Cancerland

by David Scadden

  The devilish thing about chemotherapy was that the cure rate was often improved by giving more of the drugs. This meant that even as they recognized the misery they were causing, doctors felt enormous pressure to give more of the drugs as soon as they felt a patient was recovered enough to stand it. In some ways, a physician would demonstrate his or her courage and commitment by giving more medicine than another might give. In order to be seen as good or admirable, patients were then encouraged to endure as much suffering as they could. Thus, a strange kind of challenge would arise as physicians sought to give as much chemo as possible and patients who were desperate for a cure, and to be seen as both good and courageous, accepted extraordinary amounts of suffering.

  I saw many families debate how much a patient could stand, arguing about chemotherapy among themselves and with doctors. Often, when a spouse or parent begged for the treatment to stop, he would be overruled by the frail and exhausted patient, who was both afraid of dying and afraid of letting down the people he loved. Giving up was unacceptable to him, even if he spent much of the time he gained from the therapy feeling sick, weak, and half-alive. No one failed to recognize that chemotherapy had much in common with bloodletting, trepanation (drilling holes in the skull), and other “therapies” that were inflicted upon patients before medicine recognized they were useless. The difference was that chemotherapy had shown itself to help some people live longer and actually cured some cancers.

  In the late 1970s, when I became involved in caring for patients, traditional chemotherapy was still on the upstroke of optimism for cancers broadly. The most strident advocates of aggressive treatment agreed with scientist and physician E. Donnall “Don” Thomas, who was quoted as saying, “Sometimes you have to burn down the barn to get rid of the rats.”

  A Texan who was educated at Harvard Medical School in the 1940s, Thomas was the son of a country doctor who had arrived on the frontier in a covered wagon. His first studies were done in a lab established for him in Boston by the chemotherapy pioneer Sidney Farber. In the mid-1950s, he went to work at a small hospital in Cooperstown, New York, where the inclement weather kept him inside working at his experiments.

  As Thomas recognized, those who would burn down the house faced the inevitable challenge of rebuilding. In the case of cancer treatment, rebuilding the body depended on rescuing the bone marrow, which produces all the blood and immune cells: red cells for delivering oxygen, platelets for blood clotting, monocytes and neutrophils for clearing up debris and bacterial and fungal invaders, and T and B lymphocytes that more specifically respond to and kill pathogens either directly or through antibody production. Bone marrow is the mother source of all these cells and depends on stem cells to replenish them. When the bone marrow is destroyed, life is nasty, brutish, and short, with death from infection or bleeding occurring in a matter of weeks.

  Although the science was still in its infancy, by the mid-1950s, it was known that infusions of bone marrow cells could “rescue” the immune systems of mice that had been blasted with so much radiation that all their bone marrow was destroyed. The experiment that produced this evidence was devised by R. T. Prehn and Joan M. Main, who worked at a public health hospital in Seattle. They destroyed the immune systems in mice, revived them with infusions of marrow cells, and then tested their immune function by grafting on a piece of skin from the marrow donor. The grafts took, proving that their tiny patients had received, along with marrow cells, the immune functions of the donor mice.

  Thomas’s early work was funded by the federal Atomic Energy Commission, which oversaw America’s nuclear power stations, atomic research, and nuclear weapons production at places like the Hanford Reservation in Washington State and the Oak Ridge National Laboratory in Tennessee. In these places and others, extremely dangerous materials produced in nuclear reactors were processed to create weapons-grade plutonium and isotopes for both medical treatments and research. AEC officials worried about workers who might be exposed in accidents and die from the destruction of their marrow.

  When doctors and researchers tried to imagine how to treat victims of massive radiation exposure whose bone marrow would be destroyed, they kept circling back to the idea of using healthy marrow cells to replenish the body. However, when this was tried with human beings, they were defeated by incompatibility of the immune systems. Either the recipient’s residual immune system would attack and kill the donor cells or a more common phenomenon called graft versus host disease (GvHD) would occur, where the immune cells in the donated bone marrow would recognize the host as foreign and attack it. However, it was theoretically possible that marrow that closely matched the recipient’s would not develop this reaction. In 1957, Thomas removed healthy marrow cells from one identical twin and infused it in another to treat leukemia.

  Thomas’s bone marrow research was done against the backdrop of a fierce debate among those who considered chemotherapy and radiation pathways to cures and those who did not. Oncologists who used these methods had to act with an almost ruthless attitude and sometimes pushed patients beyond what they could endure. Treatments would seem to succeed, but patients died of side effects. Critics questioned the morality of offering people with weeks or months to live such intense treatment, even with the aid of bone marrow transplants. But gradually, immunologic research permitted the screening of blood donors to find matches for cancer patients in need of marrow. A big breakthrough in this area came with the discovery, in 1958, of a human leukocyte antigen (HLA) system, which identifies foreign cells that do not belong to the body. (Much of the credit for this work goes to French immunologist Jean Dassaett, who began this work in the hematology lab at Boston Children’s Hospital.) Driven by a complex of genes, the system tends to be similar in siblings. This is why Thomas’s twin-to-twin transplant worked.

