Cancerland

by David Scadden

  After first rejecting her application in late 2014, Rosenberg enrolled a patient named Celine Ryan in their trial in March 2015. The mother of five children, then forty-nine-year-old Ryan had been treated for colon cancer with all the standard treatments—chemotherapy, surgery, radiation—only to learn she had malignancies in her lungs. Her eligibility for Rosenberg’s protocol depended on whether her body was producing the kinds of cells that could defeat her cancer, if only there were enough of them. This would require surgery to remove three of her tumors, which were studied to determine that they did contain the right antitumor immune cells. Rosenberg’s group also studied the cancer to discover the cells that produced the right antigens, which are chemicals that attract immune cells.

  Having identified both the right immune cells and the antigen-producing cells that would help them go after the cancer, Rosenberg’s team created supportive lab environments where the cells could live and multiply. Eventually they cultivated one hundred billion cells, most of which were T cells equipped to go after Celine Ryan’s cancer. She underwent surgery to remove some of her tumors, and chemotherapy, which destroyed most of her existing immune cells and made way for the new ones, which were then infused into her bloodstream. All seven of the tumors that remained in Ryan’s lungs shrank over the months following the infusion, with six disappearing entirely. The last one seemed to be affected like all the others, shrinking after treatment, but then it stabilized and began to grow. Surgeons removed the part of a lung where it resided, and Celine Ryan was given hope for a substantially longer life.

  Rosenberg’s trial provided such an encouraging result that Carl June hailed it in an editorial that was published in the same issue of The New England Journal of Medicine that included news of the success against KRas. It was titled “Drugging the Undruggable Ras—Immunotherapy to the Rescue?” The question mark at the end of the title pointed to the fact that, as with most trials, Rosenberg’s treatment of Celine Ryan raised at least as many questions as it answered. The main ones involved Ryan’s own special genetic makeup, which predisposed her to treatment success, and the fact that one of her tumors developed the ability to resist the attack of the T cells.

  When the cancer was removed, along with surrounding lung tissue, study showed that its cells no longer presented the antigen that drew the attention of the immune cells. They were, it seems, new, invisible mutants and free to multiply unseen and unmolested. When asked to comment on this development, Drew Pardoll, an immunologist at Johns Hopkins, said, “The tumor always seems to come up with a workaround.” Nevertheless, he and just about everyone else in cancer immunology considered Rosenberg’s use of immunotherapy against a cancer based on a mutant Ras gene a huge step forward.

  Rosenberg’s work also represented further support for the idea that cells themselves could be therapy. In the blood field, that is certainly not a new concept as the first transfusions were done centuries ago. Blood cell infusions have been historically viewed as supporting a depleted blood system. An extension of that thinking is blood stem cell transplant, where the cells were repleting stem cells eliminated by therapy. The engineering of immune cells or stem cells represented an important departure from the mere replacement concept. Blood or immune cells could be the definitive treatment itself. They could essentially be a drug.

  Drugs are only used after it is understood where they go in the body and how long they last. That has been extremely difficult to do for cells. To see if we could learn more about how transplanted blood stem cells behaved we teamed up with a photon physicist who is a colleague within the Harvard Stem Cell Institute.

  An extremely inventive scientist, Charles Lin has built custom instruments that use lasers to peer into tissues at the cellular level. Since we still had many unanswered questions about how bone marrow cells act and interact, we worked with him to use a phosphorescent tag derived from glowing jellyfish to paint bone marrow stem cells taken from mice. Here it helps to know a bit of physiology. Like all humans, adult mice produce blood stem cells in the bone marrow of the vertebrae, sternum, and pelvis. These structures are a little bit hard to penetrate with Lin’s lasers, but the skull, which is shielded only by a thin layer of skin, also produces these marrow stem cells.

  Lots of marrow transplant research is done with mice, so it was a matter of routine for Lin, and us as his collaborators, to perform one with cells tagged to be seen by Lin’s lasers. He then trained them on the right spot, and we saw, in real time, where the transplant took up residence in the marrow. What we saw were stem cells that were red in color migrating to microvessels in the bone marrow where they were attracted by a certain protein. I know this may sound a little abstract, but in fact, it’s the kind of thing that gets hematologists quite revved up. Finally, we were able to see at the level of individual cells the events that previously were just imagined as the likely events in a stem cell transplant. We were even more excited when we went back, seventy days later, and saw that those cells had divided. They were functioning as if they always lived there and, in fact, this defined on a functional level a home or “niche” for blood stem cells in a transplant. Why did we care? Because it meant that we could better understand a process that we knew was lifesaving. If we could understand it better, we could design rational ways to try and make it work better, be more effective for patients.

