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The Cell Lives by Its Boundary
I remember the day I first looked at a living cell through a microscope at university. Back then I assumed that the cell's "contents"—the nucleus, the organelles—would be the protagonists. But as time went on, what held my eye was something else: the thin membrane that wrapped it all and parted inside from outside. If someone were to ask me now, "What is life?" I would answer this way: life is a membrane (膜).
This is not merely my own sentiment. Paul Nurse, the biologist who received the 2001 Nobel Prize in Physiology or Medicine for uncovering the principle that governs the cell cycle, names in his book What Is Life? the cell itself as biology's great first idea. What he attends to is not the intricate parts contained within the cell, but the membrane that separates all of them from the outer world. For only when the membrane divides inside from outside and creates one distinct interior can the chemistry of life be organized rather than scattered. For him the first condition of life was neither replication nor metabolism. It was the boundary that distinguishes the self from the world—the membrane. Life begins at the boundary.
What makes a cell a cell is neither its nucleus nor its genes. It is the membrane that divides it into inside and outside. Without a membrane there is no cell. If inside and outside are not distinguished, it is merely chemicals dissolved in water. The computational neuroscientist Karl Friston explains that every living system maintains itself through a boundary he calls the "Markov blanket." Across the boundary, the inside senses the outside (receiving) and acts toward it (responding). To live, in other words, is to give and receive ceaselessly at the boundary. To have no membrane is to have no boundary, and to have no boundary is to have no existence.
What this book has said from the beginning—that existence is born at the boundary—biology tells us in the very same words. Maturana and Varela called life "a boundary that endlessly remakes itself." And they added one thing more: the living thing and the environment surrounding it do not exist apart, but shape each other. So I am not already complete before the boundary. I am made, moment by moment, at the boundary, giving and receiving with the world. The boundary is not a wall wrapped around a finished me—it is the place where I am born.
The greatness of the cell membrane lies in its being no mere wall. A wall blocks everything. But the cell membrane chooses. Some things it lets in, some it sends out, some it turns away at the door. Oxygen and nutrients it admits, waste it expels, the harmful it refuses. This is called selective permeability. The membrane divides and joins at once. And so it is alive.
A living boundary divides and joins at once.
Within this single sentence lies the cure for both illnesses we saw in the previous chapter. If the membrane opens completely and takes in anything at all—melting—the cell loses the distinction of inside and outside and dies. If the membrane closes completely and takes in nothing—hardening—the cell starves to death. The healthy cell is always in between: a membrane open yet discerning, closed yet communing. I think of two ancient Hebrew words. The two callings entrusted to humankind in Genesis: avad (to serve, to till) and shamar (to keep, to preserve). Astonishingly, this is exactly what the cell membrane does. To receive and serve, to keep and preserve. To guard the boundary is itself love, and boundless fusion is not love but death.
The cell membrane teaches us, too, what death is. When a cell dies, the first thing that happens is the collapse of the membrane. The boundary that divided inside from outside gives way, what was inside leaks out, what was outside floods in. The vanishing of the boundary is death itself. What we saw in the previous chapter as a sickness of society—"melting"—the cell knows as death in the most literal sense.
This membrane is not found in the cell alone. Our bodies hold boundaries layer upon layer, and the widest of them is the wall of the gut (腸). Spread the intestinal epithelium out flat, it is said, and it would cover the area of a tennis court. It is the largest frontline in our body where inside and outside meet. One curious fact: the tube running from mouth to anus is, topologically speaking, actually the "outside" of the body. Like the hole in a doughnut, it is an exterior that passes straight through us. So the intestinal wall is the membrane where I and the world meet most broadly—the vast bodily extension of the cell membrane.
