THE ENGLISH PHILOSOPHER THOMAS HOBBES IS PROBABLY BEST known for his pessimistic assessment of human existence as “nasty, brutish and short.”1 I can only imagine what he would have said about the lives of Tasmanian devils, compared with which the human condition is idyllic. For “T-devils,” those feisty creatures from Down Under’s down under, life is certainly nastier, more brutish, and shorter. And recently, it’s gotten a lot shorter.
A Tasmanian devil is born in a highly undeveloped state, even by marsupial standards, which are much lower than those of most mammals. The newborn T-devil is tiny, the size of a grain of rice. So the trip from the vagina to the pouch, though only 3.5 inches, is an epic journey through a forest of giant hairs. It is also a life-and-death race. A mother T-devil gives birth to thirty to forty young, yet she has only four nipples. The first four babies to the nipples win this first challenge; all of the others die. Not surprisingly, once they arrive at the nipple, they clamp on like a tick and don’t release their grip for weeks.
For those who make it this far, the ensuing few months are relative bliss. After they let go of the nipple, there is the security of the pouch, and later the lesser security of a burrow. But then the young T-devils must strike out on their own in their quest for food and a mate, endeavors fraught with turmoil and conflict.
The first part of the scientific name for the T-devil is Sarcophillus, Latin for “flesh lover,” and they do consume a wide variety of fleshy foods, most of it carrion. At a large carcass, such as that of a kangaroo, many T-devils may congregate. The ensuing melee is a noisy affair; one of the sounds produced by agitated T-devils is their shudder-inducing scream, believed by many to be the source of their devilish reputation. (Others attribute the devil moniker to the fact that when they become emotional, their ears get bright red.) T-devils can also produce foul odors during these aggressive interactions, said to rival those of a skunk.
But T-devil aggression does not end with their vocal and olfactory repertoire; they also deliver nasty bites with a force which, pound for pound, is the greatest among mammals, exceeding even that of the spotted hyena.2 T-devils often have scars on their rump because they wisely back into the carcass to protect their head and face. The backing-in technique works only somewhat, however; eventually, T-devils do get bit in the face during these encounters, when hunger wins out. Moreover, bites to the face occur during courtship, which is also a violent affair. These are essentially solitary creatures who are not real comfortable in each other’s company, whether seeking food or sex. Fortunately, T-devils have an amazing capacity to heal quickly, even huge gaping wounds—until recently.
The Cancer from Hell
In 1996, a wildlife photographer, working in Mount Williams National Park, observed a number of T-devils with strange growths on their face and mouths. Soon after, wildlife biologists in Tasmania began to see more and more afflicted individuals. By 2002, this affliction was an epidemic throughout most of the T-devil range.3 The growths, it was discovered, were a strange kind of cancer of the mouth and face, which was labeled devil facial tumor disease, or DFTD. This rapidly growing cancer eventually obstructs the mouth to a degree that the affected individuals die of starvation, usually within several months. The cancer has caused T-devil numbers to drop precipitously in the last decade, and there is no sign it is abating. If the trend continues, the T-devil will soon be extinct.
Why has this cancer so suddenly afflicted so many T-devils? Cancers are not like viruses—we don’t, fortunately, see cancer epidemics—yet that is precisely what appears to be happening to T-devils. A cancer epidemic can occur only if the cancer is infectious. But this infectious cancer is not transmitted through a virus or any other vector; it is directly transmitted from one T-devil to another during those aggressive interactions at the carcass or during what passes for T-devil courtship. When an infected individual bites another T-devil, some of the cancer cells are transferred from the biter to the bitten.4 This is truly nightmarish stuff. DTFD is a parasitic cancer.
There is a sense, though, in which all cancers are parasitic. Our immune systems sometimes treat cancer cells like external invaders. Only those cancer cells that through various ruses evade or disable the immune system eventually form tumors. Those cancer cells that evade the immune response compete with the normal cells that surround them for the body’s resources, as does any parasite.
But the DFTD cancer should be at a huge disadvantage relative to cancers that originate within a T-devil’s own body: cancers that originate outside of the body should be much easier for the T-devil immune system to identify, and hence destroy. Yet the T-devil immune system does not appear to mount any defense whatsoever against these foreign invaders. Therefore, there must be something wrong with the T-devil immune response. The problem is not a generally deficient immune response. The T-devil immune system responds robustly to most challenges, as you would expect: given their diet and frequent wounds, a T-devil with a generally understated immune response would not be long for this world.