  Photon physics is hardly the only unexpected scientific specialty aiding our stem cell and oncology research. Another key collaboration we’re exploiting involves a lab group devoted to informatics, which means tracking and analyzing so-called big data. In broad terms, big data refers to huge blocks of information that can be analyzed by various programs to detect patterns or associations. Historically, the human brain housed the best system for managing multiple inputs, but over time, the brain’s limitations became quite evident. The specialization seen in science and medicine during the eighteenth and nineteenth centuries can be seen as signs that the volume of information being produced by research was outstripping our capacity to absorb it and make sense of it. This specialization increased steadily to the point where, by the 1970s, physicians routinely complained of not being able to keep up with journal articles even if they practiced in a limited subspecialty. Bad as this problem was for clinical practitioners, who worried about providing the best care, it may have been worse for researchers, who could labor in one corner of science for many years and lose touch with the context of the problems they sought to solve.

  Repeated experience with ideas that seemed promising in a lab dish, or a mouse, or a few patients but failed to become reliable therapies for human beings teaches us that biology is incredibly complex. The chemical processes that produce life in all its forms, including mutated forms, depend not only on molecular interactions but on events within organ systems and the body as a whole. Add outside forces such as viruses and radiation and the role that chance can play in billions of daily cellular events, and the whole thing can seem beyond any individual’s ability to comprehend. This is why we often consult with colleagues who process the data streaming to us from all over the world and others who apply mathematics to cancer science on the theory that we do have the computing power to investigate problems with algorithms.

  At a lab affiliated with Harvard and the Dana-Farber Cancer Institute, a group led by computational biologist Franziska Michor studies cancer and cancer treatments, trying to figure out how the disease develops, often in a way that seems to echo evolution, and how it continues to evolve in response to treatment. Michor is working on many of the cancers that first interested me, including leukemia, and hopes to define just how malignancies evolve to become resistant to treatment. She is also determining schedules and dosing, for both chemotherapy and radiation, that would provide the maximum benefit without prompting resistance.

  Michor, who came to the United States from Austria, first became interested in her area of science when she read a paper written by Peter Nowell, who codiscovered the Philadelphia chromosome. In what
Nowell described as a kind of “thought experiment,” Nowell speculated that multiple mutations must take place before cancer gains a toehold in the body. “Over time more and more mutations accumulate,” notes Michor, “and eventually the tumor is expressed.” Nowell’s paper also predicted personalized cancer treatments of the sort devised by Steven Rosenberg with his patients’ own immune cells.

  Work that followed Nowell’s paper turned it from a hypothesis into a theory that has been supported time and again. This science confirmed that one of the tradeoffs made by animals that become multicellular in order to occupy certain environmental niches—the giraffe’s long neck is an example—is that as cells differentiate into many different types performing many different functions, the chance that something will go wrong increases. Oftentimes, evolution confers positive traits. Elephants, for example, have forty copies of the famous p53 gene, which confers protection from cancer. Humans generally have two copies. Elephants almost never develop malignancies.

  Another good-luck story of evolution and cancer involves the sharp-toothed marsupial known as the Tasmanian devil, which suffered a catastrophic epidemic of cancer, seemingly spread by bites that transmitted cancer cells, that threatened it with extinction. Devils have a short natural life span—five years on average—and scientists who studied the die-off noted rapid evolution in the animal’s genome, with cancer resistance increasing. The helpful genes were always present in some individuals, but in six generations, they became more common, and the population loss, which had passed 70 percent, appeared to level off. As of early 2017, it looked like the poor little devils would make it.

  Viewed as a whole, the human immune system could be recognized as a significant genetic response to threats from disease, including cancer. It is largely dependent on stem cells that are kept in safe corners of the body where they do their work. Our blood stem cells, for example, migrate from the liver of the fetus to a “niche” composed of two sections inside the bone. This niche is found mainly in the hollow places of flat bones—hips, skull, ribs, shoulder blades, and the like—where the bone marrow is enriched by blood vessels and capillaries. Thanks to evolution, every animal other than fish that possesses blood and a skeleton, from birds to primates, relies on this type of system. Bone, which is made of crystallized calcium and other minerals as well as fibrous collagen, is a fortress that makes the niche less vulnerable than the liver when it comes to genetic disruption from radiation and other insults.

  NINE

  FROM GORY TO GLORY

  To be involved in medical research, a seat belt is sometimes required. The flow of new information coming in from closely allied and distant fields creates its own turbulence. But perhaps the most jarring is the forward-moving research edge colliding with the black hole of our ignorance. Sometimes that collision comes when a great discovery of a prior age is seen through the lens of today.

  For example, sometimes a person’s immune system will stray beyond its boundaries and start attacking the body’s own cells. This so-called autoimmunity is what causes type 1 diabetes, multiple sclerosis, and a host of other ailments, including blood diseases. Blood stem cells, red cells, or platelets needed for blood clotting are not uncommon targets. The result can be life threatening. so for ages doctors have sought ways to treat these conditions. A century ago, it was found that infusing animal serum worked. It could raise the blood counts. I teach a course to Harvard freshman called “Blood: From Gory to Glory.” It is about how we constantly re-know things we think we already understand. Blood has been known as the stuff of life since historic time began and yet we constantly are learning new things about it, use old principles to make it better and sometimes scratch our heads at how unbelievably primitive “modern” medical science can be. I took the twelve freshman in my seminar to meet a young woman in the process of getting treatment for her low blood counts. At one of the greatest institutions of medical science in the world, Massachusetts General Hospital, she was getting what could only be considered a primitive therapy: an infusion of horse serum. It worked, but surely we could do better (and, in fact, new approaches have emerged in the intervening three years or so). For the students it was a clear indication of how the forward thinking of one era can seem like magical primitive thinking to another, and how new thinking was constantly needed to improve our condition.

