Bone marrow transplantation offered treatment possibilities for other patients with immune disorders, including the kinds of illnesses that produced the phenomenon depicted in the 1976 movie The Boy in the Plastic Bubble. The film, which starred John Travolta, was based on the life of David Vetter, who was so vulnerable to infection because of a genetic abnormality that compromised his immune system that he lived inside a sterile plastic cocoon, breathing filtered air. David would eventually undergo a successful transplant, but the marrow donated by his sister contained the virus linked to Burkitt’s lymphoma. He would die from it. But with rapid improvements in transplant techniques, other “bubble” boys and girls would receive marrow cells, develop robust immune systems, and be able to leave confinement and live normal lives. Fascination with children raised in medical isolation would fade to the point where many people were only aware of the phenomenon because of the film, and even then, there may have been confusion about whether the story was fact or fiction. Although the cure of bone marrow transplant dampened public curiosity about immunodeficiency, it did not end the drama around the treatment. Like cancer patients, children and adults who received transplants underwent chemotherapy to kill whatever functioning marrow cells or hostile immune cells they may have possessed. This was necessary to prepare the body to receive and nurture the new marrow cells.
By the end of my time at Case, victories like Laura Graves’s transplant and setbacks like the tragedy at Roswell Park had led to a standard of care that greatly improved the odds of transplant success and, therefore, cures for immune diseases and blood-related cancers. I helped to care for patients who were overseen by senior Case faculty, including the aptly named Hillard Lazarus, who, like all transplant doctors, brought patients to the brink of death with chemotherapy and then restored them to life like the Lazarus of the Bible.
Despite many setbacks, successful transplants hinted at an intriguing future for oncology. Specialties like cardiology were high profile because of the number of people affected and the emerging impact of smoking-cessation campaigns and medicines that could reduce the known risk factors of hypertension and high cholesterol. These interventions slowed disease but couldn’t be considered cures, while bone marrow transplant offered a fundamental reset. It could replace a defective blood system or enable intensive therapy to cure leukemia. That, for me, was very alluring. Make this high-drama process of transplantation safer and more patient friendly, and you might be able to build a new blood and immune system to affect all the disorders involving blood.
Likewise, it seemed that when people lacked a well-functioning immune system, they were likely to develop diseases that seemed to have few other connections. The immune system is implicated in diseases of the brain, the gut, the joints, the skin, and more. But understanding just how and why some organs are affected and not others remains a challenge. Sometimes things go haywire because of insufficient immune response, and sometimes the culprit is too much immune activity. In some people, a seemingly normal reaction to something as common as a physical or chemical insult can set off a cascade of events that produces disease. This is thought to occur particularly with viral infections. There the virus provokes a response of lymphocytes preprogrammed to recognize it with high specificity, but more cells can become involved, sometimes as bystanders caught up in the activation process or sometimes as cells with specificity for other targets that resemble part of the body. This spreading of an immune response can sometimes activate what is otherwise dormant, cells that attack the body itself. It is thought that type 1 diabetes or multiple sclerosis might be triggered by these kinds of overly aggressive immune processes. It is also thought that severe or chronic injury can provoke abnormal efforts of repair. For centuries, physicians have reported cases of cancers developing in places where people were burned or otherwise injured. The high frequency of liver cancer in parts of Asia correlates with places where viral hepatitis is more common and liver cancer occurs with increased frequency among those who have alcoholic cirrhosis of the liver. William Coley (yes, the same William Coley) treated a veterinarian who developed a tumor in the exact place where he was struck by the horn of a bull and developed swelling and inflammation. Coley treated him with his toxins, and the man went into remission. He lived for six years before dying of kidney disease. It can be debated as to whether the tumor was cancerous, as not all tumors are malignant. But it is clear that immune provocation can enhance anticancer effects. Indeed, a harmless cousin of the tuberculosis-causing mycobacterium called BCG is introduced into the bladder of people with low-grade bladder cancer and has been shown to reduce recurrence and progression.
Coley’s veterinarian and these other illustrations point to the paradox of the immune system and frankly of many systems in the body. There is an equipoise that normally balances activating and suppressing activities and shifts that balance in response to particular challenges. Both the immune system and the clotting system of the blood have countervailing activities that manage to stay steady when we are well but can dramatically activate one part of the process or another when needed. A clot must form when we are cut, but it has to stop clotting and eventually resolve as we heal. The immune system is even more complex, with many players and many molecules within those players dictating how the multilayered response is orchestrated and resolves. In the 1980s, just identifying the participants beyond describing how they looked under the microscope was new. Still today, we are defining new cell subsets that make up the system, and our known repertoire of molecular participants is likely far from complete. Since we only partially know the roster, it is no wonder that we don’t know much about how they play together. But this is slowly coming into focus. We are gaining tools for identifying and enumerating a wide range of cells, and we can now image how they move and grow and respond within tissues. We can do this over time in living animals, using special microscopes. It is starting to be possible to build predictive algorithms for how various components work together to achieve a beneficial result in the body. Of course, the hope is that this will yield more than just exciting biology and will eventually put tools in the hands of doctors so they can regulate the process in service of patients.
