Cancerland

by David Scadden

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  Some big scientific research institutes acquire (or build) large facilities and put up big signs to indicate their presence. In 2017, for example, Cambridge University in England embarked on the construction of a big, freestanding facility to study stem cells, molecular biology, and cancer. Other institutes are essentially virtual organizations in which colleagues are linked by managers and funding streams but do their work in scattered locations. Some of our scientists would be gathered together in roughly forty thousand square feet of new space being built by Massachusetts General Hospital, but we weren’t going to get our names on the building, and far more of us would work in labs and offices around the greater Cambridge area.

  The important thing wasn’t for us to all be together every day. What mattered more was that an organizational structure be created—this is was what was meant by “institute”—and that it encourage and facilitate regular communication across disciplines. This was important to stimulate creativity but also to focus Harvard’s energies in this area to set certain standards and expectations. We were serious about the lofty purpose of the university, so the institute’s ultimate goal would be treatments for diabetes and a host of other diseases and conditions, including cancer. High standards would be required to protect all of us from the pressures that scientists feel when great sums are invested in work that is so full of possibilities. In a field like stem cells, it doesn’t take much to attract the attention of the press—or, for that matter, investors—who want to be the first to learn of a breakthrough. These are just the circumstances when the temptation to cut corners, exaggerate results, or even deceive can be extreme.

  We convened the first meeting of the stem cell institute in a conference room at the American Academy of Arts and Sciences in Cambridge. Founded by a group that included John Adams and John Hancock, two of the academy’s first members were George Washington and Benjamin Franklin. Its history and membership make it one of those places where you feel a bit awestruck as a first-time visitor. But the whole purpose of the academy is encouragement, not intimidation. Like Harvard University, it is a place that gives you permission to think in an expansive way, take creative risks, and persevere. One the most sweeping studies of top scientists ever done showed that creative perseverance, which I believe is encouraged in the best institutions, is the key to success. This process was shown to be a critical aspect in productivity for scientists in any age group. According to the study’s authors, big successes come when the right person takes up the right idea at the right time. Some hit this sweet spot when they are young and so energetic they can pursue lots of concepts at once. Others just never cease and, given the right support, reach their destination in due time. As one of the paper’s authors noted, Jean-Baptiste Lamarck didn’t publish his landmark book on evolution, which preceded Darwin’s On the Origin of Species by fifty years, until he was sixty-six. Philosophie Zoologique was the product of nearly thirty years of work and was followed by a seven-volume Histoire Naturelle.

  Our group at the academy ranged in age, experience, and scientific perspective and possessed, I believe, the hard-to-define quality that the authors of the paper on successful scientists called Q. Their Q referred to the ability to find a research subject suited to their abilities and to the needs of the day. Our group—which included, among others, Leonard Zon, George Daley, Stuart Orkin, Jeffrey Macklis, Richard Mulligan, and Gordon Weir—had Q in the extreme, with expertise in cancer genetics, hematology, pediatric cancer, neuroscience, diabetes, stem cells, and more. Being nerds, we had flip charts and a big board where we could create a matrix. On the left side, we made a vertical column of interest areas—diabetes, cardiac, neuro, blood, cancer, muscle, kidney, and so on—and across the top, we listed research approaches. The more we talked, the more we realized that rather than compete with each other, we would wind up adding to existing projects and developing whole new approaches based on the fact that we discovered different people interested in the same problems—kidney disease, for example—who were making progress by approaching from completely different directions. Our institute could bring these people and concepts together. As word of what we were planning circulated, we began hearing from those who wanted to be a part of it. From this pool, we would settle on twenty-five principal investigators, who were already overseeing their own research groups, and an additional seventy-five scientists. We engaged seven of the university’s degree-granting colleges and an equal number of hospitals.

  The enthusiasm for the Harvard Stem Cell Institute suggested to us that we might have underestimated the number of our colleagues who were keen for collaboration. (I also underestimated Larry Summers’s prowess as an advocate, as he turned out to be very good at raising money on our behalf.) In short order, we had set in motion the development of an independent lab space at Massachusetts General Hospital and were planning an outreach program to alumni, a group that included many prominent people who devoted substantial sums to philanthropy. We also began recruiting top scientists within the Harvard community and outside it.

  We already knew many of the people we wanted to court. George Daley, for example, was a stem cell pioneer who had earned a doctorate in biology at MIT and a medical degree from Harvard, where he was one of only twelve people ever to graduate summa cum laude. As a young scientist, he had worked in the lab of Nobel winner David Baltimore, where he had beautifully demonstrated what Janet Rowley proposed for CML. He used a retrovirus to put the fusion gene from the Philadelphia chromosome into a normal mouse blood stem cell and converted it to a leukemic cell. That was proof that the fusion gene really did cause the leukemia rather than just being associated with it. He now wanted to see if he could make blood stem cells from embryonic stem cells. It sounded easy in theory because embryonic cells should be able to make any cell type, but it was very difficult to do. George would spend over a decade trying to do it with only now appearing to be close to the finish line. He was also a physician who wanted to see science deliver for patients. When he agreed to join us, adding the weight of his reputation to ours, the stem cell institute had more of the gravity needed to attract young stars.