The problem, it seems, is in the recognition phase. The T-devil immune system just isn’t able to identify these foreign cancer cells as foreign, as nonself. The self-nonself distinction is fundamental to the immune response. It is the reason we reject donated organs, even those from close relatives. Massive doses of immunosuppressive drugs are required for organ transplants, including skin grafts. Sometimes, when the recognition process breaks down, the immune system attacks healthy cells that have the proper self markers. The result of this hypervigilance is autoimmune diseases such as rheumatoid arthritis or lupus. The T-devil has the converse problem of immune misidentification; its immune system is too permissive.5
This blind spot in the immune response is thought to stem from a genetic bottleneck that occurred sometime after the last ice age, perhaps as recently as the twentieth century. At some point, the T-devil population may have been reduced to just a few individuals, which inbred to a degree that eliminated most of the genetic variation in T-devils even many generations removed. Something similar occurred in cheetahs, which also evidence little genetic variation, accept skin grafts from other cheetahs, and presumably would be vulnerable to a contagious cancer of this sort.6
DFTD most closely resembles a cancer in dogs called canine transmissible venereal tumor (CTVT), which is also directly transferred from one individual to another, in this case through sex.7 Here, too, the immune system fails to recognize the foreign tumor cells as foreign. But dogs with CTVT eventually do mount an immune response that completely eliminates this cancer.8 (Once an affected dog has recovered, it has lifelong immunity to further infections by this cancer.) Unfortunately, T-devils are not so lucky, which indicates that there is more wrong in the T-devil immune response to DFTD than a defective recognition phase.
Cancer and Stemness
As bizarre and unusual as the T-devil cancer is, the cancer cells themselves are fairly typical cancer cells. For example, they are poorly differentiated; that is, they bear certain resemblances to somatic stem cells. As is also characteristic of cancer cells, however, DFTD cells have some of the attributes of the type of cell that they should have become. Also typical is the rearrangement of the chromosomes in these cancer cells, which, in addition, have completely lost one pair of chromosomes.9 Chromosomal deletions (and additions) are common in cancer cells, no matter the source.
There are two main views as to the cellular transformations that constitute cancer. The traditional view, which was briefly discussed in Chapter 10, is that cancer cells are derived from fully differentiated cells, such as neurons or skin cells. As a result of dedifferentiation, these cells have regained a stem cell–like capacity to proliferate.10 This dedifferentiation would also explain why these cancer cells retain some of the characteristics of their source cells. The T-devil cancer cells are thought to have originated from a particular kind of neural tissue that controls the endocrine (hormonal) system, based on certain chemical signatures of this tissue.11
Recently, an alternative to the dedifferentiation account has been proposed. According to this view, cancer cells are actually derived from somatic stem cells gone bad.12 On this stem cell theory of cancer, the reason cancer cells resemble stem cells is that their mother cells were stem cells. After their birth, they took a wrong turn, converting from normal somatic stem cells to cancer stem cells. Actually, only a minority of the cancer cells retain stem cell properties. Like normal stem cells, these cancer stem cells undergo asymmetric cell division, resulting in one cancer stem cell and one more differentiated cancer cell. The more-differentiated cancer cells then undergo the symmetrical form of cell division typical of all non–stem cells. The net result is a tumor that consists of a small number of cancer stem cells, and a large number of cancer cells that are—to varying degrees—more differentiated. From this perspective, the goal of any therapeutic intervention should be to knock out the relatively few cancer stem cells.
I can summarize the differences between the dedifferentiation and stem cell theories of cancer in this way: on the dedifferentiation account, cancer cells move backward toward stemness; on the stem cell account, cancer cells move forward from stemness. The two theories of cancer are not mutually exclusive. Many prostate cancers show signs of dedifferentiation.13 On the other hand, cancers of the blood, such as leukemia, may be better explained by the stem cell theory of cancer.14
Cancer Genes and Wayward Chromosomes
The dedifferentiation and stem cell theories concern what I will call “cancer dynamics.” The hypotheses under consideration from here on concern the mechanisms underlying these dynamics. Most of these hypotheses are compatible with either the dedifferentiation theory or the stem cell theory of cancer dynamics.
