Cancerland

by David Scadden

  Aging and cancer were linked in the minds of cell biologists because both involve the mechanisms that govern cell growth and survival. In aging, the cells of all animals eventually succumb to the process called senescence as they gradually lose the ability to replicate and then cause inflammation. Reduced replication may thwart developing cancer cells, but inflammation pushes in the other direction. Combined with a reduced repertoire of immune competence, imbalances in the usual cell harmony emerge. This is marked by poor coordination in the immune system’s response to everything from viruses to genetic mutations. The change helps to explain not only the increased diagnosis of cancer in older people but their greater susceptibility to infectious diseases. Senior citizens who get the flu are more likely to develop pneumonia because they can’t fight off the influenza virus as quickly as can the young.

  Senescence is relevant to cancer because malignancies somehow escape its limits on growth. They multiply in an out-of-control fashion that defies the usual mechanisms of aging. As they evade the body’s defenses and replicate willy-nilly, cancer cells inexorably overwhelm and replace normal ones and eventually, like mutinous sailors, gain control of organ systems and the body itself. This is true even for very old people, whose cancers may divide and multiply as if they had drunk from the fountain of youth. Terrifying as it is, cancer’s dynamism suggests that it may have taken a page from and corrupted cellular secrets about development, longevity, and even regeneration. What if the chemical signaling that spurs normal development could reveal abnormalities in cancer and conversely, lessons from cancer could be manipulated to deliver new, healthy cells to rejuvenate aged hearts or livers? Could this mirror be turned into therapies that help people with cancer or with injuries and wounds?

  Just as scientists studied the body’s delinquents—cancer cells—in the context of those that behaved well, they looked to the defender of the body—the immune system—to suggest ways to stop malignancies. By the time I enrolled at Case, biologists understood that between normal cell division and the effects of radiation and other carcinogens, complex living creatures faced innumerable opportunities to develop cancer every day. Seen in this light, the most important question we could ask about cancer was: Why don’t we see more of it than we do? And the logical next question was: Can we mimic how the body controls cancer to help, or even cure, people with the disease?

  Two years after the press and Congress went a little crazy over the human cloning hoax, a comparably loud press response greeted news of the first genetically engineered drugs, including human insulin, growth hormone, and synthetic interferon, which was made by a Swiss company called Biogen, which had among its founders a Harvard scientist named Walter Gilbert. A brilliant man with wide-ranging interests, Gilbert was Jewish and from Boston, while his mentor was a Pakistani-born Muslim named Mohammad Abdus Salam. Abdus Salam was a giant of nuclear physics who left his homeland to protest religious discrimination. Like Gilbert, he was wide-ranging in his interests, with an expansive imagination and an open mind.

  Gilbert’s interferon breakthrough was announced on January 17, 1980. The next day, the stock of the Schering-Plough Corporation, which owned 16 percent of Biogen, surged in value. Investors were no doubt encouraged by a study published in the Soviet Union that noted that a weak interferon spray had protected a small group of test subjects against exposure to cold viruses. Other research centers were exploring interferon in cancer treatment. If interferon could fight everything from the common cold to malignancies, then the sky was the limit for the companies that could produce it and those who backed them.

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  Although basic science advanced so quickly that it was hard to keep up with the headlines, excitement around this work was impossible to ignore. Everyone, including cancer patients, seemed to believe that cures were right around the corner and that if they just lived long enough, some new treatment would save them. In reality, though, patients were being treated with the same basic interventions—surgery, radiation, and toxic chemotherapy—that had been available for decades. These drugs, which were effective against some cancers, including those of the blood (leukemias) and lymphatic systems (lymphomas), almost always produced terrible side effects, including hair loss, nausea and vomiting, and profound exhaustion. It was not uncommon for people to say that living while undergoing treatment was not much better than death.

  I saw the benefits and limitations of all these treatments on the mornings when I went from room to room, and patient to patient, to draw blood for the tests that doctors had ordered. I was good with a needle, which people appreciated, and this work paid me a much-needed income as a student. It also gave me the chance to improve my bedside manner. Many of the patients were sleeping when I entered their rooms, and they invariably struggled to recognize where they were when they awoke. I was always a little bit sorry about disturbing them and about starting their day with the pain of a needle stick, small as it might be. I learned to discern who among them wanted to chat and who preferred that I perform my duties quickly and leave. As I grew more confident, I took a little pride in the fact that I was better than most at drawing blood from children, and even infants, whose small veins and big fears made this work especially challenging.

  As I made my rounds with my needles and tourniquets and glass tubes with stoppers, I came to appreciate the ways that a touch, or a word, benefited patients who were dealing with challenging conditions. And sometimes the best I could do was not touch someone. I learned this lesson with patients who had sickle-cell anemia and often experienced so much pain that they couldn’t bear to be touched. After one intense encounter that reached the point where I was afraid a suffering man was going to punch me out, I started telling these patients in the first moments of an appointment that I knew they were in terrible pain and that they might be hoping that we would just let them get into bed, give them as much pain medication as they wanted, close the door, and turn out the lights. I then explained that I could not do that, but that I would do whatever I could to help them once we got through an exam, which I would do as gently as possible.