No cells are more essential to the life process than those that are created in the marrow. Hidden in the bones, the marrow produces cells that are circulated to every organ and tissue, where they perform functions that doctors like Don Thomas recognized, but in hazy detail constrained by the knowledge of the day. But their pioneering efforts to save lives with what was emerging biologic understanding was inspiring.
It was time for me to move from medical school to medical training, the apprenticeship time in becoming a doctor. Where you do that, your internship and residency, shapes everything about your future. It shapes how you think, how you relate to patients and colleagues and the breadth of your horizons. I knew I wanted to be in a place where medicine was twined with science: where the culture championed making decisions based on scientific evidence and where the goal was not just to deliver the best care based on today’s understanding but to help make tomorrow’s medicine better through research. I thought the Brigham and Women’s Hospital in Boston represented the best of that, deeply entrenched in the standards of excellence by being adjacent to and a part of Harvard Medical School but openly emphasizing new approaches and challenging established ideas. On the day every medical student both dreads and dreams of, Match Day, I learned we had matched: I ranked the Brigham first, and they ranked me in their top tier. I was given a slot at the Brigham. It truly transformed my life.
Bruce Walker, my good friend in medical school, also interviewed at the Harvard hospitals and was most interested in Massachusetts General Hospital (MGH). We vowed that if we both got our first choices, we would find and share an apartment midway between them—and we did. Bruce and I had one of those odd bonds unique to medicine: we had been anatomy partners. That meant we learned anatomy together by working on the same cadaver. It is a rite of passage not ver
y common in medical schools today, but then, it was an emotional and ghoulish experience, and also a deep privilege. The body is a sacred space. We were given the right to see and the responsibility to know it. We and the other two members of our team took it very seriously. Bruce and I did some extra work to really figure out the complicated structures in the head, so we shared some knowledge compulsions that made us compatible. That made living together easy, as we both tolerated heaps of medical journals and books with the bonus that we both thought a pint of ice cream was a darn good meal. With only spoons to wash!
Bruce was from an academic family and had studied chemistry, so he was much more able than I to get engaged in the science behind what we were learning. He knew that he wanted to do science as well as treat patients, and he knew he could do it. He shared my interest in the immune system. And like me, he was both frustrated by the limitations of treatments we could offer patients and intrigued by what organisms, including humans, could do on their own against disease. For every time an invading germ, an injury, or a genetic mutation made someone sick, there were countless times every day when the body resisted disease or repaired itself. And these were just the ordinary illustrations of what the body could do. Like many medical students, we had been impressed by phenomena like the abscopal effect—ab for “away from” and scopal for “target”—observed when radiation or other local therapy that hit metastatic cancer in one part of the body could destroy it elsewhere. It seemed that somehow the immune system learned something from the local death of cells and then applied it to the body as a whole. There was a resilience in the body that was sometimes evident. Commonly it involved the immune system and the blood, but it could also apply to other tissues like an injured liver. Cut out up to a third of the liver and it will grow back: remarkable regeneration, not unlike the odd salamanders I used as my specimens growing up. That seemed an area of medicine that begged to be exploited. Something that offered more than the drugs that simply try to reduce symptoms or slow but not reverse disease. The immune system seemed like the place where this was most evident and most important across medicine, so we were naturally both drawn to it.
* * *
Although neither of us was so impressed with himself that he would have said anything about making discoveries, Bruce and I felt somewhat prepared to care for patients and hoped to make some contributions, as scientists, in the area of immunity and disease. When he and I got to Boston, we found an apartment to share on Marlborough Street in a neighborhood called Back Bay, which really was a bay until it was filled in during the nineteenth century—430 acres of what was tidal marsh between the mainland and the hub of rocky prominence that was old Boston and its Beacon Hill. It was filled with redbrick town houses that persist to this day. Although the area is now gentrified, in 1980, Marlborough Street was still a place where there were boardinghouses, and many of the Victorian-era houses were poorly kept. But it was roughly halfway between the hospitals where we would be working and accessible by a combination of buses, the train known as the T, and, in good weather, bicycle.
The Brigham, where I worked, sits in the heart of an extraordinary concentration of medical facilities. It had been pastureland when the Brigham (then Peter Bent Brigham Hospital) received its charter to serve the poor and Harvard Medical School outgrew its downtown location. They served to anchor the subsequent growth of the Longwood Medical Area (named after Longwood Avenue), which grew to be a neighborhood of twelve irregular city blocks and home to three teaching hospitals, a massive cancer research center and clinic, a famous diabetes research center and clinic, the Harvard School of Public Health and the dental school, and literally thousands of labs. About fifty thousand people commuted to work in these places in 1980 (the number would more than double by 2015), and patients came from all over the world seeking care.