What, initially, causes the cancer cells to become cancerous? For the last forty-plus years, the answer to this question has been some sort of genetic alteration in a single cell, which causes it to proliferate abnormally. Further mutations accumulate in the expanding cell population, leading to genetic heterogeneity in the cancer. These different genetic clones compete with each other through further proliferation, becoming increasingly virulent, culminating in metastasis. So cancer is, first and last, from its initiation to metastasis, a matter of genetic alterations. This is known as the somatic mutation theory (SMT) of cancer.15 According to SMT, cancer is a case of evolution on a small scale.
Since the advent of SMT, more than a hundred human oncogenes (onco = “cancer”) have been discovered; when mutated such that they are expressed at abnormally high levels, oncogenes promote cancer-like cell proliferation. Moreover, more than thirty tumor suppressor genes have been discovered; as their name implies, these suppress cell proliferation. Mutations in tumor suppressor genes that cause them to be less suppressive are also associated with cancer. The mutations in these genes may be spontaneous—that is, essentially random—or they could occur in response to environmental toxins such as tobacco smoke, pesticides, or ultraviolet radiation, which we refer to as carcinogens.
From the perspective of SMT, a carcinogen is a mutation inducer. Cancer therapy should be directed toward eliminating the mutated cells. If the source of the mutated cells is cancer stem cells, they should be the focus of treatment. The standard arsenal of cancer treatments, including surgical removal, radiation, and most forms of chemotherapy, are based on the SMT model.
Colorectal cancer is the poster case for SMT.16 This cancer is initiated by a mutation in an oncogene, and each stage in its progression is accompanied by further mutations. The T-devil cancer seems to fit nicely within SMT as well. DFTD is the winner of the clonal selection process, which in addition has evolved a means to be transmitted from one individual to another. But the transmissibility of the T-devil cancer is actually not predicted by SMT. The process of transmissibility involves adaptations to the immune response, whereas SMT is primarily focused on oncogenes and tumor suppressor genes, none of which are involved in such adaptation. Moreover, immune-based forms of therapy were, rather, motivated by a perspective on cancer that differs substantially from SMT, which I will discuss later.
A second genetic theory of cancer is even older than SMT but never as popular. This theory places primary emphasis on the chromosomal abnormalities so characteristic of cancer cells, among them the loss or gain of entire chromosomes. The altered chromosome number is called aneuploidy, so this is often called the “aneuploid theory of cancer.”17 According to SMT, aneuploidy is a secondary effect of cancer. Advocates of the aneuploid theory, however, see the chromosomal rearrangements as primary. The aneuploidy hypothesis proposes that the initiation and progression of cancer is due more to the abnormal chromosomes than to mutations in particular oncogenes.
Aneuploidy messes up the regulation of many genes, which leads to further aneuploidy, which leads to even more messed up gene regulation, and so on. One of the deviant traits that results from this disregulation is an increase in the proliferation of the affected cells. But what gets the process going? According to the aneuploid hypothesis, it’s a problem with genes involved in maintaining the integrity of the chromosomes during cell division.18 The progression of a cancer, on this view, is due to the progressive disruption in gene regulation that results from increasing aneuploidy. In support for this argument, advocates of the aneuploid theory cite the fact that cancer cells do not mutate at higher rates than normal cells but cancer cells show a much higher rate of chromosomal rearrangements than normal cells.19
Like SMT, the aneuploid hypothesis is neutral as to whether the initial chromosomal destabilization occurs in somatic stem cells or in fully differentiated cells. Nor does this theory offer different therapeutic options.
The T-devil cancer presents a problem for this hypothesis, though not for lack of aneuploidy: T-devil cancer cells have plenty of aneuploidy. The problem is that DFTD cells are all aneuploid in the same way. Also problematic for the aneuploid hypothesis is that they have been aneuploid in the same way for many years. DFTD is extremely stable at the cellular level. Indeed, DFTD is a cell lineage that is much older than any living T-devil.20 This shouldn’t happen on the aneuploid account. The positive feedback process described earlier—between increasing aneuploidy and increasing gene disregulation—cannot be arrested; quite the opposite, it can only accelerate. As such, the aneuploid theory predicts ever-increasing chromosomal rearrangements and increasing variability in the chromosomal arrangements in the cancer cells of a particular tumor.