And this intestinal wall works by exactly the same principle as the cell membrane—selective permeability. The seams called tight junctions stitch the epithelial cells densely together, so that nutrients are admitted while toxins and pathogens are barred. But what happens when these seams loosen? Things that should never pass through—fragments of undigested protein, bacterial components—leak into the bloodstream, and the body, reacting to these invaders, kindles a chronic, low-smoldering inflammation. This is the state of heightened intestinal permeability commonly called "leaky gut." (In popular talk it is sometimes exaggerated as the root of all disease, but the barrier function of the gut and its permeability are, in themselves, firmly established physiological phenomena.)
Here the thesis of this book is realized, literally, within the body. The health of the intestinal wall is not achieved alone. It depends on a right relationship with the tens of trillions of microbes that live in the gut—the "other" within my own body. When we eat the dietary fiber of vegetables and whole grains, the gut bacteria ferment it and make a short-chain fatty acid called butyrate. And this butyrate is the chief food of the colon's epithelial cells. Only when butyrate is plentiful is the epithelium sturdy, the mucus layer thick, the seams tight, the inflammation quieted. Conversely, when we do not eat fiber, butyrate runs dry, and the starving bacteria gnaw instead at the mucus layer that guarded the body, breaking the boundary down. When I feed the other (the microbes), that other guards my boundary. This relationship, in which each keeps the other alive, is mutual indwelling made flesh.
What unfolds when the boundary collapses is significant too. When the intestinal wall leaks and the distinction of self and non-self blurs, the immune system falls into confusion and may, in the end, even attack the body's own self. This is autoimmune disease. The immune system, unable to distinguish self from other, attacks the self—a narcissism at the cellular level, so to speak. The "collapse of the boundary" we saw in earlier chapters as an illness of the mind appears here as an illness of immunity. There is, of course, the opposite failure. Overuse antibiotics, live too sterile a life, and exterminate the other that is the microbes altogether, and the immune system, never having learned the other, sees allergy and autoimmunity rise instead. To erase the boundary (fusion) is a sickness; to make the boundary a wall (isolation) is a sickness. The healthy gut is in between—a living membrane, open yet discerning.
This principle is guarded most strictly in the brain. The blood–brain barrier that protects the brain is the most selective boundary in our body. The brain is the "inside" that must be guarded above all, so its gatekeeper is the most vigilant. And astonishingly, these boundaries are joined to one another. When the intestinal wall leaks and inflammatory substances circulate through the whole body, they loosen even the blood–brain barrier, and inflammation spreads into the brain, summoning depression and a dull, foggy fatigue. This is the so-called gut–brain axis. Here a region of the brain I have long attended to appears—the insula. The insula is the place that translates the signals rising from the gut and viscera into "feeling," and further into the sense of "I." So when the body's boundary collapses, that collapse is translated, by way of the insula, into a wavering of the self—the sense that "I am a stranger to myself." The boundary of the body and the self of the mind meet right here.
Seen this way, our body is a single map of boundaries. Beginning at the membrane of the innermost mitochondria, through the cell membrane, the blood–brain barrier, the intestinal wall, the skin, and on to the boundary between my mind and another's—differing only in size, all do the same work. To be closed and yet open, to guard the self and yet give and receive with the world. And there is one prescription that brings all these boundaries to life at once. It is none other than exercise. Regular exercise diversifies the gut microbes and increases the bacteria that make butyrate, strengthening the intestinal wall; through brain-derived neurotrophic factor (BDNF) and the vagus nerve it governs the blood–brain barrier and neuroinflammation; and it revives the mitochondria. Here lies the reason I have called exercise "medicine" all my life. Exercise is an intervention that revives, at once, every level of boundary—from the mitochondrial membrane to the boundary of the mind. So the boundary is no abstract concept. It is the most concrete work of life, performed diligently, this very moment, by the tens of trillions of membranes within my body. I am alive by my boundaries. And this small membrane holds out one more piece of wisdom: that a living boundary does not fear a stimulus. That is the story of the next chapter.
References
Paul Nurse, What Is Life? · Karl Friston (the free energy principle) · Maturana and Varela (autopoiesis) · cf. Genesis 2:7