Cancerland

by David Scadden

  While angiogenesis research didn’t cure cancer in two years, it did and does still offer new approaches. A nuanced view of cancer at the end of the twentieth century would have revealed that painstaking work on a number of fronts was yielding real, if not-quite glamorous results.

  Most notable was the fact that the death rate for all forms of this disease had peaked in 1991 and have dropped slightly every year since. Much of the reduction was caused by antismoking campaigns and the decreased incidence of tobacco-related cancers in men. Screening for colon cancer, and the removal of precancerous growths during colonoscopy, also helped. The 1990s also saw the emergence of testing for genetic abnormalities known to raise the risk of cancer. Two genes in particular—BRCA1 and BRCA2—were so strongly associated with breast and ovarian cancers that many women who were found to carry them underwent preemptive surgeries. These operations reduced the odds of a woman developing breast cancer by half. The risk of ovarian and fallopian tube cancers was cut by more than 70 percent. But all of these can be seen as the fruits of cancer research—some from epidemiology, studying the basis for outsized risks in groups of people, and some from basic research.

  For people diagnosed with cancer, improved surgical and radiotherapy techniques also brought better outcomes. However, the advances imagined in the 1960s, when scientists began to speculate about intervening at the genetic level to stop cancer, had not arrived. In 1990, the first patients to receive human gene therapy for any illness—a severe combined immunodeficiency—did well when a functioning gene was delivered to their white blood cells with the help of a virus modified to be harmless. The fix could be permanent and it was promising enough to drive intense research for more and better gene-based therapies. Then the worst of the fears expressed decades earlier by those who doubted the safety of genetic therapies came true. In 1999, an eighteen-year-old named Jesse Gelsinger died after receiving an experimental genetic therapy for a metabolic disorder.

  The genetic cause for Gelsinger’s disorder had been discovered as scientists mapped the genetic causes for a host of illnesses. His treatment had been approved by federal authorities who had considered more than three hundred proposals for experimental therapies and approved forty-one that targeted conditions caused by single gene mutations. Gelsinger, who developed the disorder in childhood because his genetic deficiency was only partial, required a severely restricted diet and took dozens of pills per day to survive. He had told a friend that his death would be the worst possible outcome of the experiment but then added, “If I die it’s for the babies” who had the same disorder at birth. But if their deficiency was complete, it was invariably fatal.

  Jessie Gelsinger died of multiple organ failure likely caused by an immune response to the virus that carried the genes he needed. The virus used was not a retrovirus, but an adenovirus to which most people have some degree of immunity. An investigation into the tragedy pointed to the possibility that researchers overlooked signs of trouble, rendering the patient more vulnerable to an immune injury to the liver, and may have been unduly influenced by a financial interest in the therapy they were developing. As news of these findings spread, scientists working on gene therapies saw support evaporate. The federal Department of Health and Human Services imposed new regulations on gene research and sent teams to review work going on around the country. Harvard was one of ten places that would receive extra scrutiny. The local paper, the Boston Globe, discovered that roughly one-third of the gene therapy trials involving patients would be closed. When I was asked to comment for the article I stressed the positives that might emerge from the crisis. “The field is chastened in a way that will ultimately help it,” I said. “The more we can do to avoid ethical or safety issues that undermine the science the better.”

  Shaken by the Gelsinger tragedy, the angiogenesis controversy, and other factors, public trust in science and medicine, as measured by the University of Chicago’s General Social Survey, would drop sharply between 1999 and 2005. Nevertheless, doctors and scientists enjoyed a higher level of public confidence than the members of other professions, including civil servants, business leaders, lawyers, and politicians. People may have been impatient for us to make the kind of progress promised when I was a kid reading Life magazine, but they continued to have faith in us.