The lack of variation in DFTD cells is also a problem for SMT. But then, this lack of variation in DFTD cells, along with their transmissibility, is probably what most distinguishes T-devil cancer from more typical cancers of internal origin. Perhaps the two qualities—cellular stability and transmissibility—are related. It is interesting to note, in this regard, that the cells of canine transmissible venereal tumor (CTVT) have been stable for hundreds, perhaps thousands, of years. In fact, CTVT may be the oldest mammalian cell lineage.21
The Epigenetic Dimension
The somatic mutation theory and the aneuploid theory of cancer both focus primarily on genetic alterations. Both were also formulated before the advent of epigenetics. Once cancer researchers began looking for epigenetic alterations in cancer cells, they found them. First, it was noticed that the genes of cancer cells have characteristic changes in their methylation patterns, including an overall reduction in methylation.22 This global hypomethylation is one of the best early predictors of cancer. Genes that are normally repressed become active, including oncogenes. Subsequently, there are also specific changes in the methylation of oncogenes and tumor suppressor genes. Other epigenetic alterations are common in cancer as well, including the unbinding of histones to DNA, which causes an increase in the activity of the affected genes.
Advocates for SMT and the aneuploid theory of cancer do not dismiss the role of epigenetic processes in cancer but consider them secondary to the genetic alterations. Other researchers, though, see the epigenetic alterations as primary in many cases.23 On the epigenetic view, cancer is most fundamentally the result of defective gene regulation. Sometimes defective gene regulation is caused by mutations, sometimes by epimutations. Epimutations are often mistaken for mutations, especially when they affect oncogenes or tumor suppressor genes. Many cancers exhibit defective regulation of oncogenes and/or tumor suppressor genes, even when these genes have not mutated.24 These nonmutation-caused alterations in the regulation of these genes are now known to be epigenetic.
On the epigenetic view, cancer is initiated by epigenetic disruptions such as global reductions in methylation, which are often present before any known mutations in oncogenes, including benign growths that precede cancer. The hypomethylation causes the instability in the chromosomes, emphasized by the aneuploid theory, as well as an increase in oncogene expression. Subsequently, there are specific changes in the methylation of particular genes. Oncogenes are further demethylated, while tumor suppressor genes are hyper-methylated, thereby suppressing the tumor suppressors.
The progression of cancer often involves mutations and further alterations in chromosomal arrangements as well, but these genetic changes are considered secondary to the initial epigenetic changes, from this perspective. Moreover, epigenetic alterations also play an important role in the progression of cancer. That is, the progression itself is both genetic and epigenetic. This is true even for colorectal cancer, the poster case for the somatic mutation theory. As described earlier, each stage of colorectal cancer is accompanied by a new mutation. But no specific mutation can be linked to each stage. There is no recurrent mutation that can be said to cause the invasive properties of this cancer or its metastasis in all or even the majority of cases.25 On the other hand, these properties have been linked to specific changes in the regulation of particular genes.
Some of the most compelling evidence for the primacy of epigenetics in cancer comes from a study on leukemia. As mentioned earlier, leukemia cells are highly aneuploid and mutated. Yet these cells can still be normalized through epigenetic interventions.26 In this way, former leukemia cells can be made to behave like normal white blood cells. What is particularly noteworthy is that this normalization occurs without reversing the chromosomal rearrangements, which traditionally have been thought to cause the leukemia. The cells are still genetically abnormal, but they behave like normal white blood cells.
One prominent version of the epigenetic view touts the stem cell theory of cancer dynamics.27 Others though, are compatible with the dedifferentiation perspective. In either case, a carcinogen is something that alters epigenetic regulation, which broadens that category considerably relative to somatic mutation theory. The therapeutic implications are also strikingly different because epigenetic processes, unlike genetic processes, are reversible, as the leukemia example dramatically demonstrates. There are also more ways to intervene epigenetically, and research in the development of epigenetic therapies is booming.28 One potential advantage of epigenetic therapies over most therapies used currently is that they can be much more fine-tuned, compromising fewer healthy cells.