  I valued this caring element of medicine because one of the things that became quite evident in medical school was that we really didn’t know very much at all about how the body worked, and kindness was sometimes the most powerful treatment at our disposal. Of course, great advances had been made since the age of bloodletting and phrenology, but still, we lacked good medicines to treat a whole host of conditions. We couldn’t answer most of the questions that people asked about why they got sick and whether they were going to get well. Medicine’s limitations became crystal clear to me when I studied immunology, which was an area of great interest to cancer specialists, who dreamed that drugs like interferon might harness the immune response against cancer. When you look at how the body monitors for infections and cellular injuries, develops immunity, fights off infection, or repairs damage, it seems like magic.

  Case was the kind of place where med students were permitted and even encouraged to knock on doors and ask questions. I went to see George Bernier, a professor of hematology and oncology, who was one of the leading hematologists/oncologists in the country. He stopped what he was doing and just listened as I rattled off a whole bunch of questions.

  How does the body know to recruit immune cells to a particular site? You get an infection. Suddenly all the infection-fighting cells that are otherwise circulating in the blood find their way out of the blood vessels, into the precise spot where you have an infection.

  How does the immune system know when to switch on and switch off?

  How do you shut off the immune response so that you don’t cause collateral damage?

  Why do some bodies manage to repair cell damage and others do not?

  Why do medicines help some people but fail in others with the same disease?

  To each of these questions, Bernier responded with roughly the same answer, which was “These are things we just don’t know.”

  H
ere was a truly great doctor, someone who would soon be named chief of oncology at Case, and he was saying that he didn’t understand the very basic operation of the immune system. He didn’t know why treatments worked in some patients and not in others. And he couldn’t explain how the immune system recognized a threat to the body, responded to it, and then turned off its response when the crisis passed.

  To his credit, Bernier wasn’t defensive about how much he didn’t know, and he wasn’t annoyed by all my questions. When I found other students who shared the same curiosity about the immune system, we formed a group and essentially designed our own course of study. We read everything we could get our hands on, met from time to time to discuss what we learned, and met with Bernier himself. Only later, when I learned about how other medical schools worked, did I appreciate our professor’s generosity. He made us feel as if we, the students, were the most important people in the school and that whenever we sought to learn more, we had a right to study and eventually own that material. There was also something special about the students in that small group and my class. We spoke very openly about our experiences as both students and doctors in training.

  Sometimes the different roles we played—in my case, blood-drawer, student, caregiver—combined to teach us lessons that were more profound and lasting than we could have had if we’d remained in the library. One instance of this dynamic arose when I met a young man named Carl. He was just a few years older than I was and had suddenly been overcome by exhaustion. His appetite had disappeared, and he had lost some weight. He was plagued by night sweats and had a constant low-grade fever. He had also developed a lump in his neck.

  Carl was a bright, friendly guy who was more puzzled by his symptoms than worried. He hoped he had some sort of infection, like the flu, and that it was just taking its time leaving his body. I knew just enough to be more concerned than he was. After talking with him and doing the necessary legwork of admitting him to the hospital, I went to the lab and made slides so I could examine under the microscope the cells taken from his blood. Following the standard protocol, I added stains called hematoxylin, which is violet in color, and eosin, which is rosy red. (Eos was the Greek goddess of dawn.) I put the slide into the clips beneath the lens, switched on the light underneath the slide, put my thumb and forefinger on the wheel that adjusted the focus, and bent over the eyepiece.

  TWO

  SEEING CANCER

  Viewed through a microscope at low power, the stained cells from my patient Carl’s blood had far too many cells stained blue, the cells of the immune system. The cells were sometimes clustered, making deep purple collections. Since they were lighted from below, they glowed in a way that made them almost seem beautiful, like African violets. But there was nothing but horror in those blooms. Carl had Burkitt’s lymphoma, a diagnosis made definitively on the lymph node biopsy that followed that revealed the classic starry-sky appearance associated with this dreadful disease.

  In the moment I recognized that I was seeing something malignant, something truly awful, through that microscope, I experienced several different emotions. I was excited to see, in a slide I had prepared, immediate clinical evidence of a disease that had previously existed, for me, only in the pages of a textbook. I think every new doctor must feel this little rush as he or she realizes that the material learned during years of grinding study is useful and directly relevant. But of course the diagnosis was a terrible thing for my patient, and I immediately began to feel overwhelmed by what I had unearthed, an unholy foe for him that would threaten all he knew and loved of life.

  In the late 1970s, there was very little hope to be offered adults who were diagnosed with Burkitt’s lymphoma. Children were sometimes cured by two chemotherapy agents—methotrexate and cyclophosphamide—which were effective against some leukemias and were being tried against other cancers. But in those rare instances when Burkitt’s was seen in an American adult, the prognosis was bad. One of the faster-growing types of cancer, Burkitt’s typically spread throughout the body, creating tumors in almost any organ system. In adults with advanced disease, it caused death due to organ failure in a matter of months or even weeks. Thus, Carl’s slide was a view of his destiny, and it was terrible to imagine.