It was an awe-inspiring place to enter postdoctoral training. That was before seeing the portraits on walls of the legends of science and medicine. I didn’t take lightly how high the bar was set by all that history or by patient rounds with people whose names I knew from my Cleveland textbooks. Anxiety nearly crushed me. I only hoped I could give compassionate and reasonably errorless care to my patients before the gods of medicine found me out and sent me packing. What saved me was the open-mindedness of senior doctors who genuinely wanted to hear what the newly graduated might have to say and by colleagues who bantered ideas for sport. It became clear that by getting my wish to be a part of place where the science of medicine was king, I had entered a world where the unknowns vastly exceeded our knowledge and the pursuit of greater understanding was, by turns, grueling, inspiring, uplifting and devastating to experience. And sometimes you experienced all of it in a single day.
I was lucky to have, in Bruce, a roommate who understood my day-to-day experience. He would also play a central role in the most momentous night of my life. The occasion was a party I organized to celebrate his engagement to be married. I invited a crowd of our friends, including a psychologist named Stephen Shirk. For months, Steve had been telling me about a friend in his apartment building. He said, “Her name is Kathy and she’s perfect for you.” On this night he brought her as his plus-one.
Kathy, who was an artist, a one-time college art faculty member and also worked at a gallery on Newbury Street which was then, and remains, Boston’s fanciest shopping street. When she came to our apartment, I noticed. Despite the Jack Daniels and not because of it, I knew this was an exceptional spirit. We talked; she sparkled. I had to mingle and so did she; still she sparkled. It wasn’t bewitching as she’s too genuine for that, but there was a special presence and a laugh that really struck me. Everyone there was already part of the crowd. She was the only newcomer. But she wasn’t a bit fazed and engaged people with sincerity and ease. I realized that Stephen actually did know something special about people and had the two of us pegged just right.
Although I knew Kathy was special (and when my mother met Kathy she made it clear that she thought she was getting the better half in the in-law deal than Kathy’s mother was), an event a few months later made it clear. My closest friend since I was four years old phoned from his home in the Virgin Islands with a medical emergency. Tim Reynold’s wife Karen had just given birth to a baby who needed complex and delicate surgery. As they caught the first plane that would get them to Boston I set about making the arrangements with the top specialists in town.
When they got to Boston, Tim and Karen camped in the front room of the apartment I shared with Bruce. Kathy quickly became central to the support system we created for the family as days turned to weeks and then months. Someone else in a new relationship might have experienced a few days of this crisis and made other plans. Kathy did everything she could think of to help Karen and Tim and never missed a beat, never did anything without love. It was a crash course in what it means to live with the possibility that a medical crisis could, at any time, overwhelm other plans. She took it with good cheer and with grit; nothing deterred her optimistic, caring way.
After Kathy and I got engaged we went to Western Massachusetts to see her parents. We went to dinner at one of their favorite spots and noticed a couple who were in their eighties, or perhaps nineties, sitting together and laughing repeatedly, even uproariously, at some shared story or joke. We looked at each other and knew that if we could make each other laugh, we could get through whatever came our way. We married in a rainstorm of biblical proportion on June 2, 1984. My father was my best man, but had a mismatched tuxedo that Bruce Walker’s new wife had to urgently remedy. The bride’s ride got lost. An ever helpful clergyman cousin decided at the alter to change our already memorized vows (awkward pause) and guests had to slosh through Harvard Yard from the church to the reception. But we had a blast and were the last danced-out couple to leave the party, by cab. We had our first child, Margaret, in August 1985 when I was a tutor in one of the Harvard dorms. Next would come Elizabeth in 1987, and Edward, nicknamed Ned, in 1991.
As much as
I tried to involve myself, Kathy unequivocally was the parent of record. She worked full-time at Payette Associates, one of Boston’s premier architecture firms, but made the balance work as best she could. I was mostly useless as I was doing clinical work at the hospital, conducting research, and moonlighting weekends as a physician to make enough to buy ourselves a home. Our first one was a two-family that we shared with another couple. When my mother-in-law first saw it, she cried. My choosing research meant I earned less than the baggage handlers at the airport and it was not the life she had hoped for for her daughter. As a child of the Great Depression herself and having had family struggles in a financial crisis during Kathy’s youth, Geraldine Elliott knew of money problems. We were confident that better days were ahead, but there were moments, particularly when something unexpected arose, that reminded us that my choosing research was not without its strains.
One evening, when Margaret was only a few months old, Kathy brought her to the hospital to visit me in the on-call room where residents retired during break periods. I was stretched out on a bed, and Kathy put Margaret down next to me. She grabbed my necktie and, as babies do, put it in her mouth. In a flash I suddenly realized that earlier in the day I had been working in a lab with radioactive materials. In leaning forward, had I dragged the tie over ‘hot’ materials? Indeed, a Geiger counter revealed that I had. The radiation safety officer was called. His response was all irritation about the forms to be filed. Nothing was mentioned about the child until I wouldn’t relent, but nothing could be done. The incident further raised the ante on what the research path might cost our family. I knew it was right for me, but was it right to ask so much of Kathy and the children? It had to mean something more than what doctoring would. I was pretty comfortable that I could help patients as a doctor, and I knew that would be easier for us. If research was the choice, it had to be for a pretty high calling.
Cancerland Page 8