we discussed all deaths and complications. There were many deaths from mitral stenosis surgery to discuss in those early days (1948 to 1955). Sometimes the residents became restless and discouraged. They met with me privately to urge that we discontinue mitral surgery for a few months. Yet even the most skeptical of our students and residents were attentive as Dwight Harken, who was always frank, open, and self-critical in his account of each case, told what had happened and why, as well as how he hoped to improve the operation. It seemed clear to me that the results were improving rapidly and that case selection was one of the keys to mortality. We should never yield to the temptation to take on only the easy cases because they pose a lesser risk. Some of our early cases were the most neglected, high-risk ones. I later encountered a similar period of gloom among our younger staff during the early, dark days of transplantation, under immunosuppression. In both instances, we accepted plenty of the tough cases (especially at the beginning, when the “bad old” cases were still out there) as well as the easy ones. As time went on, more of the patients were those with a shorter, more recent illness and lower risk for operative fatality. Morbidity and mortality rates were discouraging at the beginning, but the gloom soon lifted with many brilliant successes and the certain knowledge that the failures were never buried in the record room or hidden in the pathology department. They were always analyzed and discussed openly by Harken and the residents. This openness led us rapidly out of the dark days.
The enigma of selecting patients for a dangerous new operation in lethal disease pertains both to new surgery and to new drugs that might be useful in desperate situations. It is tempting for the pioneer, in order to keep mortality low, to confine early trials to those patients at lowest risk (those who need the new treatment least). But always there is the pressure to offer the treatment mercifully to desperately ill patients who seek help and want the favor, the gift, of a try. They would rather die during the operation than go without trying. Harken operated in many of the most urgent and risky cases. That he succeeded as often as he did in those early days of developing the new concept of operating on the inside of the heart is a tribute not only to his skill but also to the steady improvement in all aspects of surgical care.
Soon the heart was to be opened much more safely. Before carrying that story further, we must catch up with the Gibbons in Philadelphia, as well as some remarkable surgical innovators in Minneapolis.
On May 6, 1953, John Gibbon repaired a congenital defect in the heart of an 18-year-old girl. This was an interatrial septal defect, a hole in the septum or membrane separating the two upper (low-pressure) chambers of the heart, the atria or auricles. Jack, with Maylie’s assistance, used a pump-oxygenator for the first time in a human being. With the help of this device—his new machine—he could open the heart and sew up the hole while the new device pumped and oxygenated all the blood and kept the patient alive. Once the heart was closed and resumed its beat, the machine could be disconnected. This was just 22 years after he sat at the MGH measuring the vital signs of that patient suffering from repeated pulmonary emboli.
Many of us who were friends of Jack Gibbon knew of his work in some detail and of his resolute pursuit of a single objective. Despite being subjected to a good deal of kidding about its impossibility, he persisted, from time to time publishing articles or speaking at meetings to relate his progress.
On one occasion our small travel club of surgeons was meeting in Philadelphia. One of the high points of the meeting was to be a visit to the Gibbons’ laboratory to see how the Great Machine was coming along. I remember the day well. We trooped in, 10 or 15 of us, and were asked to take off our shoes and put on rubber boots. This quaint custom is standard practice in most operating rooms in Great Britain, as if they were so accustomed to torrents of blood (as in eighteenth-century amputations) that they had never modernized their footwear as American surgeons had.
We were then ushered into the operating room of the Gibbons’ laboratory. At that time the pump-oxygenator was approximately the size of a grand piano. A small cat, asleep to one side, was the object of all this attention. The cat was connected to the machine by two transparent blood-filled plastic tubes, one deep dark red (venous, deoxygenated, go-
ing to the machine) and one bright pink (arterial, oxygenated, returning blood to the cat). The contrast in size between the small cat and the huge machine aroused considerable amusement among the audience. The bulk of the machine was not required for pumping but rather for adding oxygen to the cat’s blood and removing the carbon dioxide. As Gibbon had often described to his colleagues, this function of gas exchange had always presented the main difficulty.
Watching this complicated procedure, concentrating mostly on the cat, whose heart was about to be completely isolated from its circulation, opened, and then closed, we began to sense that we were not walking on a dry floor. We looked down. We were standing in an inch of blood.
“Oh... I’m sorry,” said Gibbon. “The confounded thing has sprung a leak again.”
There followed several noteworthy events. First, our small audience could not help but be impressed by such good humor in the face of embarrassment in front of a critical group of old friends. Second, Mrs. Gibbon, with characteristic presence of mind, quickly spliced the leaky tubing. And third, the experiment was successful in that the cat’s heart was isolated from its circulation, even if for only about 45 seconds while it was quickly opened and closed, and the animal recovered uneventfully. At that time the Gibbons’ objective was 30 minutes of successful machine perfusion with the heart open. Within another year or two, perfusions of such durations were to be achieved in human patients.
