At around the turn of the millennium, some disturbing findings surfaced in the biomedical literature. Macrophages—immune cells whose function is to attack and kill microbes and other threats to the body—do not gather at tumor sites to destroy cancer cells, as had been optimistically imagined. Instead, they encourage the cancer cells to continue their mad reproductive rampage. Frances Balkwill, the British cell biologist who performed some of the key studies of treasonous immune cell behavior, described her colleagues in the field as being “horrified.”
By and large, medical science continues to present a happy face to the public. Self-help books and websites go right on advising cancer patients to boost their immune systems in order to combat the disease; patients should eat right and cultivate a supposedly immune-boosting “positive attitude.” Better yet, they are urged to “visualize” the successful destruction of cancer cells by the body’s immune cells, following guidelines such as:
• Cancer cells are weak and confused, and should be imagined as something that can fall apart like ground hamburger.
• There is an army of different kinds of white blood cells that can overwhelm the cancer cells.
• White blood cells are aggressive and want to seek out and attack the cancer cells.
At a more respectable level of discourse, Harvard physician Jerome Groopman wrote an entire 2012 New Yorker article on scientific attempts to enlist the immune system against cancer—without ever once mentioning that certain types of immune cells have a tendency to go over to the other side.
But the evidence for immune cell collusion with cancer keeps piling up. Macrophages supply cancer cells with chemical growth factors and help build the new blood vessels required by a growing tumor. So intimately are they involved with the deadly progress of cancer that they can account for up to 50 percent of a tumor’s mass. Macrophages also appear to be necessary if the cancer is to progress to its deadliest phase, metastasis. When cancerous mice were treated to eliminate all their macrophages, their tumors stopped metastasizing.
A May 2014 paper in the journal Cancer Cell offers a chilling account of the macrophage–cancer cell interaction. Macrophages are among the most mobile cells in the body, capable of moving through the bloodstream or creeping, like amoebae, by extending pseudopods and pulling themselves along. When macrophages encounter breast cancer cells, they do not do what we would like them to do, which is to attack and engulf the “enemy.” Instead, the Cancer Cell article suggests, the macrophages release a growth factor that encourages the cancer cells to elongate themselves into a mobile, invasive form poised for metastasis. These elongated cancer cells, in turn, release a chemical that further activates the macrophages—leading to the release of more growth factor, and so on. A positive feedback loop is established. Or, to put it more colorfully, the macrophages and cancer cells seem to excite one another to the point where the cancer cells are pumped up and ready to set out from the breast in search of fresh lebensraum—in the lungs, for example, or the liver or brain.
You will find little of this drama in the article itself, and not only because it is a scientific paper that happens to have seventeen coauthors. Their data focuses entirely on the chemical exchange between the two types of cells—which is a little like describing a human flirtation entirely in terms of hormones and pheromones. But what goes on among the living cells in the body? How many cells (macrophages and cancer cells) are required before the positive feedback loop can take off? Do the macrophages and cancer cells actually touch one another, perhaps briefly fusing cell membranes, or do the chemical messages they exchange travel through the intercellular matrix? And then there are the deeper, perhaps unanswerable, questions, like what’s in this for the macrophages, which by enabling metastasis seal their own doom? Or for that matter, what’s in it for the cancer cells, which will die along with the organism they destroy?
Kill, Eat, Repeat
If science seems to balk at the behavior of individual cells (and small groups of cells), this is because twentieth-century biology, in its reductionist zeal, tended to zip right past cells to get to the more glamorous molecular level. Cancer research came to focus on the DNA mutations that predispose cells to a career of selfish reproduction. Immunology downplayed macrophages in favor of an obsession with antibodies—the protein molecules that can mark a “foreign” cell, like a microbe, for destruction—although it is chiefly macrophages that do the destroying. My first thesis advisor at Rockefeller University won a Nobel Prize for elucidating the structure of antibody molecules. My second thesis advisor got far less recognition, and a much smaller lab, for his work on how macrophages kill and digest their prey.
The cells of our body are, in a sense, tiny animals themselves.
Part of the appeal of molecules over cells is that molecules can be collected in test tubes like any nonliving chemical, stored in a refrigerator, and analyzed at leisure by the usual chemical methods. Cells can be pulverized and fractionated into their constituent molecules, of course, but living cells have to be observed with the patience of an ethnologist studying chimpanzee behavior in the wild. After months of biochemical studies of macrophages, I once had a chance to see a living one under a phase contrast microscope and was surprised, in my naïveté, to find that it was moving, its surface rippling and corrugating like that of a sea anemone. The cells of our body are analogs of, and evolutionary descendants of, the unicellular creatures that preceded multicellular life and, in a sense, are tiny animals themselves.
Only very recently, new techniques in microscopy have made it possible to track the behavior of individual cells in living tissue, and the resulting images reveal striking degrees of individuality. If you calculate the bulk average of movements within a sample group of cells, most cells turn out to be going their own way, on paths far from the average. Cancer cells within a tumor exhibit “extreme diversity.” NK, or “natural killer,” cells, which, like macrophages, attack targets like microbes, do not always kill. A 2013 article reports that about half of the NK cells sit out the fight, leaving a minority of them to become what their human observers call “serial killers.”