  I would argue that generally this faith is well-placed. Scientists and, I should add, the families of scientists, sacrifice a great deal to the cause of advancing our understanding of the world and to keep in check the competitive drive that can motivate some people to take shortcuts. At my house, Kathy, Margaret, Elizabeth, and Ned put up with my absences and the fact that even when I was present I could be distracted, because they knew that what I was doing was extremely difficult and might just be important. Much as I tried, my schedule was unpredictable, and too often I would find myself delayed in either patient care or as our group labored over a paper or a grant proposal that lacked some important detail.

  Sometimes the sticky problem that kept me working later than expected was something as mundane as a misplaced illustration. This is precisely what occurred one evening as we tried to address a critique we had received for a paper we had submitted to the journal Science. At that time, we worked with printed photographs of images of cells or other data. We had to paste those into composite figures, sometimes of many parts. Late that night as we were assembling the final versions to tuck in the mail, one small image had apparently fallen off and we could not locate it. We searched for seemingly hours and finally gave up. We resigned ourselves to taking up the search the next day and I drove home having missed one more dinner and one more round of bedtime rituals. At home I went to the kids’ rooms to check on them as they slept. When I leaned over Ned’s crib the photo fell out of my shirt pocket and landed faceup on his forehead. The dear boy saved the day without even a pause in his rhythmic slumber. If only I had come home earlier.

  FOUR

  CHEMICALS IN CONVERSATION

  Chemistry is the language of cells. The conversation begins with deoxyribonucleic acid (DNA), which directs the assembly of life in all its forms. Chemistry is also the science that brings precision to biology. Decipher how chemicals communicate to direct the activity of a cell, and you are on your way to finding interventions to halt disease and enhance health.

  In oncology, as in all areas of medicine, how chemicals communicate is through the vehicle of the most fundamental unit of life, the cell. Understanding how cells behave and how that behavior is corrupted in cancer is the holy grail. Yet, studying the cancer cell in isolation is not necessarily the way to gain understanding or dominion over cancer. A case in point can be found in James Allison’s work on T cells.

  Born and raised in a small town in Texas, Allison showed early signs of a strong and persistent intellect. In high school, he refused to take a required biology class because the teacher omitted all discussion of evolution. The board of education let him take a college correspondence course instead but did nothing to stop the taunting Allison endured from the school’s athletic coaches who spied him studying in the gym. In college, he chose science over medicine for two reasons. First, as he readily confesses, he wasn’t very good at learning vast amounts of factual information, and doctors need to know a lot of facts. Second, he feared making mistakes that might cause grievous harm. As he would say, “Doctors need to be right. Scientists are supposed to be wrong.”

  After earning a doctorate in biological sciences, Allison went into immunology and cancer research. He was, like me, fascinated by the powerful potential of the body’s ability to defend and heal itself, yet unlike me, intrigued by the chemistry that enabled this process. The most tantalizing aspect of the process was the immune system’s ability to identify and react to a huge variety of targets. In many instances, this process also produces long-lasting immunity that protects us in future encounters with the same virus, bacteria, or even cancer cell. This is the activity triggered by vaccines. But while we understood their general purpose
, so little was known about how immune cells detected invaders and then became fighters against infection and cancer that an enormous scientific field was wide open for explorers like Allison.

  In 1982, when he was at the University of Texas, Jim discovered a receptor molecule that helps T cells recognize antigens of unwanted objects like viruses and start the process of defending the body from infections or cancer cells. This he compared with the ignition switch on a car. A few years later, after moving to the University of California–Berkeley, Jim recognized that a protein called CD28 acted as a sort of gas pedal to further activate the T cells. Next came Allison’s discovery, made with his colleague Jeffrey Bluestone, that a protein called CTLA-4, which protrudes like a little tail from the surface of T cells, acts like a brake to stop them from overdoing things. (When the immune system fails to stop at the right time, it creates its own problems—autoimmune disorders—that damage the body. Lupus, rheumatoid arthritis, psoriasis, and type 1 diabetes are examples of autoimmune disorders.