With the successful operation in May 1953 and a few more like it, Gibbon retired from the operative field of cardiac surgery. He modestly stated that he was not a heart surgeon. His main interest was in surgery of the lungs. He felt there were other men better prepared as cardiac specialists to pick up where he had left off. Among them was John Kirklin of the Mayo Clinic, one of the first to put the Gibbon machine to extensive use. His first successful operation was in March 1955. Four of his first eight patients survived. All were children with congenital heart disease who were terminally ill and about to die before he operated on them. Now they were made well.
Other surgeons concerned with this matter of isolating and opening the heart while pumping the blood around by some other means were also models of ingenuity and innovation. In 1950 William Bigelow of Toronto had reported cooling a patient to about 20ºC (hypothermia) so he could reduce the brain’s demand for oxygen and thus ensure its survival and incidentally the survival of kidney and liver (and in fact, the whole patient), even though he was opening the heart and stopping all function for several minutes. Henry Swan, our classmate at medical school, and later professor at the University of Colorado, was also using hypothermia when operating on children with heart defects. In 1952 F.J. Lewis of Minneapolis further improved methods for the use of hypothermia.
Meanwhile other Minneapolitans were studying the most spectacular and possibly the most imaginative of methods for patient support during repair of the heart. C. Walton Lillehei, Richard Varco, and their team developed a method by which the blood vessels of a sick child were temporarily connected to those of its parent to allow the parent’s heart and lungs to function as a pump-oxygenator for the sick child. By conducting blood from the child’s vein to the parent and then returning it from the parent back to the child’s arteries fully oxygenated, it was possible to isolate the child’s heart, open it up, and repair it. Their first successful case using this cross-circulation technique was in 1954. In all, they carried out 45 such operations, with a 63% survival. All the patients, mostly children, were desperately ill and dying. This was a heroic, difficult, and complicated procedure, involving risk to the well donor (the parent whose heart was doing the pumping). In 1955 Richard DeWall joined them and devised a new kind of bubble oxygenator that was soon used along with the Gibbon pump to replace the awkward, cumbersome, and risky cross-circulation method.
With the ability to open the heart safely came a new era of hope for blue babies and for adults in heart failure or with cardiac pain. Progress
this far, and surely no further, could not have come about without a way to achieve more accurate diagnosis from within the heart.
In 1929 Werner Forssman, a surgical intern planning a career in urology, bravely introduced a long, thin tube (otherwise known as a catheter and usually used to empty the urinary bladder) into one of his own large veins that lie in front of the elbow. He threaded the catheter up the vein and around the bend at his shoulder. He kept on pushing until he knew, based on the length that had disappeared into his vein, that the catheter must have gone down into his heart. So he walked down the hall to the x-ray department and asked them to take a picture. There it was. The tip of the catheter sitting in the right atrium. So much of science is so simple! At least, it always seems that way in retrospect. Maybe, as in this case, it is having the idea in the first place: a tribute to the complexity of the human mind.
By means of catheterization, in which the lowly catheter was applied to the heart (as opposed to that more humble organ to which it was accustomed), cardiac surgeons could be more certain of doing the right thing.
André Cournand and Dickinson Richards of New York took up this work of cardiac catheterization in about 1945, followed shortly by our own Lewis Dexter. When you take blood straight out of the chambers of the heart and measure its pressure, oxygenation, and carbon dioxide content, you can also use the catheter to inject a dye and measure the heart’s output of blood. You can inject fluid that shows up on the x-ray and see the pattern (anatomy) of blood flow. Within a short time it became possible to pass the catheter up an artery (rather than a vein) to take blood samples directly from the high-pressure (left) side of the heart and to examine the aorta, that huge, high-pressure conduit that conducts blood from the left heart to the rest of the body. In 1956 Cournand, Richards, and Forssman were awarded the Nobel Prize for this work. Ten years later it was by this procedure, used by Mason Sones of Cleveland, that coronary artery disease could be accurately seen and then repaired.
It is a source of consternation that Nobel recognition was never awarded to Gross, Gibbon, Harken, Lillehei, Blalock, Kirklin, Rob, DeBakey, or any other of our surgical colleagues who were pioneers in
making stunning discoveries in the care of cardiovascular disease. Somehow, it took transplantation to wake up the Nobel Committee to what had been going on in surgery.
Dwight Harken also experimented with ways of fixing the aortic valve, the high-pressure one-way valve at the output channel of the left ventricle. This required a stiffer valve, for which a ball valve seemed well suited. His work with ball valves was based on the prior success of a young Brigham surgical resident, Charles Hufnagel, in perfecting ball valves for placement in major arteries. Hufnagel did this work in the dog, that sacred laboratory animal most suitable for much of the research that has resulted in so many advances in surgery and helped relieve the suffering of so many people. When it came to the development of transplantation and cardiac surgery, surely the dog was man’s best friend. Thereby hangs the tale of a few wagging tails.
