What are these potentially fractious subunits—or “building blocks,” as they are sometimes called—of the body, and how can we effectively control them? One of the first cells a biology student is likely to encounter through a microscope is not a subunit of anything. It is a free-living creature in its own right—a single-celled organism called an amoeba. Amoebae, which are easily found in pond water, swim through their environment searching for edible morsels, which they can then engulf with a pseudopod and ingest. I came across them in the laboratory of Maria Rudzinska, with whom I endured a few-weeks-long tutorial along my winding path to a PhD. Her lab was the size of a closet and she seemed annoyed at my presence, a situation that was not improved by my failure to see the relevance of her pet cells to my long-term interest in advancing human health. I was not interested in cells at all, those tiny lipid sacs containing proteins and nucleic acids. They were, from my thoroughly reductionist point of view, just distractions on the way to the real action, which took place at the chemical level that could only be accessed by bursting the cell membrane and grinding its contents into sludge. It even occurred to me that I had not been assigned to Rudzinska because she had anything to teach me, but simply because we shared the anomaly of being female in an overwhelmingly male research institute. Certainly her amoebae were not the evolutionary progenitors of, or even models for, anything human.
It took a couple of years before I began to appreciate events at the cellular level, and decades more, in fact, before I could see the connection between the lives of amoebae and those of the cells in our own bodies. One of the things that held me back was that amoebae are autonomous creatures, while the cells in our bodies obviously are not: They have “functions” to perform. But suppose that body cells, or some of them anyway, some of the time, are even a little bit autonomous?
To the extent that the individual subunits of the body, the cells, are capable of acting on their own, there is always the possibility of mayhem. One can imagine fetal cells escaping from the fetus to pop up years later in some remote part of the mother’s tissue, or an entire pregnancy being derailed when an embryo decides to implant somewhere other than in the uterus—in a fallopian tube or even the abdominal cavity. Or cancer cells from other parts of the body could occasionally sneak past the blood/brain barrier to become a fifth column among the neurons that do our thinking for us.
In fact, each of these things occurs: Women who have borne children often contain cells from the fetuses they have carried, making these women chimera, or mixtures of different individuals. Furthermore, in 1 or 2 percent of all pregnancies, the embryo arbitrarily attaches itself somewhere other than the uterus, resulting in a life-threatening situation for the mother. Even stranger, breast cancer cells have been caught “disguising” themselves as neurons to colonize the brain. Nor should we be surprised by these outbreaks of self-assertion on the part of cells and small groups of cells. Autoimmune diseases involve an apparently spontaneous attack by immune cells on other body cells; cancer is a mad pursuit of lebensraum originating in a single cell or a small group of cells.
Fortunately, from the point of view of the organism as a whole, there are plenty of mechanisms to keep adventurous cells in place. Tissue cells are bound to each other by “intercellular glue” as well as by “junctions,” some of them so tight as to be almost unbreakable. As an additional precaution, organs are often enclosed in membranes that may be difficult or impossible for a cell to breach. Then there is the steady hail of chemical signals that one cell receives from others, some of them sent from considerable distances. We can translate very few of these signals, and they appear to say things like “Danger!” or “Come here right away!” And—who knows?—some of the messages may be propagandistic, urging cells to carry on stalwartly with their appointed tasks. Then there is the final sanction for a recalcitrant cell: death. Signals come in saying “Die!” and, in a process called apoptosis, the cell obligingly shuts down its metabolism, folds neatly into its membrane, and awaits disposal.
