Cancerland

by David Scadden

  Over decades, Rosenberg and others gradually deciphered the chemical process that guided the interactions between cancer cells and immune cells. In the late 1980s, an Israeli immunologist named Zelig Eshhar was the first to create T cells with artificial antigen receptors, called CAR T cells, or chimeric antigen receptor T cells. In 1990, Eshhar spent a sabbatical year with Rosenberg, and they worked on strategies for coaxing T cells to do their work against cancer. Eventually they focused on CAR T cells that targeted melanoma. They used specific chemicals to give the T cells the ability to target melanoma cells and to heighten the power of their response.

  Biology being what it is, the job of switching on T cells to produce a response that would stop the development of cancer would not be as simple as adding a couple of bits. However, the results of these first experiments were positive, and by the year 2000, work would be under way on a host of ideas for switching on immune cells. Thousands of proteins were being screened to determine which ones might be helpful in goosing the production of these cells or changing their activity. This was somewhat similar to what we were doing with stem cells, trying to affect their fate by testing the effects of hundreds, if not hundreds of thousands, of compounds to make the cells behave in a particular way.

  Our many stem cell projects were aimed at the most basic science, including the problem of obtaining stem cells without the use of embryonic tissue. Two of our youngest team members, Chad Cowan and Kevin Eggan, plunged deep into this problem. Eggan had once considered becoming a medical doctor, but the cloning of the sheep Dolly, in 1996, had diverted him to basic science. Dolly had been created by Ian Wilmut of the Roslin Institute of Scotland, where he emptied a sheep egg of its nucleus, inserted DNA taken from an adult animal’s cell, and implanted it in a ewe. The lamb that was produced was identical to the sheep that produced the donor DNA. Noting the material came from a mammary cell, workers on the farm named the lamb after the famously endowed entertainer Dolly Parton.

  As the first cloned mammal ever produced, Dolly’s mere existence shocked the scientific community. Princeton biology professor Lee Silver told Gina Kolata of The New York Times that Wilmut’s achievement “basically means that there are no limits. It means all of science fiction is true. They said it could never be done and now here it is, done before the year 2000.” Many young people like Eggan and Cowan found this prospect thrilling and contemplated using Wilmut’s techniques. Cowan had always aimed at molecular biology and had done postdoctoral work with Doug Melton. They needed an alternative to what Wilmut had done in sheep since it didn’t work in humans. In 2005, Cowan, Eggan, Melton, and others reported that they had fused adult skin cells called fibroblasts and embryonic stem cells (instead of egg cells) and actually reprogrammed the adult cells, returning them to a state where they recovered the power to differentiate into any type of cell.

  The team’s success was dramatic, but not particularly useful as it depended on thousands of hours of solitary work, much of it performed while peering into a microscope and using foot pedals and a joystick to guide a needle into a single cell. Eggan, who would later describe this process as “the hardest video game you ever played,” developed back problems while learning how to do nuclear transfer at the Massachusetts Institute of Technology. His biggest challenge was maintaining his motivation as he failed thousands of times in experiments with animal cells.

  The exact nature of the fountain-of-youth process that Cowan, Eggan, and Melton tapped into wasn’t fully understood, but the hope was that it could be used to return other cells to a youthful state where they could develop into vibrant, functional new ones. The ultimate goal here was therapies that replaced cells that were responsible for heart failure or diseases like Parkinson’s. Such fresh cells, perfectly matched because they would be cultivated from the recipient’s own tissues, would be the holy grail of the burgeoning field of regenerative medicine. It wasn’t hard to imagine this science yielding improvements in existing treatments, like bone marrow transplants, rather quickly. Over the long term, it could even lead to the production of replacement organs. But as with every big scientific advance, regenerative medicine was bound to prompt worry and even fear in public officials and citizens. And once again, they would be given reason to be concerned about the integrity of those trusted to move research toward treatments.

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  The controversy around stem cell science, especially work that involved cloning and the use of embryonic cells, required us to be sensitive to the public relations aspect of our research. Even before the Harvard Stem Cell Institute formed, our goal of advancing stem cell research toward therapies was helped when Massachusetts General Hospital opened its new Simches Research Center and provided us with a big facility that was then named the Center for Regenerative Medicine and Technology. (In time the word technology would be removed from the name.) Stem cell research would occupy the core of the center’s work, but the emphasis on the regenerative treatments we hoped to produce stressed the benefits that could arise from the work. (With the acronym CRMT, I thought we should try to enlist Kermit the Frog as a mascot, but fortunately that idea never went anywhere.)

  The Simches building had been envisioned as a place for the most advanced types of medical research, and they admitted only five groups, including ones dedicated to genetics and computational science. The competition for these spots was quite intense and required that I present a proposal several times over. One stage of the process landed me before a review committee composed of top people outside Mass General. This was such an exclusive group that most had been awarded the Nobel Prize. Among them were Joseph Goldstein (cholesterol), Robert Horvitz (programmed cell death), and Phil Sharp (RNA). Although they did nothing to make me feel uncomfortable, I don’t think I had ever been in a room with such an intimidating amount of brainpower. I was terrified.