In the 1950s Charles Hufnagel was working to perfect a ball valve that could be used within the heart. To study these devices he placed them in the aorta in a large series of dogs in our laboratories at the Harvard Medical School. When he accepted a job as professor at Georgetown University, he asked me if he could take these dogs with him to Washington. Of course I agreed, because these dogs were extremely valuable, priceless. There were no others like them anywhere in the world. Also, they had become pets of the laboratory team. Their long-term followup over the course of years would be necessary to determine the extent of wear and tear on the ball valve.
So he loaded all his dogs into a small trailer to drive them from Boston to Washington. When he reached northeastern Connecticut, he needed to make a pit stop at a filling station. As Hufnagel disappeared into the rest room, the attendant heard a dog barking in the trailer and thought an animal probably wanted out to irrigate a local tree. So, thinking there might be one or two dogs inside, he opened the trailer door. About 25 dogs bounded out, barking and sniffing and wagging their tails delightedly. This is a part of Connecticut along the road about halfway between New York and Boston that is largely uninhabited, quite a wild
place for this canine diaspora. Yapping with joy at their release from the noisy trailer, the dogs disappeared into the hills of Connecticut.
This would have been a terrible loss to science and cardiology had it not been for the ingenuity of Hufnagel, the dismay of the filling station attendant, and the willingness of the local dogcatchers to cooperate in an unusual medical adventure. All the dog officers were given stethoscopes and were instructed to hold down any dog they caught, stray or otherwise, and listen to its chest. One of the dogs had returned to the trailer, and the dogcatchers were all given a chance to listen to what a ball valve sounded like, clicking back and forth in the chest with every heart beat. Unmistakable. If the dog clicked, keep it.
It wasn’t long (about a week) before all the dogs were rounded up from the forests of northeastern Connecticut and sent on their way to Hufnagel’s laboratory at Georgetown University. This work, these valves, and his study of these dogs in inventing a new device have given him a secure place in surgical history.
The tenacity of scientists in sticking with a problem until it is solved has often been described in this book. Prime examples were Hufnagel with his ball valves and the Gibbons spending 22 years to take the idea of a pump-oxygenator from theory to reality. But possibly the finest example of such tenacity is the work of Dwight Harken, who stayed with the problem of intracardiac surgery over the course of half a century, from his wartime work until his death in 1993. In his illustrious career, Harken also developed an artificial mitral valve as well as a way of correcting an abnormal heart rhythm by means of a new pacemaker that would take over only when the heart needed it (the demand pacemaker).
Dwight resigned from our department in 1969, the year of his 60th birthday, and was succeeded by his assistant, John J. Collins, a former Brigham resident. With a surgical team large in comparison with Harken’s one-man team back in 1948, Collins has operated upon a great many cardiac patients of all types, including transplants, and has achieved one of the lowest mortality rates in the country. As Harken’s successor, he has
mounted a remarkably successful program in cardiac surgery and transplantation.
All physicians, surgeons, and patients who are caught up in the web of heart disease owe a debt of gratitude to that hard-working Iowan. Dwight Harken died in Cambridge on August 27, 1993, as this chapter was being prepared. And now his son, Alden Harken, graduate of Western Reserve Medical School and of the Brigham surgical residency, carries on his father’s tradition of teaching and innovation in surgery as Professor and Head of the Department of Surgery at the University of Colorado in Denver.
Although formidable physiologic and medical problems are encountered in both cardiac surgery and transplantation, these two new fields would not have been brought to practical reality had it not been for the surgical laboratories in the universities of the United States. After the events of these past 50 years, surgical research need not apologize to the rest of biomedical science. Often frowned upon by those whose work is at the bench of basic science, American university laboratories of surgery (in both Canada and the United States) have brought that same quality of science from the bench to the operating room via the laboratory.
By any measure—most particularly the number of people cared for and the number of physicians and surgeons caring for them—cardiac surgery is the largest new field of surgery to have developed in the half century since World War II. As a result of their care by surgeons, thousands of people are relieved of cardiac pain, their lives sometimes prolonged; some patients with heart attacks (acute myocardial infarction) have lifesaving operations on the coronary arteries during the acute phase of that disease. Possibly most important and meaningful for society as a whole is the fact that many children, ranging from newborns to teens, can be given a whole new life now that the cardiac defects with which they were born can be repaired. The gain is in quantity of life for some and quality of life for all such patients.