  As often happens in science and medicine, Thomas couldn’t be fully aware of the process he was manipulating. Better understanding would depend on others who would identify the many varieties of cells in the marrow and their functions. Included were stem cells in the red matter of the bones, which produce blood lymphatic cells, including those that fight infection. The idea of blood stem cells had been established at least as far back as 1908, when Artur Pappenheim provided his “unified theory of hematopoiesis” (hematopoiesis is the production of blood cells). However, in 1961, Canadians Ernest McCulloch and James Till first experimentally defined that such cells—stem cells—existed. Their work was a major breakthrough and paved the way for the whole field of stem cell biology.

  Till and McCulloch were working in the context of the Cold War, a time when the horrors of nuclear weapons were known and countries were desperate to find ways to protect their citizens. It had long been known that the body can replenish lost blood, which is the main reason many ancient peoples developed the notion that blood is the body’s life force. Genghis Khan’s warriors were reputed to have multiple horses each so that they could bleed a horse they had just ridden for food and count on the horse replenishing its blood by foraging. This is said to have allowed them to cross the great steppes of Asia, where food for humans was scarce but abundant grasslands fed the horses. What was witnessed in World War II was that people could replenish their blood even after having their bone marrow largely destroyed by exposure to radiation. Some of those exposed to the explosions in Hiroshima and Nagasaki who had profoundly low blood counts and bone marrows that were largely devoid of cells recovered and did so robustly, achieving normal blood counts. That provided at least circumstantial evidence that there might be blood stem cells that could replete the blood. Countries like the United States, Canada, the United Kingdom, and Russia pushed to research the possibilities of stem cells as a radiation antidote. They fostered interactions between biologists like McCulloch, a physician, and physicists like Till.

  Till and McCulloch used mice as test subjects, using one group to stand in for victims of atomic bomb radiation and another for marrow donation. The experiment worked, showing the cells draw
n from marrow could be given intravenously and start to make blood sufficiently to allow an otherwise lethally irradiated animal to survive. When their study revealed nodules on mouse spleens, they dissected them to find colonies of donor stem cells, which they found were capable of producing a variety of different blood cells and renewing themselves, as transplanting another irradiated mouse made evident. These two traits—self-renewal and the ability to create different types of cells—were the cardinal attributes of stem cells. Till and McCulloch had shown that they indeed did exist and had profound abilities in rescuing animals from lethal radiation injury.

  The kind of basic science done by McCulloch and Till informed the experiments in treatment carried out by Don Thomas. After moving to the Fred Hutchinson Cancer Research Center in Seattle, Thomas built a thriving lab and tried to tease apart the relationship between cancer and the immune system. He would later describe the effort he made as a matter of having “one out of thirty patients who lived [for] a year.” Others considered the twenty-nine who did not survive and judged the work a failure. Thomas thought of the fact that all thirty were expected to die of their cancer in a matter of weeks and decided that one living was “highly significant.” He lived the maxim that statistics were just a tool and “if you throw a hundred balls in the air and only ninety-nine come down, it might not be statistically significant, but it is damned interesting.”

  Working with his wife, Dottie, a college sweetheart whom he’d met when she hit him with a snowball, Thomas pursued bone marrow transplantation with a single-mindedness that bordered on obsession. Many, if not most, successful pioneers in science are able to muster this kind of determination, even in the face of repeated failures. The big problem for the individual, however, is that more often than not, the very big payoff never comes. A few colleagues may understand what you are doing and support your pursuit, but with each disappointment, self-doubt grows. The feeling is surely similar to that of an artist who completes one canvas after another without selling a single one. When the rewards are so elusive, how do you know whether you are engaged in something meaningful or caught up in folly?

  Medical history is replete with stories of scientists who pursue an idea, sometimes for their entire lives, without definitive results. One of the greatest involved a young New York surgeon named William Coley, who entered practice in 1885 and was shaken by the death of his very first patient. The patient succumbed to bone cancer metastases even after Coley thought he had removed all her cancer by amputating her hand and much of her arm. As you might imagine, the operation was traumatic for the patient and, to some degree, for the doctor. The outcome tormented Coley, who began exploring hospital files on similar cases. He eventually came upon a report about a man with recurring bone cancer on his face who, after three surgeries, developed a raging streptococcus infection. After each fever spike, his remaining tumors shrank until they disappeared. Seven years after the man was discharged from the hospital, Coley found him in Manhattan’s Lower East Side, where he was in excellent health. The only evidence of his illness was a large scar, which was the way Dr. Coley had identified him.

