The Song of the Cell: An Exploration of Medicine and the New Human

by Siddhartha Mukherjee

In 1795, the movement found its richest poetic voice in Samuel Taylor Coleridge, who imagined all of “animated nature” trembling into existence as this vital force flowed through it, just as a breeze might resonate through a harp and produce music that is irreducible to its mere notes. As Coleridge wrote: “And what if all of animated nature / Be but organic Harps diversely framed / That tremble into thought, as o’er them sweeps / Plastic and vast, one intellectual breeze / At once the Soul of each, and God of all.”12

There is some debate about the origin of mitochondria. But one of the most intriguing, and widely accepted, theories is that more than a billion years ago, organelles were, in fact, microbial cells that developed the capacity to produce energy via a chemical reaction involving oxygen and glucose. These microbial cells were engulfed or captured by other cells and entered into a working partnership of sorts, a phenomenon termed endosymbiosis.

Mitochondria possess their own genes and their own genomes, which, suggestively, bear some resemblance to the genes and genomes of bacteria—again supporting Margulis’s hypothesis that they were primitive cells that were engulfed by other cells and then became symbiotic with them.

How does a cell generate energy? There are two pathways: one fast and one slow. The fast route occurs mainly in the protoplasm of the cell. Enzymes serially break down glucose into smaller and smaller molecules, and the reaction produces energy. Because the process doesn’t use oxygen, it is called anaerobic. In terms of energy, the end product of the fast pathway is two molecules of a chemical called adenosine triphosphate, or ATP.

The whole process can be imagined as an elaborate postal system. It begins with the linguistic code of genes (RNA) that is translated to write the letter (the protein). The protein is written, or synthesized, by the cell’s letter writer (the ribosome), which then posts it to the mailbox (the pore by which the protein enters the ER). The pore routes it to the central posting station (the endoplasmic reticulum), which then sends the letter to the sorting system (the Golgi), and finally brings it to the delivery vehicle (the secretory granule). There are, in fact, even codes appended to proteins (stamps) that enable the cell to determine their ultimate destination. This “postal system,” Palade realized, is how most proteins get to their correct locations within the cell.

If a single cell’s DNA could be stretched out straight, like a wire, it would measure six and a half feet. And if you could do that for every cell in the human body and laid all of that DNA end to end, it would stretch from the Earth to the sun and back again more than sixty times. String together all the DNA in every human being on the planet, and it would reach the Andromeda galaxy and back nearly two and half times.21

In humans and multicellular organisms, the process for the production of new cells to build organs and tissues is called mitosis—from mitos, the Greek word for “thread.” In contrast, the birth of new cells, sperm, and eggs for the purpose of reproduction—to make a new organism—is called meiosis, from meion, the Greek word for “lessening.”

Imagine, for a moment, the entire human genome as a vast library. Its books are written in an alphabet containing just four letters: A, C, G, and T, the four building-block chemicals of DNA. The human genome has more than 3 billion such letters—6 billion per cell if you count the genomes of both parents. Reframed as a library of books, with about 250 words per page and 300 pages per book, we might think of ourselves—or rather the instructions to build, maintain, and repair ourselves—as written in about 80,000 books.

Cas9 is a search-and-destroy eraser. To continue the analogy, it can change Verbal to Herbal in the preface to volume one of Samuel Pepys’ Diary in a college library containing eighty thousand books. Every other word, in every other sentence, in every other book in the library is, for the most part, left alone.

In one of embryology’s many ironies, having set up the framework of the embryo, the human notochord will lose its prominence and function between embryonic development and adulthood. Its only cellular remnant in the adult human body is the pulp that remains stuck between the skeletal bones. In the end, the master maker of the embryo is trapped inside the bony prison of the very creature it has created.

In 1897, a young chemist named Felix Hoffman, working for the German pharmaceutical company Bayer, found a way to synthesize a chemical variant of salicylic acid.11 The medicine was called aspirin, or ASA, short for acetyl salicylic acid. (The name was drawn from the a in acetyl, and spir from Spiraea ulmaria, the plant from which salicylic acid was extracted.)