Surgery of the heart is also the field in which surgeons have most clearly entered the previously sacred precincts of nonoperating physicians: the internist, the pediatrician, the cardiologist. The advent of cardiac surgery has given these physicians a new series of decisions to make and new avenues of hope for their patients. And even as some of the cardiac
From that first patient of mine who died after a breast operation in 1942 (Chapter 10), up to and after my retirement in 1981, I was concerned daily with cancer. General surgeons, the breed of which I was an example, are the people who take care of cancers of the breast, thyroid, stomach, colon, liver, and pancreas. The solid tumors. Cancer of the breast leads the list, being (along with lung cancer) one of the leading causes of death in American white women over the age of 50. Breast cancer is sensitive to many influences. It is a tumor that can often be cured if removed early, and one that continues to be the subject of intense research not only because of its prevalence, but also because of its responsiveness to chemical and hormonal changes. And yet, like most of the solid tumors, once it recurs after operation, cure is almost never achieved (“never say never”).
Starting in the 1960s breast cancer became the main subject of my clinical research. Despite repeated optimistic press announcements and alleged breakthroughs, it was continuously borne in on me that the solid tumors, such as those of the breast, represent the best examples of curability by early surgical removal but also our most dreadful failures once the tumors return. Then, in the 1980s, one of my former residents, Steven Rosenberg, began to achieve success with his lifelong ambition: the treatment of cancer by increasing the patient’s own powers of immunity suffi-
ciently to throw off, or reject, the tumor. This concept, that the body’s defense against a cancer could be enhanced by having the patient adopt some genetically strengthened immune cells (often the patient’s own cells, reinfused) is, in his terminology, adoptive immunotherapy.
It is the purpose of this chapter to tell the story of our years working to improve the care of cancer of the breast, limiting the extent of initial surgery; of the problems posed by advanced breast cancer and by other solid tumors; and of the new hope for cure of some solid tumors arising from Steve’s adoptive immunotherapy. But first, some definitions.
The word tumor literally means “swelling” and is indicated by the Latin suffix -oma (as in carcinoma, sarcoma, lymphoma). If, under the microscope, that swelling consists of rapidly duplicating cells, it is called a “neoplasm,” meaning “new tissue growth.” Some (but not all) neoplasms are malignant, which means they tend to spread to other organs and, if left to their own devices, will kill their host (the patient). Thus, all cancers are tumors, but not all tumors are cancers. The word “cancer” is derived from the Greek and Latin terms for crab, because of the crablike growth of some of these cancers, noted even by the most ancient physicians, the more precise term being “carcinoma” (crab-tumor). The crab is the astronomical symbol for the Tropic of Cancer. In this chapter we are using the broad term “solid tumor” to include a large but special group of cancers.
The group of solid tumors includes most of the familiar cancers. They have several characteristics in common. For one thing, they start as small cellular growths—lumps—localized to one microscopic place. The malignant process often seems to start in a single cell or in two or three neighboring cells probably subjected to the same influences and possibly communicating with each other chemically. As the solid tumors grow in size, some cells (the malignant tumor cells) begin to migrate elsewhere (metastasize), where they form additional solid masses of tumor that may be as tiny as half a pinhead or as big as an orange. Most cancer cures today are achieved by total surgical removal of very early solid tumors. Most
solid tumors are amenable to early surgical removal. Thus the solid tumors are the surgical tumors.
Four of the commonest cancers in the United States are solid tumors: cancers of the lung, breast, large intestine (colon), and skin. The group of solid tumors also includes cancer of prostate, uterus, pancreas, ovary, testicle, kidney, liver, thyroid, esophagus, stomach, tongue, and bone. If the cancer originates in the liver, it is considered a primary (rather than metastatic) solid tumor of the liver (hepatoma). Cancer of the skin may be of the skin-colored type, usually a hollowed-out ulcer (squamous cell carcinoma, caused in some cases by exposure to the ultraviolet rays of the sun), or it may be a jet-black mole-like tumor (malignant melanoma). Basal cell skin cancer (also related to sun exposure) is generally a harmless small lump. A biopsy, or removal with microscopic examination, is essential for differentiating these three very different types of skin cancers. Most brain tumors are also classified as solid tumors.
By contrast, there are the nonsolid tumors. These affect the blood and lymphatic systems and bone marrow and include the leukemias (cancer of the leukocytes or white cells), lymphomas (arising in the lymph nodes or lymphocytes), and some rare cancers of the bone marrow elements. Although these tumors are not usually amenable to early surgical removal, many are sensitive to radiation and to chemotherapy (treatment with drugs and chemicals). In fact, some of the best results of radiation and chemotherapy are achieved in these tumors.
Since World War II, an international effort has been devoted to improving the dismal outlook of patients with advanced solid tumors: those in whom, after that first hopeful removal, the tumor has returned or metastasized. Our failure here has always been the bad news.
The good news is that coming over the horizon during the past decade is an entirely new form of treatment based on stimulation of the patients’ own lymphocytes (immune cells) to improve their immune capability. These cells have been stimulated to multiply and to reject advanced cancer, wherever it is, completely and permanently. While only a start, and still imperfect, this approach is so drastically different from our old ways and has so clearly demonstrated encouraging results in a few patients that it must be included as a part of any story of cancer surgery in the last half of the twentieth century.
