As we cared for people who had AIDS in the days before treatments were devised, it was commonplace to deal with similar edge-of-death moments, but it was often in young people who otherwise were a rarity when dealing with such issues. The inevitability of death from AIDS created the sword of Damocles hanging above all who heard this news as their diagnosis. It was an unthinkable clash with vigor of the young age of most patients. In the gay community there was often enough information and community support that people were aware and prepared to consider the measures that should and should not be undertaken long before any emergency arose.
AIDS patients experienced every kind of suffering you can imagine, including deep psychological pain. In many instances, the search for equilibrium prompted families and friends to come together. We were privileged to see love and reconciliation help many people get through those terrible times.
Very few people maintain their emotional façade in the face of death. Instead, they recognize the value of the time they have left and strive to make the most of it. But sometimes even the state of emergency is not enough to heal a rift. Almost thirty years have passed since I cared for one young man who died of AIDS while refusing to reconcile with his mother. Although family conflict can still arise over issues of sexual identity, back in the 1980s, it was far more common, and the rifts that opened in relationships could be wide and deep. In this case, as in many, I came to know my patient’s family and friends, and I heard about the pain his mother felt. But her son was firm in his decision, and it was not my place to argue. In the end, he died estranged from her, and she would suffer more as a parent who lost a son in more ways than one.
Experience with HIV/AIDS patients gave every doctor, nurse, therapist, and technician the chance to become a better caregiver. Because it was a viral disease that affected immunity, it also pointed us to avenues of inquiry that were closely related to the most exciting areas of cancer research. For a century, scientists had debated the possibility that infectious agents cause cancer, but with the rare exception like Burkitt’s lymphoma, proof had been lacking. Stronger evidence supported the importance of the immune response in protecting people from cancer, and the Kaposi’s sarcoma we saw in people with HIV added to this evidence.
One of my earliest projects in the area of infection and cancer was done when I got a chance to work in the lab of the Harvard faculty member and virologist Jim Cunningham. In time, Jim’s work would range across a spectrum of important diseases, from HIV/AIDS to Ebola. He would also train a small army of scientists who would go on to do important work around the world. He was more willing than most laboratory chiefs to assign members of his team to various avenues of research on the same general topic, putting us in direct competition. (This is not something I would do today in my own lab.) Then, as now, Cunningham’s goal was to understand how retroviruses caused leukemia in mice. (One had recently been worked out, the so-called “Friend” virus, which was identified by scientist Charlotte Friend, who died of lymphoma in 1967.) What drew me to it was the fact that viruses were relatively simple entities and might be a good tool to get some glimpse of how cancer develops. The retrovirus-mouse-leukemia process was a particularly good model for anyone who wanted to explore the relationship between infection and cancer. The virus was readily available, the mice were easy to manage, and the leukemia cells could be generated in abundance, which meant that studies about molecular mechanisms could be done and the molecular reagents could be isolated in sufficient quantities
It was a time when the retroviruses seemed like they could provide deep insight into cancer. Work done by Harold Varmus and Michael Bishop, who were eventually awarded Nobel Prizes, revealed that some viruses are capable of picking up genes—the ones that control cell growth—from the cells that were infected. What was so shocking is that the cancer wasn’t developing because of the virus’ genes. Rather, the cancer was driven by the genes that were hitchhiking in the virus. The cancer came from the genes of the cell itself. Extrapolated to humans, cancer wasn’t coming from being invaded by a virus, it was coming from within—the enemy is us. It was by picking up growth controlling genes and expressing them differently, expressing them under control of the virus, that the cancer emerged. That meant that our own genes were the culprit. When corrupted, they could become “oncogenes” (onco: tumor causing): genes that normally allow us to grow could lose control and drive the unregulated growth of cancer.
Varmus and Bishop would influence generations of biologists, and they would, as evangelists for scientists, use their own experiences to urge people who didn’t fit the cliché most people imagine when they think of scientists to enter the field. As a young man, Bishop thought more about being a historian or a writer than he did about becoming a researcher. Varmus would describe himself as a good but not super student who enjoyed going to the beach more than working on science fair projects, and he didn’t pick a direction in life until college, where he spent most of his time at the student newspaper. As someone who was an English major in college who sometimes doubted his place in the laboratory, I was reassured to know that a background in the humanities didn’t preclude, and might even enhance, the ability to creatively contribute to medical science. The complexity revealed by Varmus and Bishop—who would imagine a virus hijacking DNA?—reminded the scientific world that biology is a sea of remarkable nonlinear feats of nature. Any one of them could be distilled down to the fundamental chemistry of the molecules involved or the physics of particle interactions, but knowing the chemistry and physics could not result in predicting the biologic outcome. Despite the advanced understanding of chemistry and physics by 1976, the Varmus and Bishop discovery was as surprising and as it was awe-inspiring. And it totally changed the focus of cancer research. It was no longer a search for what might come from the outside to cause this horrible disease; the answer was deep within.