  As in most fields, the most promising newcomers in science can be a little picky about where they establish themselves. Most look for places where they might access the best technology, find financial resources, and build their own teams. The Boston area was home to at least four centers that would be on any well-informed scientist’s top ten for biological or medical research in the world. This status put us at a distinct advantage when we approached budding young stars like Amy Wagers, who was working at Stanford with a legendary cell biologist named Irving Weissman.

  (Weissman and I had a bit of a history. He had once written to me to complain, quite bluntly, that I hadn’t credited him in a paper. I tend toward being extra generous in this kind of thing, so I was apologetic about the oversight. I immediately dashed off a note that said, in essence, “That banging noise you hear is me pounding my head against the wall.” We eventually became friendly enough to go fishing together.)

  As a child, Wagers had been part of a Duke University program for the gifted, where one of her first courses was in writing, which helped her develop superior communication skills, especially for a scientist. In high school, she studied animal behavior and primatology at the University of Arizona, beginning an intense review of the sciences that led her to Northwestern University and a doctorate in immunology. (Her first paper, published before she finished at Northwestern, opened a significant new avenue for research into immune cells.) At Stanford, Wagers was known for taking on so much work that Irv Weissman concluded that it was impossible to find the limit of her capacity. In our discussions, she may have been won over by the idea that her curiosity and energy would meet few obstacles and might be amplified by contact with the different perspectives we would recruit to the institute.

  Putting together our group was a bit like assembling a college football team—the best players wanted t
o know they were headed for a place where they would find competitors at their level. Soon after Wagers agreed to join the institute, we also got commitments from Kevin Eggan, who was working with Doug Melton and Konrad Hochedlinger, who had been a protégé of cloning expert Rudolf Jaenisch at the Massachusetts Institute of Technology. Konrad was also being courted by Boston Children’s Hospital and the Memorial Sloan Kettering Institute in New York. However, we managed to team him with a Harvard alumnus who would fund his work based at the MGH, and this dedicated stream of donations gave him confidence in his future with us.

  As we put our team together, we learned that others were choosing the same path, hoping to keep stem cell research going in the United States without any federal involvement. Stanford University had created a $12 million fund for stem cell science, and New Jersey’s governor made his state the first to create a local initiative, with a $6.5 million grant to Rutgers. Work was continuing at Johns Hopkins and the University of Wisconsin. In California, activists were writing a ballot initiative that would ask the state’s voters to create a $3 billion stem cell research fund. This referendum, which would pass in 2004 with a significant margin, recognized both the scientific and economic value of this kind of work. Just as computer hardware and software development made Silicon Valley and the Boston suburbs into business powerhouses, stem cell research would bring development and wealth to the locale where the most successful work was accomplished.

  The stem cell promise went beyond cancer, and even Doug’s work in diabetes, to include other diseases that could potentially be improved under a new rubric called regenerative medicine. This science considered the challenge of creating human cells, tissues, and even organs. Although it verges on science fiction, the end goal was to restore and perhaps even rejuvenate the tissue of the human body. I had seen it happen with bone marrow transplantation, where normal blood cell production could be regenerated from terribly diseased bone marrow. It was an already practiced form of regenerative medicine, but the term wasn’t regularly used until the early 1990s. Enthusiasm for the field was heightened by Thomson and Gearhart’s work on human embryonic stem cells, and ongoing research considered cellular fixes for nervous system disorders, brain damage, endocrine illnesses, and even heart disease. While embryonic stem cells were the main focus of attention, there was already evidence that therapies could be developed without the use of blastocysts or fetal tissue. Stem cells could be found in adult tissue, as well as in the blood left in the umbilical cord at the time of a baby’s birth. Although the potential of cord blood had been clouded by significant amounts of hype (some of it coming from commercial collection and storage companies), these cells were already being used in the treatment of leukemia. It was quite possible that they would be useful, with a bit of coaxing, in other diseases.

  The ultimate end point for regenerative medicine, a point rarely discussed, could be the extension of the human life span. This was not something one discussed without great care because everyone is interested in living longer and any suggestion that such a thing is possible can lead to a realm of make-believe. The first recording of the human dream of an intervention to extend the life span is a reference in the works of Herodotus, which were written about 2,500 years ago. Herodotus’s concept of a fountain of youth may have been formalized first in ancient Greece, but it’s certain the earliest human beings fantasized about life extension from the moment they recognized the reality of death. In the early twentieth century, the Life Extension Institute of New York was formed with the philanthropic goal of extending human life, but in 1936 it entered into a consent agreement that prohibited it from practicing medicine in New York. In 1972, an Arizona-based nonprofit called the Alcor Life Extension Foundation was founded to begin freezing human bodies (sometimes minus parts) moments after death on the chance that one day the technology will exist to revive them. Clients remain at −320 degrees to this day, though, prospects for their revival aren’t any better now than they were in ’72.

