Cancerland

by David Scadden

  On the day the news was announced, the headline shocked a great many doctors and scientists. We knew that genes are required to direct countless functions, from the development of an egg and a sperm to the working of every organ system. This counts for all the roughly 3.2 trillion cells of varying types that make up the human body. The discovery that the human genome is much smaller than expected would frustrate some scientists who hoped to find a single gene responsible for a discrete illness, which might then become the source of a cure. It is true, of course, that lone mutations are responsible for certain illnesses. Mutation of the gene called TP53, which is responsible for controlling cell growth, is associated with some malignancies. However, simple one-to-one, genetic cause and effect seemed less likely with the news that the genome is so small.

  Equally surprising was Venter’s observation that only about three hundred of the genes his group identified were absent from the genome of the average laboratory mouse. The rest seemed to come from a common ancestor, some one hundred million years in the past. The government team, striving to make a similar point, said they found a baker’s dozen of genes that human beings acquired from bacteria. They said they expected to find many more. This was, in Venter’s eyes, part of the wonder to be appreciated in the genome. “Some have said to me that sequencing the human genome will diminish humanity by taking the mystery out of life,” he said as the project was completed. “Nothing could be further from the truth.”

  On one level, the smaller genome and the idea that humans have so many genes in common with a tiny mouse suggested that we aren’t such a special species. This seems doubly true when you consider that a certain translucent water flea, Daphnia pulex, has thirty-one thousand genes. It’s a rather special flea, with the ability to sprout defensive armor and spines and to adapt to polluted water. However, it’s still a flea. And the thought that such a lowly creature might surpass Homo sapiens in any measure seemed just wrong to many people.

  In evolutionary terms, however, the human genome can be seen not as diminutive but as elegance itself because it does so much with so little. The only way this could happen would be if genes worked in concert to achieve the variety of expressions seen in the body. Instead of LEGO blocks clicked together or beads lined up in a row, our genes establish a huge variety of combinations similar to what you might see if you could gaze upon a city from a mile in the sky and recognize the myriad connections of the people who live there. If we could see how many people on a given block patronize the grocer on the corner, and then see how the grocer and his customers connect with others, we would be astonished by the diversity of their connections. It is in the coming together that individuals establish a functioning society, and it is in the coming together that genes create life.

  Genes power the cells to interact, with chemical compromises creating orderly growth and functioning. This is the dynamic process described by Itai Yanai and Martin Lercher in a book called The Society of Genes. As they note, the sequencing of the genome revealed a “survival machine” that requires cooperation in addition to the competition that marked an older way of considering genetics, as reflected in Richard Dawkins’s treatise The Selfish Gene.

  Dawkins, who actually inspired both Yanai and Lercher to enter biology, depicted a Hobbesian kind of war among genes, with the fittest reproducing to live on and on. This does happen and can explain certain human traits. However, we now know, thanks largely to the genome projects, that our genetic selves are extremely complex. For example, most of our roughly 3.2 trillion individual cells must be signaled by others if they are to replicate and grow. Without these signals, they do not act. When a cell does divide, it provides each “daughter” cell with a copy of its DNA. This renewal is done at varying rates. White blood cells turn over in a matter of hours; red blood cells last 120 days; some neurons are made and live as long as we do.

  Inevitably copying, which calls for each cell to reproduce over three billion nucleic acids in proper order, poses the possibility for mistakes in the form of mutations. Usually these errors are harmless. Cancer cells, as Yanai and Lercher point out, require several genetic mutations to cause disease, also known as multiple genetic “hits.” Trouble arises in the body because the mutants may self-replicate more rapidly than normal cells, may have impaired repair of DNA damage, have impaired differentiation, have less sensitivity to death signals, or a host of other functions altered in cancer. Faster rates of proliferation or less efficient damage repair means that they are more likely to acquire a second, and then a third mutation. With each new mutation, cancer cells overcome more of the body’s ways of defending against cancer until control can no longer be imposed and the cells take off as a full-blown cancer.

  The cancer tipping point depends, in part, on how often cells are replicated and thus have a chance to collect mutations. Our skin cells, intestinal and airway lining cells, and blood cells are among the most active. The number of cell divisions ongoing at any moment in our bodies is measured in the hundreds of billions. Mistakes happen in the process of replicating all that DNA. When mistakes happen that change the cycling of the cells, their ability to repair DNA mistakes, or a host of other abnormalities, abnormal cells are made. Many of them just disappear because of a natural self-destruct mechanism. The self-destruct mechanism—also called programmed cell death (PCD)—prunes away old and unneeded cells and makes way for newer ones. PCD eliminates the webbing in a developing fetus’s hands to make way for fingers. It also helps govern the number of neurons developed in the brains of both children and adults.

  Cancer cells may carry mutations that help them evade this natural process. With their systems stuck on “go,” they consume far more energy than normal cells, crowd out healthy ones, and often travel to other sites to colonize the body. If they are cancer stem cells, they may also survive the onslaught of chemotherapy and cause both recurrences and metastases and ultimately death.

