Cancerland

by David Scadden

  Moving science to create better clinical approaches is an almost painfully incremental affair, which meant that, as a clinician, I often found myself in the position of explaining the slow pace of research. Everyone hopes to learn of a new treatment or a drug in clinical trials that will provide a cure. Although all clinical trials are conducted with the hope that the impact will be great, the reality is that very few are, particularly in cancer. The work that can go on in the laboratory to determine whether a drug will work or not, be safe or not is improving, but still very limited. We were frequently implored to look for the breakthrough therapy, we almost never found one. Fortunately, most people accepted this reality, especially if we take took the time to explain things well. Most people still wish to participate, in part based on the hope for them, but at least as often, in the hopes that someone will ultimately benefit.

  The hope for scientific progress is part of the pact willing doctors and patients implicitly make. It helps to justify the fact that most trials need people to be in the “control” group. That may be a group that gets only the standard therapy and not the treatment with a new agent. It is essential to do in order to define just what is added by the new drug. But it is an extremely difficult situation to discuss and for patients and doctors to accept. If you really believe that the new drug is worth testing, why will you not be giving it to me? Often, it is just because side effects, toxicities might be worse. That makes sense and is easier for all to accept. But people come to research centers seeking what is new and are generally willing to take a risk to receive it. Being part of the group with only what is already available hardly keeps with their expectations or desires.

  The tension that creates for all involved is real and challenging. It is then that I have experienced the pulling of strings by people of influence. Efforts are made to game the “randomization,” but fortunately modern clinical trials block that. It is impossible to be anything other than an identified “number” in the process that determines what particular drug or “arm” of a trial a patient will get. People push and try to use connections and even offer money for a chance at a new drug. Part of our oath is literally to take the same care of any and all regardless of station. Compassion and good care are not bartered for cash. In principle and in practice, we do what we can for all.

  However, when you are working in matters of life and death, there’s every incentive to push considerations of status and power out of the picture. When I became responsible for patients, many of the things I used to care about just didn’t matter as much to me, and that included what was happening in popular culture. I also found I had to try a little harder to get into the social flow outside the hospital and the lab. It’s a small example, but I once ran into a friend leaving work who offered me tickets to a game at Fenway Park. I like baseball, and as always, the Red Sox were a hot ticket, but I couldn’t muster the enthusiasm to take the tickets. At around this same time, I had a second experience that I took to be a signal that I needed to make an effort to lead a more well-rounded existence. On my way home from the hospital, I had gone into a place where I expected to have a quick dinner alone, and I saw some people I knew at a table. I thought, This is great! Somebody I know. I was so out of practice socially that it didn’t register in my mind that they were there alone, together, and intentionally. When I asked if I could join them, they said, “Well, we’re kind of having dinner.” In the pause that followed, it dawned on me that I had failed to detect all the social cues and intruded where I really wasn’t welcome.

  Miscues in the outside world were inevitable for anyone who worked in the land of cancer where every day we experienced drama or trauma in ways that both truly heightened our experience of life and numbed us to its nuances. People were saved, and people died, and amid the intensity of this experience, we had to create a kind of normality that allowed us to function well. This was accomplished, in part, using a kind of dialect that allowed for us to talk among ourselves, and with patients, in a way that evaded certain realities. We spoke of “harvesting” marrow from donors and “conditioning,” “giving” it to recipients who had undergone chemo and radiation therapy so intense it was fatal without the new marrow cells coming in to “rescue” them. The marrow was taken from donors who were wheeled into operating rooms and placed under general anesthesia before we used big needles to repeatedly pierce the pelvic bone and attach syringes to draw out the marrow cells. This was strenuous labor involving up to one hundred insertions, which became a bit easier because the bone became sort of spongy under the assault of the needle.

  With each puncture of the bone, a small amount of reddish- brown, gelatinous marrow was drawn into a syringe and deposited in a sterile bucket until a quart or more was collected. This was done with some risk to the donor, including, in some rare cases, nerve damage that could cause long-lasting pain and numbness. Back then, recovery involved as long as a week in the hospital. Although it sounds like we removed a substantial amount, in fact we took only about 5 percent of a donor’s marrow. The portion left untouched continued to function, and the places that were harvested recovered quickly.

  For recipients, the transplant odyssey involved two days of intense chemotherapy followed by total-body irradiation, which killed all their functioning marrow cells. We could give the chemotherapy at the Brigham of Dana Farber. As we did this, our patients would lose the ability to fight infection, which meant we had to confine them to special environments sealed by sterile plastic. They ate food that was irradiated to kill all germs, drank sterile water, and breathed air that was cleaned of all contaminants. No one could enter these spaces without donning sterile gowns, masks, and gloves, and in some cases contact was achieved only via sleeved gloves that were built into a plastic barrier that separated patient and caregivers.