  The diagnosis and prognosis came as a horrifying shock to Carl. He had never suffered from any serious illness and was expecting to lead a long and productive life. It was extremely unsettling to me too. I was a doctor in training who was eager to treat and even cure people with serious diseases. But there I was, face-to-face with someone who was very much like me—young, optimistic, hopeful—and he was being confronted with an undeniable and yet unacceptable truth. He had developed an incurable, fast-growing cancer that was going to end his life at a time when he felt like it was just beginning.

  Life is never long enough, but if we are alert, we can develop an appreciation for it, and with this appreciation we may accept it as a limited gift. Indeed, the natural life span, which for Carl would have been about seventy years, gives us the chance to really know ourselves, love others, and experience the world. Few people in their twenties or thirties acquire much of the wisdom that comes with age. For this reason, and many others, they find it almost impossible to understand that their time is running out very quickly. Carl quite naturally entered a state of psychological denial. He could hear what we were telling him, and he knew he was in a crisis. But he considered the warm, intelligent people who were his caregivers and all the resources at one of the most advanced hospitals in the most advanced country in the world, and struggled to comprehend that we couldn’t save him.

  As we developed a relationship, I came to know that Carl had a keen sense of humor. He was also a baseball fan. One of his favorite books was Eight Men Out, which told the story of the Black Sox cheating scandal. When I saw him, he often repeated the phrase “Say it ain’t so, Joe!” For a while, he would repeat the line, which has long been attributed to a little boy who begged the ballplayer “Shoeless” Joe Jackson to refute the charge that he had cheated. Legend has it that Shoeless Joe never did say, “It wasn’t so.” Neither did I.

  The best we could do for my Carl was chemotherapy that barely touched his tumor and then palliative care, which meant making him as pain-free as possible. We also tried to comfort him emotionally, but we were limited in this regard too. Nothing that could be said would change the fact that this young man was being cheated out of a full life. He remained in the hospital and died in a matter of weeks.

  Although I knew what was coming, I was not prepared for Carl’s death, and it filled me with sadness. Some clinicians may try to develop what’s called “professional distance,” which they imagine will help them cope with traumatic situations, but I doubt that such a thing really exists. Medicine is an intimate enterprise in which every interaction is an emotional experience. The idea of distance connotes a sense of remove that is more likely a kind of denial and would require denying the humanity of the person who is your patient. This distance makes it harder to enjoy the happier aspects of just being with a patient who brings his or her own sense of humor, irony, or grace to a clinical moment. It also deprives us of the clarity that comes with the pain of someone’s suffering or death. If being numb is what a doctor seeks, he or she has surely chosen the wrong profession.

  In the bustle of life, it is very easy to overlook the blessing of a well-functioning body and the gift that is each ordinary day. When you work with people who cannot take these things for granted but who often meet their pain with clear-eyed determination and even humor, you are reminded that most of what we worry about every day is neither profound nor worthy of much attention. In medicine, real care often comes down to staying open to what patients like Carl are experiencing and teaching us even in death. Stubborn adherence to some standard that says we must be calm and emotionally removed can easily make patients and their loved ones feel as if we don’t appreciate the gravity of what’s happening before their eyes. Nothing is more profound than death, a
nd any attempt to act professionally in some artificial way will be felt as alienating and disrespectful. This type of denial also deprives doctors of the genuine experience that helps us move through grief. It is the loss that is denied, and not addressed, that erodes our ability to recover and move forward.

  The pain that I experienced when Carl died included a hard lesson in the limits of science and medicine. We may have discovered the double helix and begun to practice genetic engineering, but we were still unable to save people from most forms of malignancy. Indeed, most of the tools we have are sadly inadequate, often barbarically crude. Unsatisfied with the limitations of what I could offer patients as a doctor, I recognized that if I wanted to really make a difference in ways beyond comforting the person in front of me, I needed to do science as well as medicine, and I devoted more time to studying the basic mechanisms of cancer. I joined a group of students who met regularly with research scientists who were happy to add to our formal medical education. One of these professors, Adel Mahmoud, was a brilliant physician and biologist with a generous spirit. He was a small man who made a big impact as he gestured with his hands and spoke in a great rush of words whenever he was excited by a scientific concept, which was quite often.

  Mahmoud had been educated in Cairo and London and was deeply interested in infectious diseases and vaccines. His main interest at the time was schistosomiasis, a disease caused by a parasitic worm—also called a blood fluke—that affected an estimated two hundred million people in the developing world. Sometimes referred to as “snail fever” because each parasitic worm spends part of its life inside a water snail, schistosomiasis causes organ failure and death. It was, and is, endemic in Mahmoud’s home country of Egypt. It is also so common and has been for so long that ancient sources referred to the bloody urine of males, a common symptom, as a sign of maturity comparable to menstruation.