Individual cells have no mental life—no thoughts or feelings—at least none that we can imagine, if only because they lack nervous systems. But macrophages and NK cells are capable of “memory,” or different responses to stimuli they have encountered before. Risking anthropomorphism, scientists now speak of “decision-making” by individual cells such as macrophages. The cells sniff the chemicals in their microenvironment, seem to weigh their options, and then decide whether to attack or withdraw, move forward or remain where they are. As one science news site put it:
Cells are constantly making decisions about what to do, where to go or when to divide. Many of these decisions are hard-wired in our DNA or strictly controlled by external signals and stimuli. Others, though, seem to be made autonomously by individual cells.
Just a decade ago, any talk about cellular “decision-making” would have been taken for whimsy. Cells, as we knew them then, were programmed both genetically and epigenetically (through chemical modifications to DNA occurring during development) to perform their functions in the body. Heart cells beat, intestinal cells secrete digestive enzymes, nerve cells conduct electrical signals, etc.—and those that falter at their tasks obligingly commit suicide through a process called apoptosis. Furthermore, most body cells, most of the time, are fixed in place by glue-like attachments to other cells. Individual cells have no decisions to make, we used to think, because they have no choice but to serve the organism by tirelessly carrying out their assigned roles.
But that old deterministic model of cell behavior offered little insight into cellular rebellions such as cancer. Many cells may be exposed to a carcinogen, but only some turn into cancer cells, and of those, only a fraction go on to a career of metastasis. “Decisions” are made. As for macrophages, collusion with cancer cells is only one of the ways they can undermine the organism. Overly ambitious macrophages play a central role in autoimmune diseases and the many inflammatory ailments, like arthritis, that plague the elderly. In coronary artery disease, macrophages pile up on the arterial walls, where they fatten themselves on lipids until there is no space in the artery for blood to flow through. The macrophages are doing what comes naturally to them: eating. Unfortunately, there is no central authority to tell them to desist lest the whole multicellular contraption that is the body come to grief.
As an analogy to the erratic immune system (which includes macrophages, NK cells, and a host of other cell types, including antibody-producing lymphocytes), biology teachers often invoke the military. Any human society within a spear’s throw of potential enemies needs some kind of defensive force—minimally, an armed group who can defend against invaders. But there are risks to maintaining a garrison: the warriors may get greedy and turn against their own people, demanding ever more food and other resources. Similarly, in the case of the body, without immune cells we would be helpless in the face of invading microbes. With them, we face the possibility of insurrection and self-inflicted death.
It is disconcerting to think of the biological self, or body, as a collection of tiny selves. The image that comes to mind is the grotesque portrait of a super-sized king in the frontispiece of Hobbes’s Leviathan: on close inspection, the king turns out to be composed of hundreds of little people crowded into his arms and torso. Hobbes’s point was that human societies need autocratic leaders; otherwise they risk degenerating into a “war of all against all.” But no “king” rules the body. Despite, or sometimes because of, all the communications—chemical and electrical—that connect the tissues and cells of the body, chaos can always break out.
The “wisdom of the body” does not always apply at the microscopic level. An individual cell can sabotage the entire operation.
It would be nice to think that the brain, with which we do our thinking, is a more tightly disciplined place, set off as it is from the turmoil of the body by the blood–brain barrier, like a computer kept in a dust-free, air-conditioned room. But living brain cells are not entirely predictable. The glial cells that support and nourish neurons can become cancerous (as, more rarely, can neurons themselves). Then too, the brain has its own army of macrophages, or microglia as they are called, and overactive microglia can, like macrophages in other parts of the body, create damaging inflammations, leading to neurodegenerative diseases. Bizarrely enough, new research this year shows that breast cancer cells sometimes “disguise” themselves as neurons, penetrate the blood–brain barrier, and start fresh tumors in the brain. If individual cells have functions, they do not always seem to know it.
It took science until 2012 to officially acknowledge that nonhuman animals possess feelings and consciousness. It may take a bit longer for biology to admit that the cells in our bodies are not simply automata, that they possess, if not consciousness, at least some sort of agency. As recently as 2008, an article on the confusing taxonomy of macrophages proposed that a new, “more informative” classification “should be based on the fundamental macrophage functions,” which are defined as “host defence, wound healing and immune regulation.” What about macrophages’ role in abetting cancer—or in instigating life-threatening inflammatory diseases? What “functions” do these activities represent? The “wisdom of the body,” which supposedly keeps the body unified as a single sustainable organism, does not always apply at the microscopic level, where an individual cell can sabotage the entire operation.
Natural selection should weed out cellular traitors, you might think, since people who are vulnerable to cancer, autoimmune diseases, and pathological inflammation—at least at early ages—are less likely to reproduce. The truth is, though, that we do not know for sure what natural selection means at the cellular level. Often, when a person with cancer is subjected to chemotherapy, some of the cancer cells survive through what can only be called natural selection. A victory at the cellular level may mean defeat for the organism.
This is madness, of course. But then, who are we, as human beings, to be appalled by the irresponsible “decisions” of our body’s cells? We too are biological organisms, supposedly doing our best to survive and promote the survival of our kin. And we too, like rogue cells in our bodies, can be murderous, suicidal, and systematically destructive of our physical habitats. We, of all creatures, should appreciate the perversity, as well as the clockwork precision, of biology.