  Prior to Allison’s work, it was thought that the little-tail protein served the opposite purpose, signaling T cells to take action. This belief was so entrenched that for several years, controversy raged over Allison’s finding. The idea that immune cells must be subject to more complex controls than simply “ignition” and “acceleration” made sense, but it was raised at a time when much of science was focused elsewhere. Allison would recall that during this period, he was sometimes teased by colleagues who thought his interest was so implausible that they would jokingly cough and cover their mouths as they said, “Jim is a”—cough—“tumor immunologist.” Although he dreamed of developing chemicals that would work on CTLA-4 to treat people with cancer, Allison received so little support that his progress was slow. For years, he remained what he called “a mouse guy,” testing his ideas in his lab and seeking both the breakthroughs and the backing to move from mice to human beings.

  The T cells that Jim Allison sought to manipulate came from the bone marrow stem cells that provide almost all the power of the body’s natural immune systems. Work done on other types of stem cells suggested the very strong possibility that they could be manipulated to produce remarkable results. In 1958, John Gurdon of Oxford University used ultraviolet light to kill the nucleus of a frog egg and then inserted a single cell from the lining of a frog intestine. Gurdon was testing what was unknown at the time: whether all cells share the same DNA. It was not known if DNA remained the same throughout the lifetime of a cell or if cells parceled out and lost some of the DNA as they took on the specialized characteristics of a mature cell. He ingeniously thought he could figure this out by taking the nucleus containing the DNA of a mature cell and putting it into a context where all the cells of the body needed to be made—the fertilized egg. He did it in frogs because of the large size and number of their eggs. They could be easily handled and a lot of them could be tested in short order. He turned out to be right, as the egg became a tadpole and then a frog capable of reproducing normally.

  Gurdon’s successful nuclear transfer marked a giant step forward in cell biology and suggested that actual cloning would be possible. It indicated not only that DNA stayed quite intact during the process of cell differentiation, but also what that DNA expressed. The genes expressed to make a cell of the intestine were very different from those expressed in a so-called “totipotent” (toti: all; potent: capable)cell like the fertilized egg. Yet, the intestinal cell DNA could be “reprogrammed” to express what it took to become totipotent and make a whole new organism. The implications were enormous and represented cloning. A new animal was made from a single cell of a fully formed one. Gurdon was so modest that he refused to speculate about its importance. TV newscaster Walter Cronkite visited him for an interview and asked him when cloning would be done with mammals and, ultimately, human beings. “No idea,” replied Gurdon, “but somewhere between ten years and a hundred years.”

  Playful and self-effacing, Gurdon was the unlikeliest of scientific superstars and would long preserve an evaluation written by one of his teachers. It begins with the sentence, “It has been a disastrous half” and notes that Gurdon had “been in trouble, because he will not listen.” The most revealing comments appear in the professor’s conclusion:

  I believe he has ideas about becoming a Scientist; on his present showing this is quite ridiculous. If he can’t learn certain Biological facts, he would have no chance of doing the work of a Specialist, and it would be [a] sheer waste of time both on his part, and of those who have to teach him.

  Diverted by academic professionals, Gurdon went to graduate school at Oxford intending to study literature, but a mix-up at the admissions office allowed him to take courses in zoology. Here his creativity and spirit—the same spirit that annoyed his undergrad professor—flowered, and he became a shining light as an undergraduate and graduate student, eventually publishing his paper on nuclear transfer. The cloning question was exciting for people to consider but it obscured the more important issue of reprogramming that Gurdon’s science illustrated. Theoretically this meant that science could turn back the clock on adult cells, making them behave like the most powerful stem cells of all: the fertilized egg. Those cells are capable of making every component of an organism and are therefore totipotent. In the human that roughly means two hundred and twenty different cell types. Taken to its logical end, Gurdon’s work meant that cells and whole organisms could be rejuvenated.

