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

by Siddhartha Mukherjee

The cell’s original replication system was almost certainly made of a strand-like molecule called ribonucleic acid, or RNA. Indeed, in lab experiments, simple chemicals, placed in conditions that resemble the atmospheric conditions on primitive Earth, and trapped within layers of clay, can give rise to precursors of RNA and even strands of RNA molecules.

But the reigning theories suggest that specialization and cooperativity conserve energy and resources while allowing new, synergistic functions to develop. One part of the collective can handle waste disposal, for instance, while another acquires food—and thus the multicellular cluster acquires an evolutionary edge. One

using a virus that could glue cells together, they fused the B cell with a cancer cell. I am still awestruck by the idea. How did they even think of using the undead to resuscitate the dying? The result was one of the strangest cells in biology. The plasma cell retained its antibody-secreting property, while the cancer cell conferred its immortality. They called their peculiar cell a hybridoma—a, well, hybrid of hybrid and oma, the suffix of carcinoma. The immortal plasma cell was now capable of perpetually secreting only one kind of antibody. We call this antibody of a single type (in other words, a clone), a monoclonal antibody. Milstein and Köhler’s paper was published in Nature in 1975.

Aspirin, for instance, jams itself into the lock cyclooxygenase, an enzyme involved in blood clotting and inflammation.

The lungs were bogged with fluid; debris from dead cells clogged the air sacs. “There appears to be a fork in the road to immunity to Covid-19 that determines disease outcome,” Iwasaki told me. “If you mount a robust innate immune response during the early phase of infection [presumably via an intact type 1 interferon response], you control the virus and have a mild disease. If you don’t, you have uncontrolled virus replication in the lung that […] fuels the fire of inflammation leading to severe disease.”

I knew that serotonin, the neurotransmitter, had something to do with it. Paul told me the story of the origin of the “brain chemical” theory of depression. In the autumn of 1951, doctors treating tubercular patients at Sea View Hospital on Staten Island with a new drug—iproniazid—had observed sudden transformations in their patients’ moods and behaviors. The wards, typically glum and silent, with moribund, lethargic patients, were “bright last week with the happy faces of men and women,” a journalist wrote. Energy flooded back and appetites returned. Many patients, ill and catatonic for months, demanded five eggs for breakfast. When Life magazine sent a photographer to the hospital to investigate, the patients were no longer lying numbly in their beds. They were playing cards, or walking briskly in the corridors. Researchers later discovered that iproniazid had, as a side effect, increased serotonin levels in the brain. And the idea that depression was caused by the paucity of the neurotransmitter serotonin, in the neural synapse, gripped psychiatry. There isn’t enough serotonin in the synapse, and so the electrical circuits that respond to the chemical don’t get enough stimulation. The inadequate stimulation of mood-regulating neurons results in depression.

Serotonin, Greengard and other researchers had found, doesn’t only act as a “fast” neurotransmitter, and depression isn’t just a malfunctioning neuronal circuit that can be reset by increasing serotonin in the synapse. Rather, serotonin sets off a “slow” signal in neurons—biochemical signals that come on cat’s feet—including altering the activity and function of several intracellular proteins that Greengard’s lab had identified. Paul believes that these proteins, which modify neuronal activity, are crucial to the slow signaling in neurons that regulate mood and emotional homeostasis. In his earlier work, he had shown that one such factor, called DARPP-32, is critically responsible to the way a neuron responds to another transmitter, called dopamine, which is involved in many other neurological functions, including our mind’s response to reward and addiction.

Using powerful imaging techniques, the circuit mapping of neuronal cells, and neuropsychiatric tests, Mayberg found one area of the brain, called Brodmann area 25 (BA25), the presumptive residence of cells that seem to regulate emotional tone, anxiety, motivation, drive, self-reflection, and even sleep—the symptoms that are markedly dysregulated in depression. BA25 was hyperactive in patients with recalcitrant depression, Mayberg found. Chronic electrical stimulation, she knew, can diminish the activity of a brain area. This may sound like a contradiction but it isn’t; chronic electrical stimulation of a neuronal circuit at high frequencies can depress its activity. Mayberg reasoned that electrical stimulation delivered to cells in BA25 might relieve the symptoms of chronic, severe depression.