But there are some cells that are required, by their agreed-upon “function” in the body, to be adventurous, inquisitive, and even aggressive: leucocytes, for the most part, or the white blood cells that fight microbial diseases. Like red blood cells, many leucocytes originate in the bone marrow and are carried around passively by the bloodstream. Others, however, are capable of moving on their own, even through the dense and slippery spaces between cells in a tissue. With the exception of stem cells, there is probably no cell in the body more versatile than the macrophage, which originates, like so many other leucocytes, in the bone marrow. Immature macrophages, called monocytes, are released into the bloodstream, where they may become attracted to a stationary object, like a dead or injured cell, and settle down to devour it. As the macrophage eats, it grows and becomes “activated”—filled with vacuoles containing digestive enzymes that allow it to eat still more. My PhD research eventually involved “harvesting” macrophages from mice and studying this transformation. Although its significance was unclear to me, I could see immediately that a mature macrophage resembles nothing so much as a free-living amoeba. The resemblance is so striking that it has tempted some scientists to speculate that there may be some kind of evolutionary connection between the two types of cells, although of course they come from totally unrelated lineages.1 Like a free-living amoeba, a macrophage can move around by extending a pseudopod and dragging itself along; it can dispose of dead or injured cells in a wound; it can attack and eat microbes that have found their way into the body.
As the all-purpose handyman of the body, the macrophage has gotten very little respect from mainstream science. It’s a blue-collar worker, and since it’s responsible for removing cell corpses and other trash, it’s been called the “garbage collector” of the body and even, given its lethal capacities, a “thug.” The macrophage’s M.O. as a killer is indeed rather brutal and thuglike: It engulfs its prey in its cell membrane and proceeds to digest it through the same process of phagocytosis that amoebae use, which is to say it turns its body into a terrifying mouth, like the vagina dentata, or toothed vagina, of folklore. Some killer cells of the immune system, more fastidiously, inject their prey with poisons and move on; others extrude extracellular threads that entrap and kill microbes. But the macrophage actually eats its prey, and this may give it a measure of independence unknown to most other body cells, which are totally dependent on the bloodstream for their nutrients.
Until recently, though, immunologists were far more interested in antibodies than in macrophages or any killer cells. Antibodies are the ingeniously bespoke protein molecules designed to bind to particular antigens—or patches of a microbe’s surface—either disabling the microbe or marking it for destruction by macrophages. In the grand drama of antibody production—which was really the only drama in immunology once the molecular biologists seized center stage—macrophages were given only a minor supportive role. Their job was to “present” bits of foreign material (or antigens) to the presumably far cleverer white blood cells called lymphocytes that would manufacture the appropriate antibodies. As philosopher of science Emily Martin has pointed out, there is also a gender dimension to the derogation of macrophages, which have been described in the immunological literature as “housekeepers” and “little drudges.”2
But here I must pause to confess that I am simplifying to an extent that would annoy many cellular immunologists. The alternative would be to descend into the dizzying detail of technical debates over the classification of cells. Some sources, for example, insist that the central antigen-presenting cells are not macrophages, but a related cell type called dendritic cells, which also arise in the bone marrow, and are also phagocytic.3 Others argue that dendritic cells do not exist as a cell type separate from macrophages, pointing out that both these putative cell types possess the same chemical markers on their surfaces and react the same way to chemical growth factors in their environment.4 More important, both types are capable of presenting antigens to lymphocytes and causing them to produce the appropriate antibodies, so that whether we call them macrophages, dendritic cells, or something more indecisive, they get the job done. This kind of taxonomic puzzle arises again and again in cellular immunology, where the mutability and mobility of individual cells constantly thwart rigid systems of classification. A macrophage, bursting with ingested material, in no way resembles a newly minted monocyte entering the bloodstream for the very first time.
The simplest system of classification is between the good guys and the bad guys—the latter being microbes and other threats to the body. Without any question, macrophages were the good guys, gobbling up microbes and often going on to help generate the production of antibodies that would coat any identical microbial invaders to make them even more appetizing to macrophages. How creative a role macrophages play in defense of the body—whether they are simply the cleanup crew or are more intimately involved in antibody production—is still not entirely clear. But to me as a lowly graduate student, they were heroes, always rushing out fearlessly to defend the body against microbes or other threats. They might be slow-witted compared to lymphocytes that produce antibodies, but they were in the vanguard of bodily defense.