  I was reminded of the relentless quality of metastatic cancer in the 1990s when my father was diagnosed with cancer. Like so many northerners he had moved to Florida to be outdoors more. I went to visit him in March 1995. He was fit and active and we played tennis but when we finished he felt some back pain. It didn’t seem to get better even with rest and in May he had an x-ray. That was when his doctor called me, not my father, to reveal the news. By June 1995 he was being transported by ambulance, twice a day, for radiation treatments. I’m not sure there is ever a case when twice-daily radiotherapy is required for any patient. In his case it was certainly not the standard of care and it resulted in much suffering. The inevitable bumps in the road on transport were deep jolts of near unbearable pain in tumor-ridden bones. I could tell from my father’s reports and from the information I gleaned from his doctors that he had only a few months to live.

  When he finally talked with me about this, he accepted his prognosis philosophically, reassuring me that he felt he’d had a good seventy-four years.

  I wasn’t so philosophical. It seemed to me that my father was getting therapy that had no chance of curing him: the goals were strictly to palliate misery. Why then would twice-daily misery be considered appropriate since the long-term benefits of twice-daily therapy were unproven? It was hard not to draw the conclusion that for Medicare data support, Florida’s senior citizens were considered by the unscrupulous as a kind of medical gold mine. Florida Medicare fraud stands apart from any other state in the country. For-profit hospitals certainly don’t help. I visited my father when he finally had to be hospitalized to find that despite a less than one-week stay, he had been ignored sufficiently in the for-profit hospital chain to develop deep ulcers on his heels. Complications occur of course in every hospital, but experience with my father leads me to strongly support the policymakers emphasizing payment based on patient outcomes, not just procedures performed.

  If the genome is considered a rough script for the development and functioning of living things, then stem cells are the star players in the production. They are the
heroes that build the body, maintain it, and repair it. They even verge on superhero status because of their ability to create multiple types of offspring and their near-immortality. Similarly, cancer stem cells are like fallen angels, or the villainous Agent Smith in the Matrix movies. Smith replicates with terrifying ferocity and can reappear after what seems like a total defeat. So it is with cancer stem cells.

  With stem cell features being shared by both cancer cells and the cells at the foundation of our body’s well-being, it has to be an area rich with opportunities for scientific understanding of health and disease. The challenge is that stem cells for most of our tissues are only recently recognized so we have limited information about them. We also don’t have good measures of how things change over time at the level of single cells. This means we mostly glimpse events indirectly and imprecisely in the body. This may partly be why biology is perceived as the least linear of all the sciences. It is very difficult to directly connect cause and effect. Although physics, chemistry, geology, and even astronomy have unresolved mysteries, they generally yield to mathematical logic: A interacts with B and you get result C. In biology, a cell labeled “A” may have dozens of vertices that can contact any number of adjoining cells conveying a range of messages with varying intensity. Some of the messages change the neighboring cell temporarily, others permanently, and messages convey very different meanings depending on the other messages that are happening at a given time. It is likely that as we gain quantitative measures of each message and each effect it elicits, biology will reduce to more discernable logic. However, it is now a science of complexity; progressively more awe-inspiring with each dimension we unveil. The processes that give us life, animate us, and burden us with disease are astoundingly complex.

  That complexity is exemplified by the many unanticipated consequences that eventually show up with medical interventions. Breast implants have been used for purely cosmetic purposes, but are also often a part of the care for a woman with breast cancer. Breast removal is still performed (though not with the “radical” extremes that Halstead championed) for cancer therapy and is increasingly used to prevent cancer in women who have known genetic predispositions. Angelina Jolie is someone who preferred bilateral mastectomy to bearing the risk to her and her family of breast cancer. Undoubtedly, consideration of mastectomy is influenced by the ability to prevent disfigurement through breast implants. They may well be considered an ancillary to cancer prevention in such settings. Unfortunately, as with all technologies, they have a downside and, in this case, a cancer downside. While a rare event, women who have received breast implants with textured surfaces have increased risk of an otherwise very rare cancer of the immune system. They can get a so-called Anaplastic Large Cell Lymphoma of T cells. The T cells that are such an important part of immunity against infections and against cancers can be provoked in this setting to go sufficiently awry to result in a very aggressive cancer. Notably, this does not seem to occur with smooth-surfaced breast implants. The risk is not substantial enough to warrant implant removal, but the FDA does recommend increased awareness on the part of patients and their physicians. This one example points to the near incomprehensible complexity of the body and, in particular, the immune system.