  After the chemo, we had to complete the patient’s preparation for transplant with total-body radiation. The linear accelerator that delivered the radiation was in one spot, underground. We reached it via a network of tunnels that connected the basements of the hospitals. I can only imagine what someone lying on a gurney, whizzing through this space and staring up at the passing light fixtures, must have thought and felt. With careful technique and advanced medicines, the outcomes for bone marrow transplants improved steadily. In 1984, the number done across the United States exceeded five thousand per year, and the risk of death declined to 30 percent. (This sounds high, but for a radical and dangerous therapy in the early stage of its use, it was a decent record.) We did better than average, which meant that the great majority of our patients recovered and left the hospital with their cancer in remission and their new immune systems functioning well. One of my mentors at the Brigham, Joel Rappeport, achieved many milestones in their period, including the first effective transplants to cure a number of immune-related diseases, including one that was always fatal in children.

  Our successes were thrilling. The trouble for everyone came when patients died of infections that occurred despite all our efforts, or could not be cured with even the most powerful drugs at our disposal. For people with CML, the outcome depended mainly on whether they were at the beginning stages of the disease or the more virulent, so-called blast phase. In the late 1970s and early 1980s, a little more than 60 percent of people with early-stage CML were alive three years after transplant. Only 16 percent of blast phase patients lived this long.

  The losses were especially hard to take because during treatment we became attached to our patients and their friends and families. No amount of professional distance prevented us from becoming emotionally drained by our work. More than once, I left the hospital so exhausted that the bus driver would reach the last stop on the line, park, and walk back to awaken me because I had fallen asleep and missed my stop. At other times, I would become so discouraged that I came close to giving up my career. No one case dragged me down deeper than caring for the father of a friend. We just couldn’t do anything more and watching this distinguished, well-loved man drift away wa
s more than I could take. The night of his demise, I was on call. I was paging the senior physician, but in those days before cell phones, he had to find an exit off a highway before he could get to a pay phone to return my call. It was agony to have to speak to the family as a mere doctor-in-training. Finally, he made his way back providing the calming comfort the family needed. Fortunately, something positive would always happen to lift my dark mood. In the early days of my work on transplants, it was common for residents to leave the hospital in scrubs. One day, I stopped in a shop near the hospital to buy a bottle of wine before heading home, and a man in the store noticed what I had on.

  “Excuse me,” he said. “Are you a doctor?”

  I said yes and made some sort of quip about how there were so many doctors in the area you had to walk carefully to avoid stumbling over them.

  While I paid for what I was purchasing and the clerk made change, the fellow asked about my medical specialty. I mentioned hematology/oncology, and he said, “Do you work on bone marrow transplants?”

  Given my experience, I wondered for a moment if he had known someone who had undergone the procedure and, perhaps, died. I gathered my courage and said, “As a matter of fact, yes.” His next words almost shocked me.

  “Good,” he said. “I had one, and it saved my life.”

  After a brief chat about his recovery from CML, the man shook my hand and we parted. What were the odds of such an encounter?

  I guess the fact that we met in the Longwood Medical Area meant they were higher than they might be anywhere else. But still, it was such an unexpected exchange that it took me a few moments to let it sink in. It was an incredible uplift. It made the drama of caring for the complicated process and its untoward consequences seem trivial. Nothing could reduce the extraordinary lightness of being in one young life pulled back from a certainty of death. It made cancer seem more vulnerable and it made transplant seem the ultimate extension of scientific reasoning turned into palpable tools of hope. That hope was changing dramatically. It was clear that what my classmates and I had tried to understand as we raised questions with George Bernier at Case Western was coming into focus. Much was still seen through a gauzy haze of only partial understanding, but it was making a difference. No area more limited in understanding but rich in potential than that of stem cells. But as so often happens in science, we were working with phenomena that we didn’t fully understand and getting results we couldn’t predict.

  Bone marrow stem cells are the reason we are capable of making blood cells, lymphoid cells, and the whole range of infection fighters we call our immune system. These cells are remarkably varied. The neutrophils, for example, take more than a week to be made, but then generally last less than a day. Stem cells are the stark contrast. They have an ability to divide asymmetrically with one “daughter” cell going on to mature to a fully functioning cell while the other becomes a replica of the parent cell: a process called self-renewal. This perpetual regenerating ability is one of the distinguishing features of stem cells. But unlike cancer cells that also can self-renew, a normal stem cell has the ability and inherent function of moving offspring or itself into a differentiating process. Blood stem cells can keep on creating new functional blood cells (proliferation) and new copies of themselves (self-renewal) indefinitely. If transplanted, they will take up the same work and, again, do it until the recipient dies. Should the transplant be repeated, ad infinitum, they could be considered immortal.

  Bone marrow stem cells also create most of the cells that monitor the body for malignancies and pathogens, including viruses, bacteria, and parasites, and mobilize against them. One of the most intriguing theories about how this system is able to act against specific invaders was devised in 1957 by an Australian doctor named Frank Burnet. Burnet suggested that particular blood cells, so-called B cells made by marrow, stood in reserve in the lymphatic system and then, when called upon, produced antibodies tailor-made to deal with specific invaders. Remarkably, this system also seemed to form memories of defeated invaders and thus confer immunity to future attacks. He was largely right though it was years before it became clear how some cells in the immune system could be able to respond to only specific targets.