  Fortunately, in addition to making everyone without a Nobel Prize a bit intimidated, the level of excellence one encounters at Mass General tends to produce scrupulously fair processes that favor the best ideas. The review board, for example, was developed to assure that internal politics wouldn’t drive the decision making. No one in this group had a favorite among the competitors or a stake in the outcome. The priority was to take advantage of the incredible resources available, especially the human resources, to accelerate the development of treatments. The possibilities for collaboration and, to use a tired term, synergy, were so great that once you tuned in to the possibilities, it was hard to contain your excitement. This is what happened with the board of consultants. Their faces showed they understood the possibilities at hand, and my heart stopped pounding. Soon we were talking about what would emerge as the regenerative medicine center was established, not if.

  Frequently ranked the best hospital in America, Mass General excels at both clinical care and research. Many of our key allies would work in the MGH cancer center, where they were leaders in sophisticated molecular biology. The center’s chief, Daniel Haber, ran labs with dozens of scientists and physicians who, like me, blended investigations with caring for patients. One of Daniel’s big interests was cancer genetics, and he had recently assessed the genome of various lung cancer cells to discover why some could be stopped with a drug called gefitinib (the brand name is Iressa), but others could not. This was one of the early advances in personalized treatment for cancer patients. Daniel would go on to make great progress identifying how cancer cells circulated in the body, causing metastases even after patients were seemingly cured.

  Patients who developed new cancers after they underwent successful treatments could be emotionally devastated by the appearance of a new malignancy, and doctors generally felt the same way. It was known that cancer cells circulate in the blood, but scientists had trouble tracking them. Larger cancer cells could be caught in a filtering system, but this method was rudimentary and missed many. Haber and his colleagues would address the problem from the other direction, capturing far more of the bad-guy cells by removing everything
else. The process of doing this is part of a new field called microfluidics, which, as Haber describes it, allows for cells to be lined up and passed through a channel where they can be separated. Eventually this work would mean that a simple blood sample could be used to track the ways a cancer evolves in an individual and plan for treatments even before a person feels sick.

  As he worked in the context of a one-thousand-bed hospital that accepted the toughest cases, Haber was driven by the needs of real patients facing life-threatening diagnoses. My own contacts with patients, most of whom had abnormalities, leukemia, or lymphoma, made me acutely aware of the fact that we weren’t dealing with mere laboratory abstractions. We were seeking ways to help people who had received terrifying diagnoses and faced the prospect of difficult treatments, including surgery, radiation, chemotherapy, and bone marrow transplant. On the positive side of the clinical equation, we had treatments that worked and had refined them to reduce the suffering people experienced. However, everyone who came to us for care knew they faced a traumatic process. Treatment also meant helping people deal with the psychological realities of cancer, and this element of oncology always reminded me that our work in our sparkling labs equipped with DNA sequencers, centrifuges, and other pieces of expensive equipment should be devoted to the cause of the people we met in our clinics every day.

  In rare cases, it seemed like the dreadful prospect of conventional cancer treatment, as people understood it, actually turned out to be fatal. I’m thinking of a man I tried to treat during the early years of the stem cell institute. He was in his midthirties and had Hodgkin’s lymphoma. This disease is routinely treated with a drug protocol called ABVD, for adriamycin, bleomycin, vinblastine, and dacarbazine. The first component was found in the soil in Italy. The second was discovered by Japanese scientists working with bacteria. Vinblastine was derived in Canada from a plant found in Madagascar, and the dacarbazine was synthesized at a lab in Alabama. For people in my patient’s age group, only 10 percent who got ABVD would have a return of cancer. It was less toxic than the regimen it replaced, but this improvement was relative. ABVD still caused much of the suffering associated with chemotherapy (nausea, vomiting, hair loss, intense fatigue, etc.), and it was hard for some people to accept that this was the pathway to a cure. However, I had never heard anyone decline it.

  In this case, my patient was relatively young and strong and absolutely certain I couldn’t help him. I worked with a team of doctors and nurses, and when we met to discuss his case, I said, “For some reason, I’m not getting through, but maybe there’s some other direction that we can go in. Let’s each try.”

  When one of the residents went to speak with this fellow, she asked, “Do you have a problem with Dr. Scadden? If you do, that’s okay. Tell me. We’ll find somebody else. We’re here for you.” Several people tried this approach, and no one could get him to budge. He understood he had cancer, but he wasn’t ready to be treated. As he made his decision, he didn’t have any particular organ involvement that would have caused him discomfort, like shortness of breath. Some people never experience acute symptoms. Instead, they just get progressively more fatigued. They stop eating, curtail their activity, and very slowly die. This is what he chose. It was heartbreaking for his caregivers. These are rare instances, but when they happen, they’re just so striking you don’t forget them.

  Few things will bother a doctor more than a patient who chooses death over life, without offering any explanation. Years of experience don’t make these cases easier, and despite my best intentions, I sometimes struggled to leave the feelings provoked by them at the hospital.