Or so I thought until around the turn of the millennium, when some disturbing findings surfaced in the biomedical literature. Macrophages had been known since the nineteenth century to gather at tumor sites, leading Virchow and others to speculate that cancer is caused by inflammation, meaning a gathering of leucocytes at some site of injury or infection. Or, more optimistically, one might imagine that the macrophages were massing for an assault on the tumor. Instead, it turned out that they spent their time in the neighborhood of tumors encouraging the cancer cells to continue on their reproductive rampage. They are cheerleaders on the side of death. Frances Balkwill, one of the cell biologists who contributed to the recognition of treasonous macrophage behavior, described her colleagues in the field as being “horrified.”5
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:
Philosophically, it is not easy to imagine one’s own immune cells becoming accomplices in the deadly project of cancer, and denial has lingered on even in far more reputable venues than the self-help literature. In 2012 the distinguished physician and science writer Jerome Groopman wrote an entire article in the New Yorker on scientific attempts to enlist the immune system in fighting cancer without once mentioning that certain immune cells—macrophages—have a tendency to go over to the other side.7 The omission is made all the stranger by the fact that Groopman introduces his essay with a story about a young woman in 1890 whose hand injury led to a long and painful inflammation, which was followed by a fatal metastatic sarcoma. In the article, he assures us, without explanation, that the sarcoma was “unrelated to her initial injury.” By 2012, though, there had already been reports about the role of macrophages in injury-induced sarcomas.8 Similarly, a 2016 New York Times article on “Harnessing the Immune System to Fight Cancer” makes no mention of macrophage treason.9
The evidence for macrophage 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, and if a cancerous mouse is treated to eliminate all its macrophages, the tumor stops metastasizing.10
Just in the last decade, scientists have begun to understand the perverse interaction that can lead macrophages and tumor cells to pool their resources and overwhelm the organism. The first part of the story can be expressed almost entirely in terms of chemistry. Any reasonably genteel meeting of two cells begins with an exchange of chemical messages, more or less like an exchange of business cards between two professionals, only in the cellular case the transaction can quickly get out of hand. As a 2014 article on breast cancer in the journal Cancer Cell 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.11 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 territory to conquer—in the lungs, for example, or the liver or brain.
But describing the cellular interactions strictly in terms of the exchange of chemical messages is like trying to portray a human courtship as little more than an interaction of pheromones. For a more intimate view of what goes on between cells in the living body, we need to turn to the results of ingenious new techniques of microscopy capable of visualizing individual cells in the opaque environment of an active tumor. A kind of “intravital” microscopy, developed at John Condeelis’s lab at the Albert Einstein College of Medicine, reveals that macrophages from within the tumor pair off with cancer cells to enter a blood vessel that would otherwise be impenetrable to the cancer cells. The macrophage has the chops, so to speak, to pry apart two adjacent blood vessel cells and make a hole through which the cancer cell can escape to colonize other parts of the body.12 And the cancer cells are desperate to escape, since their own reproductive success creates a suffocatingly crowded environment within the tumor, dangerously short of oxygen. So it doesn’t take just one rogue cell to create a metastatic cancer; it takes two—a cancer cell plus a normal, healthy, and all-too-helpful macrophage.
A science writer has to guard against overdramatizing and anthropomorphizing the events she is reporting on, but here the scientists involved have already done that for me. In 2015, two younger members of the Condeelis lab put together a short film showing the macrophage–tumor cell interactions that lead to breast cancer metastasis—both in animation and live footage of the microscopic events. The film begins with one of the narrators, a graduate student, wondering aloud, in an ominous tone, what genre of movie it belongs to: “horror…action…or war.”13 In his blog, the director of the National Institutes of Health likens the film to Mission: Impossible and writes almost breathlessly:
Without giving too much of the plot away, let me just say that it involves cancer cells escaping from a breast tumor and spreading, or metastasizing, to other parts of the body. Along the way, those dastardly cancer cells take advantage of collagen fibers to make a tight-rope getaway and recruit key immune cells, called macrophages, to serve as double agents to aid and abet their diabolical spread.14
Breast cancer is not the only form of cancer that depends on macrophages for access to blood vessels and hence metastasis to new sites in the body. So far, there is evidence that macrophages assist in the metastasis of lung,15 bone, gastric, and other cancers. And the macrophages’ fiendish role in the growth of cancer does not end after they have escorted tumor cells into the bloodstream. Once at the remote site where the tumor cells have decided to settle, macrophages get to work on the job of angiogenesis—building new blood vessels to nourish the tumor.16 (Whether the same macrophages that guide cancer cells into the bloodstream go on to do the work of angiogenesis is not known, at least as far as I can tell.)