The Varmus and Bishop discovery was that our cell’s own growth governing processes could go awry. It was clear that growth involved signals in body that were transmitted to the cells to turn on genes promoting cell division. Their work discovered genes that executed the growth program, but others then found viruses could also reveal the signals that triggered growth. One virus induced a red blood cell leukemia despite being able to infect a number of cell types. This so-called Friend virus apparently took advantage of some signaling process restricted to red blood cells. Studying it finally revealed that the virus worked by attaching to a receptor on the cell surface and that receptor regulated signals the body uses to make more red cells after a bleeding episode (or high altitude). Viruses might then teach us not just about the internal executors of cell growth but how signals from the outside can turn cell growth on or off. That was where I came in to the field: on the idea that knowing how viruses entered cells might lead to discoveries of new growth regulators at the cell surface.
A new Harvard faculty member was trying to discover the portals or receptors that other retroviruses used to enter cells. His name was Jim Cunningham and he had come from the lab of Robert Weinberg at the Whitehead Institute, a giant in the oncogene field and a personal hero of mine. Jim was thought sufficiently brilliant that he was given a Howard Hughes Medical Institute supported position, the most prestigious in basic life science work. I became his first postdoctoral fellow. I could barely speak the language of molecular biology when I started and had to learn it on the fly. I also still had clinical duties and the contrast between the worlds could not have been starker. Clinical decision making was based on limited data, was fast-paced and multidimensional: family meetings, reviewing x-rays, calling consultants, and deciding therapies filled every hour to overflow. Lab work meant thoughtfully designing and analyzing experiments where time lines were often long, never emergent, and all about precision. Jarringly different worlds with vastly different challenges and rewards, but all exhilarating. I loved it, but more than once nearly stopped the tough uphill climb of learning and doing science to embrace the clinical world I alread
y knew and knew I could do with some competence. But the draw in the lab of affecting a disease, and not just the individuals suffering from it, was a Siren song I could not deny. Admittedly grandiose, it was the motivation that fueled me and I think most physicians who do laboratory-based research.
I was to find how the cancer-causing Moloney retrovirus got into cells. The approach was to transfer the DNA from a cell susceptible to Moloney infection into noninfectable cells. If cells acquired the ability to be infected, then they must have acquired the receptor that was the portal for the virus. That seemed like a straightforward, simple strategy. It was, in concept, and that is the beauty and the beast of science. Simple concepts are very compelling, but often inexplicably hard to execute. It’s why it is so hard for people with an illness to understand why on earth it is taking so long to get something done. I will try to illustrate with my experiment.
The plan to take the DNA from one cell, break it up in fragments, and transfer all the pieces into a large group of other cells was technically challenging. Selecting the cells that became infectible was challenging. But technical challenges are just about rolling up sleeves and getting things done. Sometimes they bring things to a halt, but I have rarely seen that. Most of the time, scientists are creative enough to overcome or work around technical hurdles. Some win Nobel Prizes for doing so. The more difficult problem is interpreting the results.
When starting an experiment, you pose a question based on what you already know. In my experiment, we knew that we were moving DNA from one cell to another: one cell donating DNA to another. If that donor DNA allowed for virus infection, then the new genetic material in the now infectible cell had to be from the donor or the virus. So, we reasoned that all we had to do was find the donor DNA and exclude the virus genome, and we would have the gene that was the virus receptor. What we didn’t know was that viruses are not very discriminating. They not only carry their own genome, which may include hitchhiker oncogenes. But, they transfer lots of other genetic material outside their genome. Who knew? I pursued lots of hitchhiker vagabonds until it dawned on me that my assumptions about viruses were very wrong. I learned something I think could still be relevant for viral diseases, but I went down too many rabbit holes because of my presumptions. Fortunately, my labmate, Lorraine Albritton, was pursuing an independent path and found the receptor gene. Wonderful person that she is, she included me in the success (and publication in the prestigious journal, Cell) while not discounting my stumbled-upon discovery (published in the Journal of Virology). I was delighted to have something from my lab efforts in print.
With the exception of my work under Adel Mahmoud, my only previous research project had been done as an undergraduate at Bucknell in an honor’s thesis on the poet William Butler Yeats. A complex and contradictory man, Yeats captured yearning, passion, ecstasy, and loss in lyrical, almost musical terms. And he often did it by invoking images of nature. That is probably what most drew me to his work, but there was resonance in so many matters of the heart that I stayed with him delving into his off-beat mysticism and seemingly stoic, art-obsessed personal life. Oddly, it was spending the time digging deeply into Yeats’s work that convinced me I could take on scholarship and pursue bigger issues that were often complicated and difficult to conceptually unravel. It gave me the confidence to go to medical school and it gave me reference points for themes of personal life that I often heard in my patients. Yeats echoed often for me in hospital halls filled with people’s struggles. His art seemed to offer transcendence as it made many of the specifics of the moment part of the nobler endeavor of life we all share.