During this half century, there have been persistent efforts to expand the scope of the initial surgical removal of the original tumor by extending the primary operation and removing more nearby lymph nodes and even normal tissues on the grounds that they might contain cancer cells.
In Latin, the word radix means root. A radish is a root. Things that dig at the roots are radical. A radical operation attempts to dig out and remove all the tumor at its very roots. To save something is to conserve it. Conservative operations conserve or spare more of the patient’s normal tissue. These clinical meanings are important, particularly as they stand in contrast to the usual political or social meanings of these words. In medical discussions we should stick with the medical meanings. Thus, radical is not always new or destructive and conservative is not always old and safe.
Around the turn of this century, advances in surgery, especially the increased use of blood transfusions, made it possible to develop more radical operations for early cancers. In the case of breast cancer, the prototype was radical mastectomy, developed by William S. Halsted at Johns Hopkins around 1890. Similar extensions of surgery were developed in other countries and for other cancers. For breast and other types of cancer (colon, prostate, and uterus all being examples), the more radical operation was at first a great improvement over the crude efforts to remove cancers by conservative limited excision, which often led to disastrous spread. In the world of 75 to 100 years ago, radical operations were a breakthrough, curing patients who previously had no hope of cure. Although we are moving away from them now, let us give them credit for the very real improvement they conferred over what went before.
Then, near the time of World War II, there occurred two simultaneous but divergent departures from the accepted surgical approaches of the time: one further to extend and the other drastically to constrain the removal of early solid tumors. Not only have many surgeons of our generation participated in these changing surgical modes and methods, but we have also been keenly aware of the public accounts of these changes as reported in papers and magazines and on television. I cannot blame the
public for being totally confused. It sounds almost as though one surgeon or one medical school was advocating a new procedure on the basis of local pride or prestige, staking out turf, while others found fault. In point of fact these more radical departures were always undertaken for a specific reason, to be justified by increased survival of patients having such operations, on the basis of 5-, 10-, or 20-year followup and as contrasted with other procedures. At their worst, these conflicts over how much to undertake at the first operation have been a war of words and a battle of personalities; at their best, they are a war of numbers, a vast battlefield of statistics. And if we are talking about 5-year survivals, do not forget that it will always take at least 5 years—and more realistically, 8 or 10 years—to gather such data for a large number of patients. Attempts to extend the radical operation for breast cancer were undertaken, particularly by Jerome Urban in New York and Owen Wangensteen in Minnesota.
At that same time (approximately 1945 to 1960), other surgeons began a move in the opposite direction, advocating only limited removal of small, highly localized, early and favorable (i.e., not aggressive) tumors. Those interested in this more conservative approach pointed out that if the tumor is found to be local, well defined, and unlikely to recur, local surgery should suffice and nothing further needs to be done. In such cases radical mastectomy is an unnecessarily extensive operation. I was of this school. On the presumption that some tumor cells were likely to be left behind, we often combined restricted local removal with radiation therapy, as did McWhirter of Scotland, one of the earliest and most vocal advocates of surgical restraint immediately after World War II.
Curiously, advocates on both sides of this controversy agreed that less is better if the tumor is local, not aggressive, and noninvasive. A big if. Starting about 1960—a little later than many, but sooner than most— I abandoned radical mastectomy save in a few special instances, as mentioned above. I favored using the simple mastectomy, in which the breast alone is removed and the lymph nodes under the arm are sampled to see whether or not radiotherapy or chemotherapy should be given. The woman no longer has a breast. But she has a better likelihood of 5-year survival than if the lump alone is removed. Many patients of mine who were in their middle 40s or 50s, who had borne and nursed their children, and whose husbands did not require the cosmetic/erotic symbolism of an
intact breast, said to me, “Dr. Moore, take off my breast if it is necessary. What I want is to be alive to see my teenage children graduate from college.” Besides removing the local tumor, we removed some lymph nodes to examine them under the microscope and find out whether or not the tumor was truly local, favorable, and noninvasive. A vocal feminist claque grew up around this problem, loudly proclaiming any removal of the breast to be brutal and unnecessary mutilation. Few patients agreed with such a polarized view.
One is left with a clear sensation of forward movement away from the automatic, unthinking application of the Halsted radical mastectomy. And a reaffirmation of the faith that patients should seek a doctor whose honesty and experience they trust, one who will not pressure patients into doing his (or her) own thing. If the doctor is a radiotherapist, for example, we hope the opinion of a surgeon will be sought, and vice versa. If a team exists in the modern configuration of a tumor clinic, all voices must be heard.