  Alcor’s approach to longevity is a great example of the way that a little bit of scientific truth can be misapplied to reach an extreme conclusion. In reality, some substances like bone marrow can be frozen and thawed and retain their life-giving qualities. However, this can only be done with materials that don’t allow water crystals to form. Once water starts to crystalize, the expansion that comes with it bursts cells just as it does frozen pipes. The chemicals used to store cells prevent water crystal formation, but they just cannot get into whole organs sufficiently to allow the organs to be preserved. Thus, a frozen organ, like the brain, cannot be frozen and thawed, no matter how carefully, and have any normal function. Perhaps fortunately, such limitations keep the events of Mary Shelley’s Frankenstein fictional.

  There is another reason why cells just cannot be made to grow forever and it is called the Hayflick Limit. Named after Leonard Hayflick, it is based on his careful work sixty years ago showing that cells can only grow and divide in culture forty to eighty times before they stop. The number of cell divisions varies depending on the cell type, and stem cells may be able to overcome the Hayflick Limit. But more mature cells cannot. The basis for the limit is thought to be the gradual loss of the ends of chromosomes called telomeres. These serve almost as bumpers—caps at the ends of chromosomes to prevent them from being chewed away by enzymes or getting into mischief with other parts of chromosomes. The problem is that they do not get fully replicated with the rest of the chromosome during cell division. The telomere then gradually shortens until it is sufficiently depleted, at which point cells get into trouble with any further cell division and stop. Stem cells and cancer cells can rebuild those telomeres and so are less subject to the Hayflick Limit—they can keep dividing. But even our stem cells start to decline in function over time. It is thought that part of the limited ability to regenerate as we age is the loss of functional stem cells. Regenerating them is critical for regenerative medicine.

  Pluripotent embryonic stem (ES) cells offered the possibility of making all kinds of stem cells for organs that needed regenerating. That was part of the hope in our nascent center: We thought the ES cells could make the mature cells of a particular organ and the stem cells of that organ to sustain it. We knew stem cells were also cells that could be genetically manipulated. If that could be done to replace missing or defective genes then the new stem cells might correct the basis for some diseases. Stuart Orkin was internationally recognized for understanding the genetic basis for horrible diseases like thalassemia and was a stem cell expert; his joining us made it possible to envision new blood-based stem cell therapies. Jeff Macklis was showing that neurons in animal adult brains could be provoked to reform the circuits necessary for function, giving us hope that we could develop stem cell approaches to brain disease. Doug Melton was showing the adult pancreas didn’t have stem cells capable of making new insulin-producing cells, but he was systematically finding out how ES cells could. The possibility of regenerating or repairing injured organs using stem cell biology was the light that drew us together. The shadow was the possibility that these cells could teach us about or even cause cancer. That was a lingering issue only time could unveil.

  SIX

  SNUPPY THE HOUND AND IPSCS

  As we announced the creation of the Harvard Stem Cell Institute, the science around cancer and the other diseases we would study continued to race forward. Research on the immune system, which got a big boost with the work done on T cells—a subtype of white blood cells—during the AIDS crisis had progressed steadily under the leadership of scientists like Steven Rosenberg at the National Cancer Institute.

  For years, Rosenberg had doggedly plotted the relationship between cancer and the cells the body can deploy to defeat it. The wellspring of these immune cells is the bone marrow, which deploys them via the bloodstream and lymphatic system. (Hence, the vital importance of blood and bone.) In 2004, Rosenberg started a small human trial—seventeen patients in all—using genetically altered T cells against
the most serious form of skin cancer, melanoma. Perhaps the most intriguing thing about his approach was that it drew from the two most promising areas of cancer science: genetics and stem cells.

  Understanding Rosenberg’s work requires recalling that for every mutation that evolves into a disease called cancer, we experience countless ones that are identified and halted by our natural defenses. This defense depends on the fact that malignant cells emit chemicals called antigens, which signal the waiting fighters of the immune system to take action. These defenders, which are mostly T cells and B cells, must also possess an antigen receptor that responds to the antigen and continues the immune response.

  When cancer progresses, it’s often because we don’t have enough immune cells equipped with the right receptors. However, a few properly outfitted immune cells generally do appear, and they will get through to do a bit of damage to the growing malignancy. Rosenberg theorized that if he could find these effective immune cells and somehow create more of them, he might be able to intervene and tip the scales.

  Rosenberg had become intrigued by the potential of the immune system when, as a surgeon, he performed a gallbladder surgery on a man who had had a stomach cancer removed in a previous operation. Reports from the original surgery noted that the cancer had metastasized to his liver, but when Rosenberg searched for those tumors, he couldn’t find them. Further investigation confirmed the patient no longer had cancer at all. Intrigued, Rosenberg wondered if the man’s immune system was somehow superpowered. Knowing that the blood was one place where he might access this power, he experimented with a transfusion of the cancer-free patient’s blood to one with a similar malignancy. The transfusion didn’t work as a cure, but it did set Rosenberg on a lifelong quest to discover how the seeming miracle of the missing metastases occurred. The key, he knew, was in the man’s immune system, which had failed against the mass in his stomach but managed to succeed in his liver. “Something began to burn in me,” explained Rosenberg later in life, “something that has never gone out.”