  Settings of chronic injury are known to increase the risk of cancer. Cigarette smoke and lung cancer is a classic example. Chronic liver injury from alcohol, hepatitis, or some parasites (including Mahmoud’s Schistosoma japonicum) resulting in liver cancer is another. These are cancers of the cells within the injured organ and have some intuitive logic. The constant wounding and repair process might eventually end up with a repair process that is abnormal and eventually out of control: a cancer. Even a damaged immune system resulting in immune cancer makes some sense. People with some autoimmune diseases like Sjogren’s syndrome or lupus have a slight increase in B cell lymphomas. But T cell tumors are rare, not associated with underlying immune disorders, and could not be expected to result from a specific type of implant. Why textured and not smooth implants? Why T cells and not breast cells? Why the particular type of T cell cancer? All are impossible to understand based on our current state of knowledge and could certainly never have been anticipated. Where to even begin to explore how an external stimulus like the textured implant could eventuate in a rare immune malignancy is unclear. I for one could never undertake investigating a problem for which there are so few clear threads of connection. It is important to be bold in taking on important problems, but scientists have to balance their desire to solve a problem with the hard-nosed judgment of whether they can. It is often a cause of great frustration by the public and, particularly, patients with the problem. Why can’t doctors and scientists do better at solving my problem? It is not for lack of interest. It is for a lack of solid footing in a bog of biologic complexity.

  Getting that footing often happens with the establishment of very discrete findings. Jim Allison provided those for cancer immunotherapy, Montagnier and Barré-Sinoussi for AIDS, and James Thomson and John Gearhart for stem cells.

  FIVE

  STEM CELLS AND A RENEWABLE YOU

  James Thomson of the University of Wisconsin and John Gearhart of Johns Hopkins isolated and grew human pluripotent stem cells in their labs and reported their success within weeks of each other in 1998. The importance of this breakthrough was lost on no one, as it pointed the way to make any cell in the human body. These were the ultimate stem cells and no matter what disease or cell type you studied, these cells offered the possibility to gain more direct insight. Most prior work depended on getting rare samples from people and most such samples didn’t last in culture. Or they depended on easier to culture cells from mice. Getting human embryonic stem (ES) cells meant human cells could be cultured long-term and then allowed to differentiate to become mature human cells of different types. Getting them to grow was pretty straightforward, particularly with Thomson’s work as a guide. It required a special media in which to grow the cells, but once they were established they could grow indefinitely. Getting to become a cell type of interest was a challenge.

  Sometimes, simply changing the media to a different type allowed the cells to spontaneously mature into a cell of interest. Looking into a microscope and seeing cells beat like a heart was pretty compelling theater. And pretty compelling evidence that heart cells could be obtained. Everyone in the field thought that was likely to be a shortcut to making cell patches for damaged hearts—a kind of therapeutic holy grail for people who suffered heart attacks and subsequent death because they had lost too much muscle. It has yet to be effectively done. It has taken years to learn how to make the cells not just any heart cell, but the ones of the adult heart that make up the parts of the pump damaged in heart attacks. Similarly, human ES cells spontaneously make neurons. That has certainly inspired much excitement about implanting cells for a host of brain and nervous system disorders.

  There was no question that human ES cells would make a difference, though there was also no question that it would take the concerted effort of many. Assembling teams, aggregating data, and sharing ideas was essential. At Harvard, hundreds of people in various disciplines from hematology/oncology to neuroscience and embryology worked on stem cell–related projects, but we encountered each other mainly by accident. It didn’t take a genius to recognize that this isolation deprived all of us from both raw information about important advances and the kind of water cooler talk that spurs new ways of thinking about difficult problems.

  In the highly competitive world of science where people can be quite guarded about sharing what they know, lots of attempts have been made to create interdisciplinary teams to jump-start research. With the rare exceptions like the still fractious Human Genome Project, these collaborations tend to fall apart. However, stem cell research offered the possibility of regenerative medicine, an area of such profoundly humanitarian consequence that it seemed we simply had to corral our egos, and join our talents and resources to take a team approach. We had one m
ember of our faculty who was recognized as an expert, and around whom we could rally. And by the way, it wasn’t me.

  Douglas Melton had done his doctoral work under John Gurdon, the pioneer who wasn’t even supposed to be a scientist who had successfully cloned frogs in 1958. (Doug was five years old then.) In the 1970s, Gurdon headed Cambridge University’s molecular biology lab, which had supported Watson and Crick and three other Nobel laureates. Gurdon would be awarded a Nobel in 2012, and many of the methods he devised in the 1950s and 1960s remain in use today. At Cambridge, Melton worked with Gurdon and managed to publish five papers on genetics and cloning before he was awarded a doctorate. This remarkable record helped him to become a professor at Harvard the next year. He was all of twenty-eight years old.

  Although he was anything but one of those laboratory egomaniacs who bully their way to the top, Doug was confident in a way that I was not. He too had shifted focus from the humanities to science, having studied philosophy as an undergraduate at the University of Illinois. But his ability to flourish in the Gurdon lab seemed to give him grounding and his inherent brilliance typically had him a step or two ahead of his peers in ideas of consequence.