  With more case studies, Coley came to believe that postoperative infections actually improved outcomes for cancer patients, and he theorized that the body’s natural immune response helped rid the body of cancer. He tested his theory, which might also explain cases of spontaneous remission previously categorized as miracles, by trying to induce strep infections in people he operated on. The results included some responses and some deaths. Coley tried to make the process safer by using various dead bacteria that were eventually called Coley’s toxins, and which caused fever but no deaths. The treatment was dismissed by many of his peers, some of whom called it quackery. However, others began to use infectious agents to treat diseases with some success. In 1927, Julius Wagner-Jauregg was awarded a Nobel Prize for using malaria to enlist fever to cure syphilis. Coley soldiered on with his research, and his treatment worked often enough to remain available to doctors who wanted to try it. However, when he died in 1936, his hypothesis was still unproven conjecture.

  In the decades after Coley’s death, great strides were made toward understanding the immune system, which defends us from the staggeringly plentiful microbes that surround us. Resident in and on us is a microbe burden that is thought to exceed the number of cells we have in our body tenfold. So every moment of life beyond the womb entails ongoing immune system combat with viruses, bacteria, and fungi that unchecked can readily overwhelm us. At risk of carrying the war analogy too far, the immune system maintains communications, develops weapons, identifies enemies, and moves against them with a variety of cells and proteins. This immune system also clears the cells lost by attrition and handles most of those abnormal enough to possess malignant potential. The whole thing is stunningly complex and filled with remarkable cell characters. Macrophage cells, for example, will devour and break down a hundred bacteria apiece. If they can’t do the job of defeating an infection, they literally call for backup by emitting a protein that summons neutrophils, which are so fierce they are programmed to die within one to five days to prevent collateral damage to healthy cells. The process of threat assessment and communication can also enlist T cells and B cells in the campaign. When the conflict is over, memory and B cells retain information about the invader, which makes it possible for the body to repel future infections, generally without any signs of illness. This is immunity.

  Awesomely powerful, adaptive, and effective, the immune system is so exquisite that it makes our intervention on the body’s behalf, even with a complex of therapies, crude in comparison. It is so essential to survival that scientists like Don Thomas could only consider wiping it out if they were reasonably certain they could restore it. If Thomas experienced real doubts of his eventual success, he never voiced them to the men and women who worked in his lab. When they were asked about their boss, they described him as a man on a mission who responded to failure by saying, “Let’s try again.” Near the end of his life, a researcher named Beverly Torok-Storb said she once asked colleagues if they could share a funny anecdote about the man. No one could. “There are no funny stories about Don,” she said. “None. He had a mission. There was nothing funny about it.”

  Although Thomas was remarkably even tempered, he was surely affected by the deaths he attended. Yes, the patients he treated were already desperately ill because of their disease, and no one promised anyone that that intense treatment followed by a transplant would work. But when the course ended with death, no amount of admiration for patients’ courage erased their suffering or the grief of their loved ones. Thomas mourned the deaths but drew motivation from his successes. “Evidently it could be done,” he would eventually recall. “We just have to find out how.” The “how” would come to include refined techniques for harvesting, processing, preserving, and transplanting blood stem cells, as well as elaborate systems to safeguard patients from infection.

  By 1979, the Fred Hutchinson Cancer Research Center was ready for a ten-year-old leukemia patient named Laura Graves, who traveled from her home in Colorado to Seattle to be treated. Although she did not have a sibling match for her marrow, the cancer center maintained a registry of staff blood donors, which included information on bone marrow compatibility. For the first time, a match was found in a registry. Laura Graves underwent an intense regimen of chemotherapy that destroyed her immune system. She then received the marrow harvested by needle from the donor’s pelvis.

  Laura recovered in a special room where caregivers were experienced with preventing infections. With their immune systems devastated, transplant recipients were so vulnerable to infection that they could die from microbes that are otherwise harmless. In one tragic case that illustrated the danger of infection, eleven transplant recipients would die at Roswell Park Cancer Institute in Buffalo when the delivery of air filters was delayed and an airborne fungus caused infections. Laura was protected in a hyperclean environment where she received medicines
to stop infections as well as transfusions of blood and platelets. Laura recovered and left the hospital in good health with a functioning immune system. The cancer eventually returned and took Laura’s life, but the successful transplant signaled the value of registries and procedures using unrelated donors and recipients.

  The team at the Fred Hutchinson Cancer Research Center wasn’t the only one working on the use of intense chemotherapy and rescue of the immune system with bone marrow transplants. Progress made by teams around the country contributed to the advances, as did the development of drugs that reduced the risk of GvHD. Further research on the harvesting and freezing of patients’ own marrow, after the patients were treated into disease remission with anticancer drugs, would eventually make it possible for many more people to receive their own preserved marrow in autologous transplants. Their own stem cells were saved at a time when they were in a tenuous and inevitably short remission. Those cells could serve to bring back their immunity after the intense therapy that was strong enough to kill the patients and their cancer were it not for the stem cell “rescue.”