Yeats was, as I suppose most poets are, also very nonlinear. He forced thinking about things obscurely referenced in his words, but captured in his rhythm or in the associations of objects in particular settings. For me, it stretched my thinking. The closest connection was not the discussions of literature I had in most classrooms, but more the digesting of religious readings I had to sit through as a child. Bless my grandparents for making me, despite any and every effort to avoid it, attend church no less than once a week. The teachings were mostly deadly dull, but at least I had to do some tangential pondering. That’s what I turned to to figure out Yeats, and I do think it helps me still in overcoming false assumptions like I had made with my first real scientific project. Some mixing of logic and “what-if” conjecturing about alternative ways to put things together is both the joy and beauty of science for me. Nothing as profound as a “Sailing to Byzantium,” sadly, but complexity gaining form.
An enormously complex situation was playing out around me, when I was studying viruses as a simple form of cancer model. That was the AIDS epidemic that transitioned from rare curious case to a full-on epidemic of furious consequence during the time of my clinical and laboratory training. While I was working on retroviruses a specialized type of that kind of virus was identified as the basis for AIDS. I started my work on the idea that retroviruses had much more to teach us about cancer, but the cross-currents of science are such that, ironically, it was a failed cancer drug that provided the first glimmer of light for AIDS
Azidothymidine, which came to be called AZT, was developed in the early 1960s by a Wayne State University researcher named Jerome Horwitz. When AZT failed against leukemia in mice, Horwitz concluded it was a medicine “waiting for the right disease” and turned to other projects. Two decades later, as scientists and doctors scrambled to find something that might work against HIV, the drug company Burroughs Wellcome asked the National Cancer Institute to test AZT. The NCI, which was acting as a screening center for drugs submitted for testing by scientists, companies, and institutions, had a system for determining in a matter of days which substances were active against HIV. In early 1985, azidothymidine was one of a small number that showed promise. In July, it was ready to try on human subjects.
The first HIV/AIDS patients who received AZT developed moderate fevers, and their blood showed an immediate rise in the “T-helper” cells critical to immunity. In addition to the evidence found in the blood, doctors saw patients who were sick improve markedly. Their fevers subsided, and they started to recover from the opportunistic infections that were part of the HIV syndrome. The trial was stopped because patients on the placebo were dying and it seemed unethical to deny them the medicine that was working for those who received it. Burroughs Wellcome filed for the patents that Horwitz and Wayne State had neglected to obtain.
With AIDS deaths rising to forty thousand per year and advocates building a political movement to demand action, the Food and Drug Administration accelerated the process it used to consider the safety and effectiveness of new treatments. Rumors about AZT spread throughout the community of people with HIV, and patients clamored to join the few trials under way. A few, including the Republican power broker Roy Cohn, used their connections to jump the line to get it. (His illness was too advanced for the drug to help him.) In March 1987, FDA approval was granted, and thousands of prescriptions were written. Within a year or two, it became clear that the drug wasn’t equally effective in all cases, and HIV developed resistance to the medicine.
How did this resistance arise? For the most part, it was a matter of accelerated natural selection. Like cancer cells, which tend to grow faster with more DNA mistakes than normal cells, viruses that evade the immune system move quickly and mutate wildly. In the case of HIV, this frenzied activity inevitably produces some viruses that can survive in the presence of the drug. These survivors in turn produce copies of themselves and pick up where the original infection left off. But the fact that AZT had some positive effect pointed to promising areas for research. It also encouraged efforts on antivirals to treat a host of diseases. For generations, we knew that bacteria were vulnerable to attack by all sorts of medicines, from penicillin to ceftolozane. However, viruses had generally defeated the science applied to stop them. With the impetus of the AIDS crisis, crash efforts yielded other drugs that worked like AZT and could be used to treat herpes, fl
u, and other conditions.
AZT was followed by new categories of drugs, including protease inhibitors, which stop the production of new viral material. By 1996, combinations of drugs that were called HARRT—highly active antiretroviral therapy—produced a steep decline in AIDS deaths. It was a truly extraordinary time. Patients who had written their wills and said good-bye to family and friends were, within months, up and resuming a full life. Comparing some to Lazarus of the Bible was not a stretch—they literally arose from their death bed. It was also at this time that I was recruited to the Massachusetts General Hospital where I joined my dear friend Bruce Walker and the most extraordinary oncologist I have ever met, Bruce Chabner. Bruce Chabner was fabled for his leadership at the National Cancer Institute and was just arriving at the MGH to establish a patient-focused clinical Cancer Center: one that could leverage the new science emerging from Boston’s burgeoning megaplex of biopharma. But what made Bruce special was his humanity. He sincerely cared about patients and the people who took care of them. The explicit ethos was always, patients first. It sounds so obvious, but it is often left unspoken in the flight plan of academic centers. That was not true at the MGH and one of the reasons I love being a part of it to this day. In one of my first meetings with Bruce after he recruited me, we were speaking about my plans and as I was about to leave, he said, “And how can I help?” I had never heard that said in over fifteen years of various meetings with Harvard hospital and medical school leaders. It sounded a bell for me that I was now in a place I could call my professional home. I try to echo his words and sentiment in meetings ever since.
Cancerland Page 12