  The ancient Greeks opened veins and drained blood from the sick because they thought many illnesses were caused by an imbalance of the “humors,” which also include bile and phlegm. Blood-letting remained part of medicine for more than a thousand years. After he suffered a seizure, England’s King Charles II was subjected to so much bloodletting by his doctors that he lost one quarter of all his blood. His treatment also involved enemas, emetics, and quinine. Of course he died. The same fate met George Washington, who, when he suffered an extreme throat infection, ordered a servant to open a vein before his doctor arrived to continue the procedure. Belief in this therapy persisted until the second half of the 1800s, when Louis Pasteur and other pioneers of modern medicine began to discredit it.

  Lacking the ability to intervene with the body, except to manipulate fluids, physicians turned to bloodletting because it seemed rational in the pseudoscience of the day. The ancient Greeks constructed a logical order of things in nature as comprised of earth, air, fire, or water. That four-part rationality was applied to the seasons of nature and of life and to what gave us life in the four humors: blood, black bile, yellow bile, and phlegm. Each was given significance in our personalities and in our health, particularly by Hippocrates, the great proponent of rationality in medicine whose “Oath” is still recited by doctors receiving their medical degrees today. When health failed, it was regarded as an imbalance in the humors and the response was to purge or bleed. Remnants of this seemingly rational, but highly unscientific reasoning continues today with “cleansing enemas.” Physicians commonly used the application of leeches or simple bloodletting well into the twentieth century in part goaded by the imbalance theory, but also because it allowed them to do something dramatic in the face of suffering.

  Blood being central to life is something no one could dispute. Old medical practice leveraged that instinctive knowledge and in so doing also indirectly claimed connection to higher powers. Blood is a part of virtually every mythology and every religion, particularly religious ritual. Blood sacrifice was a critical component of ancient Mesoamerican practices as a means to feed the gods so their gift of a good harvest would continue: blood was a kind of restorative fuel. In ancient Middle Eastern traditions, it was often used in sacrifice. The word origin of sacrifice is to “make sacred,” a way of connecting us to what is holy. In South Asian traditions it represented the fearsome power of the gods, as in the terrifying Hindu goddess, Kali. The ancient Greek myths perhaps synthesized the duality of blood’s power to take and to give life in the story of Asclepius, the son of Apollo and a mortal mother. He was taught by the centaur, Chiron, in the healing arts and was said to be given by Athena two vials of blood: one from the right side of the head of Medusa that gave eternal life, and one from the left side that gave instant death. Blood was the basis of both and yet Zeus, angered at the notion that Asclepius could use blood to change the order of things, struck him down with a thunderbolt. No matter what power may appear to be in the hands of healers, it is the fate the gods impose that ultimately wins out.

  The duality of blood embodied in the myth of Asclepius is mirrored in the stick he is often depicted as carrying. It is entwined by a snake—a fearful creature, but one that also has great regenerative power; it sheds its skin and creates it anew. That combination of horror and regeneration is associated with blood in a more modern tale, Dracula

  The tale of Dracula, first published in 1897 by the Irishman, Bram Stoker, borrows from much older Eastern European tales of vampires. But while Stoker’s nocturnal, pale-faced monster might be considered elegant and magnetically appealing, the traditional vampires that inspired him were hideous, r
uddy-faced corpses that became animated and pursued their prey day and night.

  Experts in myth say that every monster we invent is a reflection of some basic human fear—most often our fear of death—and that in confronting these creatures in stories we gain some mastery over existential realities. In the case of Dracula and other bloodsucking creatures we can also see that on a conscious and even subconscious level blood is our well-being, both physical and psychological. As Dracula takes the blood of innocents, he converts the victims into creatures of evil, building on the fearful notion that blood can create a contagion. Central to the story is that blood rejuvenates Dracula, not just giving him life but making him younger and more vigorous. This is a theme that permeates all the vampire myths and has gruesomely played out in some historic circumstances. The Countess Elizabeth Bathory of Hungary murdered hundreds of young women in the sixteenth century to bathe in their blood so as to retain her youthful looks. Despite the clear madness of such magical thinking, there is some scientific basis to the idea that in the blood there is youth.

  Recent animal studies tested whether the changes with age were transferrable by blood. Mice were connected by a skin flap so they exchanged blood over time. Connecting a young mouse to an old one remarkably made the older animal heal better. The blood allowed for rejuvenation, but what in the blood caused this has been difficult to define. A single chemical in the blood may not be sufficient, but candidate molecules are now being tested with some benefit in animals. The fearsome elements of the vampire myth may yet prove to give us hope for healthier aging.