Once the first deed is done—that is, the primary treatment (usually surgery, often with radiation and sometimes with chemotherapy) is complete—and all known or visible disease has been removed or treated, the patient enters the free interval. “Cure” means that the free interval will last 5 or 10 years or for the rest of the patient’s life. In essence, cure means that the patient will die of something other than cancer.
If the free interval comes to an end much too soon, after a month or even a decade, because the tumor has returned either at the same place (local recurrence) or elsewhere (metastases), we then encounter nature’s obstacle, a wilderness of the unknown. It is important to realize that biomedical science deals with such a wilderness at every frontier. In recurrent cancer this is a wilderness with many points of entry but no clear trail to the clearing on the far side. The stark reality is that almost all patients who enter this wilderness with advanced disease will die. We are unable to guide them through.
Here is where our own efforts in breast cancer were expended most intensively over a period of almost 30 years. Certain hormones
stimulate the growth of breast cancer. Removal of the glands secreting those hormones was often helpful. We carried out many total adrenalectomies to remove one source of the stimulating estrogen or female hormone. Working with Donald Matson, we removed the pituitary (hypophysectomy) to eliminate all endocrine influences. We used cortisone in conjunction with chemotherapy, employing various types of drugs and chemical substances. Some of our most successful cases were those in which the ovaries and then the adrenals were removed and, even before the patient came out of anesthesia, high-dose chemotherapy was started. Surprisingly, a few of those patients are still alive and well after 20 years. In these trials we were working with new combinations of old methods and trying with some success to give our patients a few good months or years.
Maybe the most important thing I did during these years was to encourage wide collaboration within our hospital. We never instituted treatment of advanced or recurrent cancer without seeking the opinion of those who had skill and experience in other forms of treatment: radiation, drugs, or hormones.
It was against this background of frustration with the ineffective treatment of advanced cancer that we hailed the first reports by Steven Rosenberg of his use of genetic manipulation to treat late cancer as a ray of hope.
In 1962 Crick, Watson, and Wilkins were awarded the Nobel Prize for discovering the precise arrangement whereby an array of chemical substances—nucleic acids, the genetic material—is transmitted with exact accuracy from parent to offspring. They had done this work about 10 years previously. Those precise sequences were shown to encode the choice of amino acids for protein synthesis on minuscule assembly machines (ribosomes) in each cell. These molecular sequences, programming the synthesis of proteins, exist in large molecules of deoxyribonucleic acid, or DNA. DNA contains all the genes of the person, and the gene-encoded control of protein synthesis governs the character of everything of which we are composed, from the most subtle enzyme reactions
to the color of our eyes and hair, the shape of our heads, and the way we walk, talk, and think. And why we resemble our parents. Discovery of the genetic code and its mode of transmission changed all of biology, and now—long predicted and hopefully anticipated—it is finally bringing new hope in the treatment of cancer.
In 1985 Rosenberg reported some of his first results with the application of genetics in the treatment of cancer using the patients’ own lymphocytes and compounds made by genetically engineered bacteria. For the first time in history, doctors heard reports of patients who had been near death with recurrent masses of a solid tumor but who were now alive and well, no visible tumor anywhere, after their own lymphocytes were stimulated to become better tumor killers and then given back to the patient.
The principle he set forth was to borrow some of the patient’s lymphocytes, identify those particularly prone to kill cancer cells, grow them rapidly outside the patient’s body by using a cell stimulant called interleukin-2 (IL-2), and then inject them back into the patient, maintaining their growth stimulus with more IL-2. He had been working with certain very recalcitrant solid tumors, especially malignant melanoma and cancer of the kidney. Some of the early results were encouraging. A few were spectacular.
Crick and his coworkers were neither the first nor the last to win the Nobel Prize for elucidating the chemical compounds within the cell that pass along genetic traits to offspring. And Rosenberg was not the first—and surely will not be the last—to treat cancer by changing the patient’s immunity, an idea that goes back many decades. Other attempts to alter the patient’s immunity in cancer have involved some immunologic stimulus, such as the toxins used by Bradley Coley in the 1920s, the tubercle bacillus, or another bacterium called Corynebacterium parvum. Contrasted with these efforts, Rosenberg’s work is unique because it involves, not a toxin, but rather the patient’s own immune cells. After the cells were reintroduced, there was a remarkably favorable response in many patients. About 10% were completely rid of their cancer, some maintaining this tumor-free status after treatment was stopped. Rosenberg was the first to bring such a method to reality.