The epigenetic approach has some interesting implications for the T-devil as well. One tactic under discussion in the fight to save T-devils is a vaccine for DFTD. The problem with any vaccine is the evolution of genetic variants that allow the target of the vaccine to elude it. There is as yet little evidence of genetic variation in DFTD cells, but some researchers have begun to wonder about epigenetic variation.29 This would present an even bigger problem than resistance based on standard genetic evolution, because epigenetic evolution is potentially much faster. It will be particularly interesting to know whether or how epigenetic variants function in evading the immune response of T-devils and the normalizing effects of the host tissue.
The Cancer Microenvironment
Genetic and most epigenetic theories of cancer are concerned primarily with what goes on inside the cancer cell. Recently, however, more attention is being paid to the microenvironment of the cancer cell. There are several distinct aspects of this environment, including the immune system, blood supply, and the normal tissue from which the cancer cells are derived—all of which have become important research areas. Collectively, these microenvironmental approaches take us furthest from SMT. They invite us to zoom out from the interior of the cancer cell to the surrounding tissue. It is only from this perspective that we can understand certain aspects of cancer behavior, not least of which is spontaneous remission.
Here I will focus on one of the microenvironmental approaches, called the tissue-based theory of cancer, according to which, cancer is the result of a breakdown in normal cell-cell interactions.30 Call it a failure to communicate. The tissue-based theory of cancer complements and extends the epigenetic approach in important ways. First, it provides a mechanism for the initial epigenetic alterations, such as demethylation, that occur early in cancer development. Second, it provides a framework for understanding the genetic and epigenetic alterations that occur during cancer’s progression. From this perspective, cancer’s internal dynamic is largely a function of the normal cells from which cancer cells are derived and subsequently interact. These interactions can spur cancer development, or they can arrest its development and even eliminate every last vestige of a cancer. I have already described an example of the latter in Chapter 10.
Recall the study in which malignant melanoma cells were normalized by a microenvironment of embryonic stem cells. This is mysterious from the perspective of SMT; it is, however, not at all mysterious from the tissue-based perspective, but rather well within the range of normal cancer behavior. However, the embryonic stem cell environment is special in many ways. It is especially noteworthy, therefore, that other studies have found that cancers can be normalized by fully differentiated tissues.
Mary Bissell and her colleagues at University of California, Berkeley, constructed an artificial breast-tissue environment that simulated the essential qualities of normal breast tissue in three dimensions. They then introduced malignant breast cancer cells into this environment and waited to see what happened. The result came as a surprise to many, though not to Bissell: the cancer cells were normalized.31 They lost their cancerous nature, in part through interactions with normal breast cells, arranged with the normal tissue architecture. But another important factor was the chemical composition of the extracellular matrix, the gel in which all cells are immersed. This gel is one of the primary ways through which cells chemically interact with each other during both normal development and cancer.
It is worth noting that Bissell came to cancer research with a background in developmental biology, and hence knowledge of the sort of cellular interactions that comprise normal development. For Bissell and other advocates of the tissue-based theory, cancer should be understood as a disruption of normal development, a disruption which, in some cases, self-corrects. This self-correction can occur in either the stem cell environment or in fully differentiated tissue.
Cancer, from this microenvironmentalist view, results from the disruption of normal interactions between cells. The disruption of cellular interactions alters the internal environment of the cells, which results in hypomethylation and other epigenetic changes. A carcinogen, on this view, is carcinogenic by virtue of disrupting normal cellular interactions within a tissue. Cancer development can potentially be detected much earlier on this view than it could on the SMT account, simply by monitoring the tissue architecture. Moreover, cancer therapies should focus more on helping the normal tissue cope with the cancer, the opposite of what occurs as a result of radiation and most forms of chemotherapy.
The tissue-based theory of cancer may also help shed some light on the T-devil cancer. From this perspective, DFTD represents a special challenge to normalization. Before this cancer evolved its transmissibility, it had to escape the normalizing influence of the normal tissue of the T-devil in which it initially evolved. That is a prerequisite for its metastasis. DFTD was then transmitted in this metastatic state. Metastatic cancer cells lack the organization of earlier-stage cancers; in fact, each cell is more like an individual organism. As such, DFTD cells are even immune to the influence of other DFTD cells. They are truly free agents and must be dealt with individually by the normal tissue in the T-devil’s face and mouth.