  Lymphocytes—of which B cells are one type (the other major type being T cells)—have an inherent ability to undergo a set of genetic mutations that modify a particular part of their genome. That part of the genome represents genes that encode receptors expressed only in the particular lymphoid cell. That is, B cells express the B cell receptor (also functioning as an antibody) and T cells express the T cell receptor. The mutations occur at a particular point in the maturation of those cells. When the mutations begin, they undergo a beautifully choreographed set of maneuvers that involve cutting the receptor gene and repairing it, but adding some random variants into the repair process. As the pieces are reconnected, some are lost and some have new bits added to them. That controlled chaos is what converts the receptor gene that starts out the same in every cell, into a collection of distinctive receptor genes. Each receptor gene then can have its own special “signature.” That signature is what allows the receptor to identify specific targets. It is remarkable on many levels. First, it allows for an immense diversity in what targets can be recognized. By allowing some random variation to become part of the cell’s DNA, individual lymphoid cells now have their own special identity and capability. That builds in response to a range of targets that can be as diverse and subject to chance as are the invaders the cells have to face. Our genes could never have encoded for all the new invaders that nature throws at us. Instead, our genes accept a degree of randomness that allows for new abilities of B and T cells to be generated and emerge as needed, allowing new defenders to be forged with an ability to adapt to new enemies. It gives us both adaptability and resilience, keys for success in any endeavor, but particularly necessary for protecting us in the ever-changing world of microbes.

  The second lesson from this aspect of the immune system, is that not all mutations are bad. We tend to regard genetic mutations like a bad accident. And mutations in the wrong place are how cancers begin and progress. But most mutations are silent. They happen and are of no major consequence. This is most evident in skin cells. The constant bombardment of radiation from the cosmos induces mutations in most of our skin cells. Fortunately, few of those are of any consequence. And some mutations are good, as in the case of the B and T cells of our immune system. There, the powerful good of mutations is evident in providing new capability: diverse recognition of invading microbes. In evolution, mutations are of course how new adaptations emerge. When mutations result in better tolerance of a stressful challenge, those mutations are preserved. If they occur in our germ cell stem cells, the cells that form sperm and eggs, the mutations pass along to new generations.

  The lymphoid cells bearing their newly mutated recognition receptors do not all survive. Some are selectively killed, culled from the herd of cells. They die for two reasons. Some have mutated receptors that just don’t work. They are either not produced by the cell or recognize nothing of consequence. They serve no purpose and so die out. Others recognize something within the body and are so overstimulated by it, that they trigger a process called programmed cell death: a kind of cell suicide. Even among cells that survive, if they react to the body, they often reprogram to become inert or nonreactive, or become cells that actively suppress the immune system. These mechanisms result in what is called tolerance, an enforced calm against ourselves while allowing a fierce rage against outside invaders.

  In the twenty-first century, it is common for scientists to imagine that the body is comprised of networks and systems—including living cells—that could operate with the seeming intelligence of the immune system. But in the early 1980s, when I began my career in science, little was known about how cells accomplished this work. One of the first to think very deeply about the question was a molecular biologist named Joshua Lederberg, who, after winning a Nobel Prize for his w
ork in genetics, began to study artificial intelligence. Lederberg was interested in understanding how a computer might be trained to respond on its own to inputs and “learn” on its own. He also theorized about how collections of different types of cells might do the same.

  Lederberg first proposed his concept of “tolerance of self” in the late 1950s, hypothesizing that lymphocytes do learn from what they experience in their development. If they are responding too vigorously, it is likely they are responding to the body itself and they are instructed to just sit down and shut up. And for the most part, they do. It wasn’t for three decades that any mechanisms for how this happens were evident, but his concepts are now validated and well defined; defined enough to be turned into methods for manipulating immune tolerance and reactivity as clinical therapies.

  The fields of stem cell transplantation and organ transplantation were those where tolerance and reactivity meant everything. A lack of tolerance in the immune system and the engrafted organ or bone marrow would be immediately targeted and rejected. In the 1980s immune typing was becoming increasingly sophisticated. It had started as just mixing blood cells from the donor with those of the recipient and seeing what happened. That was how blood typing got started. Literally, Lederberg mixed patients’ blood and, depending on who clumped with whom, he broke them into groups, A, B, and so forth. For that he won the Nobel Prize in 1930 and revolutionized blood cell transfusion. Immune typing progressed beyond that by measuring whether mixed lymphocytes from donor and host resulted in proliferation, growth of lymphocytes, as evidence of activation. The basis for some people’s lymphocytes reacting against another was being defined and was the basis for Human Leukocyte Antigen (HLA) typing that is a critical component of defining who can safely donate to whom. Developments in that field in the time I was in training made transplantation far safer and far more accepted as a reasonable approach to devastating disease.