Steven Rosenberg was born in New York City in 1940. After
attending the Bronx High School of Science, he graduated from college at Johns Hopkins in Baltimore and completed medical school there in 1963. He then began a surgical internship in our department at the Brigham. Three years into his clinical work he took time off to do postgraduate study for the Ph.D. degree in biophysics at Harvard. Between 1968 and 1974 Steve completed his senior and chief residency in surgery at the Brigham and the West Roxbury Veterans Administration Hospital. Again he took time out for a year of study with John David at the Harvard Medical School in the field of molecular immunology, which focuses on the chemical weapons that immune cells use to kill invading cancer cells. He then spent 2 years in postgraduate study of immunology at the National Institutes of Health (NIH). There has always been a joke over the fact that surgical residencies at the Johns Hopkins seem to last longer than they do at the Harvard hospitals. Steve’s residency in our department, lasting almost 11 years, probably set some sort of record. Steve says, “It took that long for Dr. Moore to approve me as a surgeon.” Since he was, from the start, clearly an able operative and clinical surgeon, his comment refers modestly to the fact that he took time off during his residency years to earn his doctorate and to become an expert in protein structure and immunology.
Upon completing his surgical residency at the Brigham, Steve was made Chief of Surgery at the National Cancer Institute (NCI) as well as Professor of Surgery at both the Uniformed Services University and George Washington University.
In 1978 Steve Rosenberg began to study the production of a growth factor for T lymphocytes. This substance was later identified as a lymphokine (or lymph-cell stimulator) known as IL-2, mentioned above. Genetic modification of a bacterium was used to synthesize this human-type cell stimulator in large amounts—an early example of genetic engineering. He then showed that mouse lymphocytes multiplied a thousand-fold or more when grown in a tissue culture along with IL-2. Thus stimulated, some of those cells attacked fresh tumor cells, and he called these “lymphokine-activated killer” (LAK) cells. After several years of
experimentation in animals, he was ready to introduce LAK cells in the treatment of human cancer.
The story of one of his early successes tells the tale better than I could. This story appears in Steve’s recent book about his research, The Transformed Cell. I am indebted to him for permitting me to retell this story here and for contributing additional details.
Lieutenant L.G. first came under Rosenberg’s care at the NIH in 1983 at the age of 33. A naval officer doing many energetic and challenging jobs usually carried out by men, she was a doer, an achiever, a matter-of-fact person accustomed to accomplishment, with a considerable personal investment of skill and effort. As we shall see, these habits of work and lifestyle explain, at least in part, her tenacity in weathering the prolonged, uncomfortable, and stressful treatment that lay ahead.
A few years before L.G. came to Rosenberg, a black skin mole behind her right shoulder had started to look different and become more active. When there is a change in the way a black mole feels or appears or if it develops a red border, the person should consult a doctor without delay. Being a naval officer, she was taken care of at the Bethesda Naval Hospital. Biopsy revealed a malignant melanoma (the dangerous black cancer of the skin). While the lymph nodes draining the area appeared normal under the microscope, the melanoma was thick and invasive. Melanoma is one of the tumors where, under the microscope, one can make a pretty good guess as to whether it is a rather harmless tumor or a dangerous one. This one was the dangerous kind. After removal of the melanoma she entered her disease-free interval, full of hope and confidence.
Early in 1983 she was transferred to a position in Guam as lieutenant commander and flag secretary, working with the admiral’s staff. Within a few weeks she began to notice some hard lumps under her skin. The Navy doctor biopsied one of these and discovered that it was the same malignant melanoma. Her disease had returned and metastasized. As we have seen in breast cancer, so also in melanoma, this occurrence has always spelled the beginning of the end.
Like so many patients in this ominous fix, she was willing to try anything reasonably likely to ensure her survival. She underwent some experimental clinical treatments at several naval hospitals, but without
success. One of her physicians mentioned Steve’s beginning work at the NIH, so she went to Bethesda to explore this possibility. On her arrival she was found to have many round lumps of tumor in her lungs and hundreds of lumps under her skin. Her sense of participation and determination to get the job done was expressed in her main fear (as she described it) on entering this complicated new treatment: that she might not measure up to the doctor’s expectations.
She began her new treatment under Steve’s care in November 1984. To begin with, some blood was drawn, the lymphocytes were separated, and killer cells were isolated and stimulated to grow by using the genetically engineered IL-2. On November 29, 3.4 billion killer cells grown from her own lymphocytes were infused back into her bloodstream. This treatment made her ill, an illness made worse by repeated infusion of more IL-2 used to stimulate the LAK cells even further. Although IL-2 alone is toxic and makes patients sick, its bad effects usually wear off completely.
This intensive cycle of treatment continued for 6 days, at which time the dose of IL-2 was further increased. Now Lt. L.G. became extremely ill with nausea, vomiting, and muscle weakness. Despite this, she wanted to go ahead, to continue with the treatment to stimulate the killer cells. On December 10 she received a seventh infusion of her own lymphoid cells and two more doses of IL-2.
