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

by Siddhartha Mukherjee

The final element of a pump is a rhythm generator, or a metronome. Physiologists found that specialized nerve-like cells, resident in the heart, generate paced, rhythmic electrical impulses that stimulate the contraction. Yet other nerves—fast-conducting electrical wires—carry these impulses throughout the heart, first to the atria, and then to the ventricles. Once the impulse reaches one cell, the junctions between the cells ensure that all cells contract together.

Cajal used these drawings, as tenderly beautiful as they were forensically accurate, to propose a theory of the structure of the nervous system.

nerve cells “chattered” with each other—collecting inputs (via dendrites) and generating outputs (via the axon). And it was this cellular chatter—or rather, intercellular chatter—that gave rise to the profound properties of the nervous system: sentience, sensation, consciousness, memory, thinking, and feeling.

It is one of Cajal’s legacies that he never performed a single experiment in cell biology—or at least an experiment in the traditional sense. To see his drawings of neurons is to realize how much can be learned by just seeing. It is to return to characters such as Da Vinci or Vesalius who imagined drawing as thinking: an astute observer and draftsman could generate a scientific theory as much as an experimental interventionist. Cajal sketched what he saw, and his understanding of how the nervous system “worked” emanated entirely from drawing cells and drawing conclusions.

we should imagine the neuron not just as a passive “wire” but as an active integrator.IV

This fetal warm-up act—the soldering of neural connections before the eyes actually function—is crucial to the performance of the visual system.

The world has to be dreamed before it is seen.

“How does a microglial cell know which synapses to eliminate? […] We know that synapses compete against one another, and the strongest synapse wins. But how does the weakest synapse get tagged for pruning? The lab is now working on all these questions.”

Recent experiments suggest that dysfunctions in glial pruning may be related to schizophrenia—a disease where the pruning doesn’t occur appropriately. Other functions of different glial cells have been linked to Alzheimer’s disease, to multiple sclerosis, and to autism. “The deeper we look, the more we find,” Stevens told me. It’s hard to locate an aspect of neurobiology that doesn’t involve the glial cell.

Karl Popper, the eminent historian of science, once recounted the story of a man in the Stone Age asked to imagine the invention of the wheel in some distant future. “Describe what this invention will look like,” his friend asks. The man struggles to find words. “It’ll be round and solid, like a disk,” he says. “It will have spokes and a hub. Oh, and an axle to connect it to the other wheel, also a disk.” And then the man pauses to reconsider what he’s done. In anticipating the invention of the wheel, he has already invented it.

Banting would describe his notes from that October evening much like the invention of the wheel. As far as he was concerned, he had already discovered the hormone that controls sugar, later to be named insulin.

much has been written about the joy of being precisely right about a hypothesis or a theory. In the early 1900s, Einstein’s proposal of the constancy of the speed of light would spectacularly validate earlier experimental observations made by Albert Michelson and Edward Morley. (“If the Michelson-Morley experiment had not brought us into serious embarrassment, no one would have regarded the relativity theory as a [halfway] redemption,” Einstein would write later.) But there’s a second kind of joy in science: the peculiar exhilaration of being precisely wrong. It is an equal and opposite sensation of joy: when an experiment proves a hypothesis wrong, and the truth turns, as if on a pivot, to point exactly in the opposite direction.

Osteoarthritis, perhaps, was a disease of stem cell loss. The cells that were being worn out—in its first stages—were the cartilage-making stem cells, and they could no longer keep up the genesis of cartilage. The balance between growth and degeneration had been disrupted. What the injury had thrown off was the capacity of cartilage at the joint to maintain its internal balance—between the growth of new cartilage (via the stem cells) and the decay of old cartilage (via age and injury).

We proposed a radically new hypothesis about osteoarthritis. It isn’t merely a degeneration of cartilage cells, caused by grind and tear. It is, first, an imbalance caused by the death of Gremlin-marked cartilage progenitor cells that cannot generate adequate bone and cartilage to keep up with the demands of the joint.

there are some general principles: organs have resident “repair” cells that can sense injury and aging. But the idiosyncrasies of repair in each organ suggest that the individual cellular Band-Aids were cobbled together and remain unique to every organ. To understand injury and repair, then, we have to do it organ by organ and cell by cell.

One astonishing feature of cancer is that any individual specimen of cancer has a permutation of mutations that is unique to it. One woman’s breast cancer can have mutations in, say, thirty-two genes; the second woman’s breast cancer can have sixty-three, with only twelve overlapping between the two. The histological, or cellular, appearance of two “breast cancers” may look identical under the pathologist’s microscope. But the two cancers may be genetically different—they behave differently and may require radically different therapies.

When the flask was full of millions of cells, Jafarov drew them up into a tiny needle, about as thick as two strands of human hair, and injected them into the knee joints of mice. He’d been working on the procedure for months and perfected it slowly: he had to enter the joint with the needle causing no injury, like a perfect diver slicing into water without causing a splash. A few weeks later, he showed me the knee. The cells had formed a thin layer of cartilage at the joint. We had made a chimeric knee, with a jellyfish protein in its cells, glowing silently within the mouse. It was far from perfect—just a few cells had engrafted—but it was clearly the first step to build a new cellular joint.

In 2004, Sandel consolidated his ideas in an essay, “The Case Against Perfection,” which he soon expanded into a book. Reviewing the book in the Times, the ethicist William Saletan wrote: “[Sandel’s] deeper worry is that some kinds of enhancement violate the norms embedded in human practices.

To argue against human enhancement, Saletan continues, “Sandel needs something deeper: a common foundation for the various norms in sports, arts and parenting. He thinks he has found it in the idea of giftedness. To some degree, being a good parent, athlete or performer is about accepting and cherishing the raw material you’ve been given to work with [italics my own]. Strengthen your body, but respect it. Challenge your child, but love her. Celebrate nature. Don’t try to control everything […] Why should we accept our lot as a gift? Because the loss of such reverence would change our moral landscape.”