  Besides hinting at a pathway to cloning, Gurdon had also pointed to new ways to understand cancer. The first pluripotent human embryonic stem cells would be derived from testicular cancer cells. This was done in the 1980s by scientists who noted that the human cells behaved quite differently from those that came from mice.

  Cardinal features of stem cells are that they can self-renew (make more of themselves) and differentiate. What Gurdon’s work indicated is that differentiation is not necessarily a one-way street. Cells, or at least the DNA within them, can be made to reprogram and go backward to a more primitive state depending on the conditions. A question that is naturally extended from this work is whether some mutations could cause mature cells to reacquire the functions of stem cells? Perhaps not the differentiation property, but what if they could reprogram to become self-renewing when they should otherwise not have that feature? Such a cell, particularly one that was stuck at a particular stage of differentiation, would almost certainly be cancerous. The concept of cells in cancer reflecting features of stem cells was something tested by John Dick, a pioneer in stem cell biology and cancer. In 1994 in Toronto, Dick, who had been trained by fellow Canadians McCulloch and Till, published a paper describing leukemia stem cells. He did it by using the same transplantation techniques that his mentors had used to first demonstrate the experimental proof that stem cells existed. He did so by first generating a mouse so deficient in its immune function that it could tolerate human cells—it would not reject them. Stem cells from human blood engrafted in these animals and made human blood cells. Dick used the model to test whether some cells within the swarm of cells that were human leukemia could make the mouse leukemic. They were and did so even when transplanted a second time into another mouse. That provided evidence of cancer stem cells. He and others then went on to demonstrate that similar types of cells exist in some if not all human tumors. He has since used it to determine that the frequency of the cells was shown to correlate with poorer prognosis in some leukemias. He also looked to see if they could be targeted by chemotherapy. They would need to be if a cure was ever to be achieved for they are capable of regenerating a full cancer. If they were not wiped out, the cancer would recur. Targeting leukemia stem cells is an active area of research and it is not yet fully defined as the difference between remission versus durable cure.

  That Dick’s discovery would be made in the blood was to be expected. Blood is accessible and readily observed, and thus most useful for scientific inquiry. Fortunately, it often provides reliable hints for studies in oth
er parts of the body. After Dick’s findings, stem cells were identified in cancer of the breast, liver, brain, colon, and more. These cancer stem cells could be the result of random genetic errors or outside influences, such as radiation or chemicals. In every case, the cancer stem cells could both replicate themselves and create descendant abnormal cells that may not have the full features of a stem cell but can disrupt normal cell function and kill.

  * * *

  Cancer cells have long been understood as rapidly proliferating things. Some tumors, called teratomas, contain such varied types of cells—bone, muscle, skin, hair, teeth, and so forth—all jumbled together, that they suggest a kind of biological madness. In fact these grotesque collections are evidence of the power of stem cells run amok. Not only do they not know when to stop replicating, they don’t know which cells they are supposed to create and how. In the 1970s, Martin Evans of the University of Cambridge was able to keep mouse teratoma cells alive and differentiating into various new cells indefinitely. Then, in the 1980s, Evans and others identified embryonic stem cells that could be cultured to create viable, fertile mice. If the culture was adjusted genetically the results would be mice with one or more genes “knocked out” (and sometimes replaced) to create the perfect specimens for research purposes.

  The knockout mouse was a great boon to scientists because it gave them access to populations of identical animals—essentially clones—selected for a specific trait. If you wanted to find out what a gene does, the best way to do so was to engineer a mouse that was deficient in it. Eventually the technology also progressed so that it was possible to selectively deplete the gene in particular cells. What this has done is to allow the definition of what a gene does in particular organs or cells types—heart, blood, brain, for example. It is also now possible to do so whenever in the lifetime of a mouse was of greatest interest. Gene function early in the development of a fetus might, and has been shown to be for many genes, very different in an adolescent or even an aged mouse. This kind of precision has been enormously productive in teaching us about the particular functions of genes. It has also been helpful in defining how they relate to disease.