Despite her resulting illness and some worrisome signs, and with her full approval, Rosenberg and his team persisted. While she seemed to be tolerating the treatment a little bit better, she had a severe crisis a few days later. She was not breathing adequately. Her life was clearly threatened by the treatment itself. She developed pulmonary edema (water accumulating in her lungs) and appeared to be on the brink of total respiratory arrest. As an emergency procedure, she was intubated, oxygen was administered with assisted respiration, and she was given drugs to hasten excretion of water and salt, which helped to unload all that excess fluid. Not only had she been through a severe crisis resulting from an absolutely maximum push of IL-2/LAK treatment, but in fact she had received more IL-2 and killer cells than had any other patient up to that time.
As she climbed out of this crisis, she showed emotional scars from
her terrifying experience. At first, her tumors showed no change. But there was one hopeful sign. The day she was returned to her regular ward from the intensive care unit, biopsy of the tumor showed focal necrosis of tumor cells under the microscope, a pathologist’s term meaning that some of these cells were dying. In due course she was discharged from the hospital, her status insecure, and her outcome uncertain.
About 2 weeks later, she came back for her first follow-up appointment. She was feeling much better. Maybe this was the best sign of all. Another biopsy was done and the pathologist now saw “the appearance...of tumor cell ghosts consistent with [the] previously diagnosed malignant melanoma.... Lymphocytes were seen.... No viable (i.e., living) tumor is identified.” As you might guess, cell ghosts are the shadowy remnants of dead cells as seen under the microscope. While this was a remarkable phenomenon and one rarely seen before in such widespread malignant melanoma, there were some worrisome developments. In some of the metastatic areas of tumor spread (especially her lungs), the tumors were not getting smaller. This was puzzling and discouraging. With such a new treatment, no one could predict what lay ahead.
A month later (March 20, 1985) the patient returned again for follow-up and immediately told Steve, “My tumors are going away!” Many of the tumors she could feel under her skin were shrinking and disappearing. Again there was a biopsy. All the tumor cells were dead. Before treatment, x-rays had shown a great many tumors; now there was none visible anywhere or discernible by x-ray, CAT scan, or MRI. Her cancer had completely disappeared. Here was the dream of every cancer patient, every family, every cancer researcher for the past century, coming true.
Typical of her indomitable spirit, she was now applying for return to active duty in the Navy. Since none of the navy physicians had ever seen a patient who was dying of malignant melanoma get well and go back to work, she had a bit of trouble with her petition. In fact, it required action from the Secretary of the Navy, who promoted her to Commander.
Without going into some of the exciting details of the later career of this naval officer, so devoted to her national service responsibilities, I will add that L.G. has remained well and completely free of tumor. Seven
years after her treatment (at about the time Rosenberg was writing his book about this work) and when he was helping me describe her case here, she was perfectly well. She has remained well now for 9 years.
How could anyone fail to see a bright light of hope in the gloom of the cancer problem in such a patient as this and the many others like her in Rosenberg’s studies at the NCI. “One swallow does not a summer make” and one case does not make a series. But there have been many instances in these 50 years when one case made a splash whose ripple spread very far: Gross’ first ductus closure, Harken’s first mitral valve repair, Murray’s first kidney transplant, and now one of Rosenberg’s first IL-2/LAK patients.
Not all Steve’s patients do this well. About 35% show tumor shrinkage, 10% show complete disappearance of tumor, and 5% remain free of tumor after treatment is stopped. That is why he and the many others who are following his lead are trying to improve this approach to immune treatment.
Favorable responses to the treatment of late cancer have been gauged by reductions in the size of the tumors, in symptoms, or in the adverse physiologic effects of the tumor. The frequency of this response is then expressed as a rate or percentage of treated patients who respond. In considering positive responses to adoptive immunotherapy such as those of Lt. L.G., we are encountering an entirely new phenomenon: an early response that is not a mere shrinkage indicating borderline, arguable improvement, but one that involves complete destruction and disappearance of the tumor. While the statistical cure rate is still low, it is significant that such responses occur at all.
Because of the work of Rosenberg and others involved in genetic manipulation, the treatment of advanced cancer has taken a new shape and will never be the same again. These patients and this work have demonstrated a new way out of the wilderness. The detailed procedures in use at this moment are surely not the best, the safest, nor the last word. Progress thrives on constant change. Malignant melanoma and cancer of the kidney have been the most responsive to adoptive immunotherapy; trials have now begun in cancers of the breast, bowel, and lung.
We owe a debt not only to Steven Rosenberg, but also to French Anderson, Vincent DeVita (recently director of the NCI), and their many
collaborators. They are a part of our national scientific establishment at the NIH, supported by a nation of taxpayers. If ever there was a national effort, this is it. Many other cancer centers both here and abroad have taken up Steve’s work, sometimes modifying it in an effort to improve the results.
Who will be helped? Only a few of us in the older generation. Many of our children. Some sort of immune treatment will be a commonplace for our grandchildren’s generation as they reach the cancer age. Were they to develop advanced cancer from one of the common solid tumors, they will enjoy the option of immunotherapy based on genetic engineering, a new and more hopeful treatment that might return them to a normal life.