In cell biology and genetics—in fact, in most of the biological world—learning and memory typically happen by mutation, not instruction or aspiration. A giraffe’s long neck isn’t the product of generations of its ancestors aspiring to stretch their necks to reach tall trees. It is the consequence of mutations, followed by natural selection, that produces a mammal with an extended vertebral structure that, in turn, creates a long neck.

In 1958, Sanger was awarded the Nobel Prize for solving the structure of a protein—a monumental achievement in molecular biology. And in 1980, he would win a second Nobel for learning how to sequence DNA.

The trick to a muscle cell’s contraction is that these two fibers—actin and myosin—slide against each other, like two networks of ropes. When a cell is stimulated to contract, a part of the myosin fiber binds to a site on the actin fiber, like a hand from one rope gasping the other. It then unclutches it and reaches forward to bind to the next site—a man suspended on one rope, grasping and pulling on the other, one fist upon the next. Clutch. Pull. Release. Clutch. Pull. Release.

one peculiarity of the system is that it is the release of actin from myosin—not the binding of the fibers—that requires energy. When an organism dies, and the source of energy is lost, the muscle fibers, unable to unclasp their fists, are caught in a permanent grip—bound. The cellular ropes in every muscle tighten. The body hardens and contracts into the permanent clasp of death—the phenomenon that we call rigor mortis).

In its resting state, the heart cell has low levels of calcium. When it is stimulated to contract, calcium floods into a heart cell, and it instigates contraction. And calcium’s entry is a self-feeding loop: the entry of calcium releases more calcium from the heart cell, resulting in a sharp, steep spike in calcium levels. The interconnections between the cells—those “junctions” that were identified in the 1950s—carry the ionic message from cell to cell.

In Graz, Austria, another neurophysiologist, Otto Loewi, also converged on the idea of chemical neurotransmitters.16 The night before Easter Sunday, 1920—in the brief lull of peace between the wars—he dreamed of an experiment. He remembered very little of the dream, but perhaps it involved a muscle and a nerve in a frog. “I awoke” he wrote, “turned on the light and jotted down a few notes on a tiny slip of thin paper.17 Then I fell asleep again. It occurred to me at 6.00 o’clock in the morning that during the night I had written down something important, but I was unable to decipher the scrawl. The next night, at 3.00 o’clock, the idea returned. It was the design of an experiment to determine whether or not the hypothesis of chemical transmission that I had uttered seventeen years ago was correct. I got up immediately, went to the laboratory, and performed a simple experiment on a frog heart according to the nocturnal design.”

Specialized cells known as microglia—spidery and many-fingered—had been seen crawling around the brain, scrounging for debris, and their role in eliminating pathogens and cellular waste had been known for decades. But Stevens also found them coiled around synapses that had been marked for elimination. Microglia nibble at the synaptic connections between neurons and pare them away. They are the brain’s “constant gardeners,” as one report put it.29

I sometimes think of the Greek story of the Delphic boat. The boat is built of many planks. Bit by bit, the planks decay and are replaced by new ones, until all of them are new. But has the boat changed? Is it even the same boat?

Theseus boat

Hemoglobin is a complex of four proteins; and it’s shaped like a four-leafed clover. Two of the “leaves” are formed by a protein named Alpha-Globin, while two are another protein named Beta-Globin.

Red blood cells contain hemoglobin molecules that contain heme that, in turn, clasps iron atoms. It’s the iron that binds and unbinds the oxygen.

The red cells pick their payload—oxygen—from the capillaries of the lung and ferry it around. And when the cells reach oxygen-poor environments in the body—with the heart muscle pumping and pushing them around minute after minute—hemoglobin, literally, twists and unclasps the oxygen that the iron atoms have bound. Hemoglobin is blood’s hidden secret—a complex of proteins so vital to our existence as organisms that we have evolved a cell whose principal job is to act as a suitcase to carry it around.