Obviously, the fewer DFTD cells the infected T-devil has to deal with, the better. But even a relative few DFTD cells pose a problem for normalization because they are derived from different tissue than the host cells. It’s as if they speak a different dialect, if not language, than the host cells. As such, it is more difficult for the normal cells to rein them in. That is true of metastatic cancer cells generally. But even metastatic cells can be normalized under the right conditions.
Should Father Damien Be a Saint?
By my lights, Father Damien was certainly saintly. He lived among and ministered to the lepers on the island of Molokai, until he himself succumbed to the disease. But that alone does not qualify him for sainthood according to the Catholic Church, which has some rather stringent criteria in that regard. One criterion seems particularly onerous from a scientific perspective: to be a true saint, you need to be responsible for two verified miracles. To make things a little easier, you can perform the miracles after you are dead. That is how Father Damien passed the threshold.
Being held responsible for curing advanced cancers has become a popular route to sainthood. Father Damien is only the latest example. A Hawaiian woman, Audrey Toguchi, went to Father Damien’s gravesite and prayed for him to intercede with the divine to cure her of metastasized cancer. Her prayers, it seemed to her and the Catholic Church, were answered; she was soon cancer-free. Her doctor was as surprised as anyone. The Catholic Church determined that this remission could not have occurred without Father Damien’s miraculous intercession. He was officially deemed a saint.
If the somatic mutation theory of cancer were gospel, the Catholic Church would be on solid ground. For a metastasized cancer to disappear, given SMT, it would have to undergo a series of extremely improbable reverse mutations. The case for sainthood becomes much weaker, though, if viewed from the epigenetic and especially microenvironmental perspectives. For example, the immune system might have come to the rescue in the nick of time, much as it seems to do in dogs with CTVT. I have also outlined another way that this woman could have been cured. Cancer, even in its most advanced stages, can be normalized through interactions with normal cells, whether in a stem cell environment or in that of fully differentiated tissue.
Spontaneous remissions of advanced cancers can occur without saintly intervention—even in atheists. Though unusual, this is well within the range of normal cancer behavior, at least from a microenvironmental perspective. That spontaneous remission can be explained without recourse to saints is a problem for the Catholic Church. That spontaneous remission seems miraculous from the perspective of the somatic mutation theory is a problem for the somatic mutation theory.
The microenvironmental perspective also provides some hope for the Tasmanian devil, even should the vaccine prove unworkable. Drugs that boost the immune response, as well as those that promote normalization, could be helpful. But the best hope for T-devils is for them to naturally develop immune or normalizing responses to this cancer much as domestic dogs have done to CTVT. In the meantime, it wouldn’t hurt to pray for the devil.
Devils and Saints
The T-devil’s cancer is both typical and exceptional. It is typical at the cellular level, in being poorly differentiated and aneuploid. And though we can’t know for sure, there is no reason to believe it had an atypical origin, whether from stem cells or fully differentiated tissue. Nor is there reason to assume that the mechanism underlying its cancerous transformation and progression required different processes than other cancers. But it is these processes that are most in dispute.
The SMT account is based on the executive view of genes as cellular directors, with an emphasis on oncogenes and tumor suppressor genes. The aneuploid theory also stems from the executive gene view, but with a different set of genetic actors as initiators of the cancerous transformation, then shifts to a more macroscopic chromosomal perspective for the further transformations during cancer development. On the epigenetic account, both genetic theories have missed the first step in cancer development, the step before any mutations occur, which is a reversible epigenetic event. From this perspective, even very advanced cancers are also epigenetically reversible under the right conditions. The microenvironmental perspective, which includes tissue-based theories, supplements the epigenetic approach in demonstrating what those right conditions are. The epigenetic and microenvironmental models of cancer are more compatible with the executive cell perspective.
What is exceptional, though not unique, in the T-devil’s cancer is its transmissibility. We can consider this the next stage after metastasis, a stage which, fortunately, most cancers never get to. Transmissibility appears to require a degree of stability at the cellular level that most cancers aren’t able to achieve. Also required are evasion of the immune response and the normalizing influence of the host tissue—microenvironmental factors both. Given the power of cancer microenvironments to either eliminate or epigenetically reverse even the most advanced cancers, there is reason for hope, even for those without recourse to saints.