Their complicity in cancer should be enough to disqualify macrophages as good guys, but that is not the only form of mischief that macrophages get into. Many pathological or at least annoying conditions, from acne to arthritis, arise from inflammation, and inflammation, which involves a variety of leucocytes, is spearheaded by macrophages. Acne, for example, is widely attributed to a bacterial infection, including by the manufacturers of a bactericidal cleanser called pHisohex, who advertise that their product will “Fight the bacteria, dirt and oil that bring on acne and pimples,”17 although it is now well known that these ugly eruptions can occur in the absence of the bacterial suspects.18 At a later phase in the human life cycle, we find macrophages involved in arthritis and diabetes, as well as chewing away at living bones to produce osteoporosis.
The blood vessels leading to the heart might be one of the last places you would expect to find errant immune cells, and for years the narrowing of these vessels—which can lead to heart attacks and strokes—was understood to be a result of fatty deposits along the arterial walls. Anyone seeking “heart health” was exhorted to eliminate saturated fat and cholesterol from their diet, if not all red meats and all forms of fat. “Atherosclerosis [narrowing of the cardiac arteries] was all about fats and grease,” according to Peter Libby, a cardiologist and professor at Harvard Medical School. “Most physicians saw atherosclerosis as a straight plumbing problem.”19 Then came the discovery that the “bad” cholesterol in these arteries can trigger an inflammation that sets off strokes and heart attacks—another case, according to Libby, of “our body’s defenses turned against ourselves.”20 Inflammation means an accumulation of macrophages, which a 2015 article asserts play “important roles in all stages of atherosclerosis.”21
At this point, the emphasis on inflammation as a cause, if not the cause, of human ailments has achieved the dimensions of a fad. In a 2015 New Yorker article by Groopman (which is significant, among other things, for granting macrophages a status higher than janitors), he reports that “a growing number of doctors…believe that inflammation is the source of a wide range of conditions, including dementia, depression, autism, ADHD, and even aging.”22 It is no longer enough to eliminate fats and cholesterol from one’s diet; an “anti-inflammatory diet” excludes processed foods, dairy products, and, commonly, meat. While such a diet may lead to weight loss, which can be a good thing, there is no hard evidence that it curbs inflammatory disorders or does anything else to tame the behavior of macrophages.23
One approach to the apparent unpredictability of macrophages is to abandon the category of “macrophages” and postulate that there are several subcategories of cells doing the various things we attribute to them. Supposedly, each category of macrophages has its own set of genetic instructions, which it obediently follows. For a while the favored division was between “M1 macrophages,” which are responsible for killing microbes, and those of the “M2” variety, which focus on wound healing, but this classification does not account for the fact that the M2 designation “encompasses cells with dramatic differences in their biochemistry and physiology.”24 Or as one frustrated team of researchers put it, “Instead of having a finite number of variants that can be easily counted, we have an infinite number of polarized [activated] macrophages.”25 A common response has been to double down on the functional classification of macrophages, as a 2008 article proposes:
We suggest that a more informative foundation for macrophage classification should be based on the fundamental macrophage functions that are involved in maintaining homeostasis [a state of balance supposedly necessary for the health of the organism]. We propose three such functions: host defence, wound healing and immune regulation.26
But what about macrophages’ role in abetting cancer—or in instigating life-threatening inflammatory diseases? What “functions” do these activities represent? As it turns out, the macrophages that launch tumor cells into the bloodstream do not seem to fit either canonical category M1 or M2,27 suggesting that we should be focusing less on static categories than on the mutability of individual macrophages. Maybe, crazy as it sounds, they are not following any kind of “instructions,” but doing what they feel like doing.