  My family, like many doctors’ families, did their best to accept that I was distracted, or impatient, for reasons that had nothing to do with them. Kathy had an adult perspective that helped her know what to ignore, but Margaret, Elizabeth, and Ned sometimes struggled to understand that my impatience really had nothing to do with them. They were also challenged to accept my clumsy efforts to make up for lost time with them. A good example would be the time I rushed home with the idea that we should all go pick raspberries because they happened to be ripe. In my mind, this seemed like a perfectly reasonable notion, but I hadn’t slowed down enough to notice that no one else was interested in this activity. As much as I wanted to make up for my absences, for the times when emergencies took precedence, it couldn’t be done on my schedule.

  The burden of being a doctor’s kid is always added on to the more typical challenges all children face. Our family had some idiosyncrasies that already made us “weird” as far as they were concerned. For one thing, we expected them to come to dinner every night ready to share something, even something very minor, that they had learned during the day. It could be a new word, a fact discovered at school, or an item they read in the newspaper. Kathy and I also required that our kids do all their school projects themselves, without our help. Our community was full of professors and scientists and engineers, so you can imagine what their peers brought in for the science fair.

  Our hands-off approach to school projects was intended to encourage self-sufficiency. I’m not sure it worked. But if our kids were a bit frustrated, the experience hinted at the challenge adults face when they take on difficult tasks, from raising children to navigating a career, understanding that success is never guaranteed and that, generally speaking, no one is standing by to rescue you from a jam.

  Stem cell science remained one of the most promising avenues for research that might lead to treatments. This work required the best technology and people, and our institute was well outfitted and staffed. Our gleaming, well-equipped space provided laboratory facilities and office support for dozens of scientists, many of whom would lead their own small groups. The work was a matter of developing and refining concepts, conducting experiments, and then reviewing the results to determine the next steps. Experiments with stem cell transplants take sixteen weeks, at minimum, to complete. The results often show that your original concept was not accurate and send you back to the starting blocks.

  Frustrating as it may seem, experiments often end with a result that disproves your theory. Every finding has value, so I’d be reluctant to call these outcomes failures. But because eureka moments are so rare, I intentionally sought independent, almost-stubborn people to work with us. Colleagues around the world recommended candidates who possessed these strengths. We then searched among the candidates for a mix of backgrounds and strengths. We wanted some who had worked on genetic models in animals, others who had focused on bone, and some who had just worked on human cell lines and had done molecular biology techniques. We needed a spectrum of technical expertise as well as ways of thinking. It wasn’t as specific as filling out the roster of a baseball team and thinking, I need another infielder, but we were mindful of getting the balance right and maintaining it as the science changed.

  When people arrived, I encouraged them to speak frankly. Most, though not all, agreed to call me David and not Dr. Scadden. We did not assign research to people. Instead, we expected them to develop their own targets for investigation. They could ask big questions, and we would give them the tools to seek the answers. But I also required every newcomer to find a new collaborator for the lab. I never hired robots. I wanted people to connect with the fundamental humanness of what we were supposed to be doing, and I think unless people really feel that, it’s hard for them to deliver on what I believe is our mission and our responsibility.

  Most young scientists imagine they will one day have their own labs, perhaps at a university or in a biotech company, and we wanted them to develop the experience and talents to do this. But in addition to ability, top scientists must have the right temperament. They have to be willing to ask, “Am I crazy to be doing this? Is the data telling me to stop?” There’s only so much time and so much money. If you can’t interrogate yourself and decide when to stop, you can dig yourself into a hole. You’ll be eight miles deep and thirty miles off course with no chance to getting where you s
et out to go.

  Of course, no one is left alone to wander in the wilderness indefinitely. We regularly convene what’s called the Lab Meeting, where people are required to review their progress and then the group offers both critiques and advice. We ask for all the available data and spend lots of time pushing to see if it’s being used and interpreted in the right way. What is fact? What is opinion? Can you hold yourself to the standard of truth and ignore your desire for a certain outcome to your experiment? The point here is that everyone wants to find cures. But cures emerge from the kind of basic, incremental science that yields positive, negative, or ambiguous results. The key to thriving in this setting is to accept that a clear answer is the goal regardless of what the answer might be. Without this acceptance, you can become vulnerable to the forces that move people to fudge their results and commit fraud. The danger here is very real. Science itself is damaged by fraud, and those who commit it can experience such shame that they feel the only option is suicide. In 2014, Haruko Obokata, a Japanese stem cell scientist, published a fraudulent paper claiming a major breakthrough. After the fraud was discovered and investigated, her mentor, whose name was on the paper, killed himself.

  Given the stakes, the Lab Meeting is a serious matter. The critiques can be done cruelly or collegially, and we always stress the latter. This isn’t just to be nice. People cannot speak freely about their work if they fear being humiliated in front of their peers. Instead, they will hide their disappointing results, choosing to deceive rather than risk feeling ashamed. However, if everyone reports fully on results that are often puzzling or disappointing, we all get the idea that this work is extremely difficult and never proceeds in a straight line from problem to solution.