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

by Siddhartha Mukherjee

I use the phrase “new human” throughout the book, and in its title. I mean it in a very precise sense. I explicitly do not mean the “new human” found in sci-fi visions of the future: an AI-augmented, robotically enhanced, infrared-equipped, blue-pill-swallowing creature who blissfully cohabitates the real and virtual worlds: Keanu Reeves in a black muumuu. Nor do I mean “transhuman,” endowed with augmented abilities and capacities that transcend the ones we currently possess. I mean a human rebuilt anew with modified cells who looks and feels (mostly) like you and me. A woman with crippling, recalcitrant depression whose nerve cells (neurons) are being stimulated with electrodes. A young boy undergoing an experimental bone marrow transplant using gene-edited cells to cure sickle cell disease. A type 1 diabetic infused with his own stem cells that have been engineered to produce the hormone insulin to maintain a normal blood level of glucose, the body’s fuel. An octogenarian who, following multiple heart attacks, is injected with a virus that will home to his liver and permanently lower artery-clogging cholesterol, thus reducing his risk of another cardiac event. I mean my father, implanted with neurons, or a neuron-stimulating device, that would have steadied his gait so that he might not have suffered the fall that led to his death.

I use the phrase “new human” throughout the book, and in its title. I mean it in a very precise sense. I explicitly do not mean the “new human” found in sci-fi visions of the future: an AI-augmented, robotically enhanced, infrared-equipped, blue-pill-swallowing creature who blissfully cohabitates the real and virtual worlds: Keanu Reeves in a black muumuu. Nor do I mean “transhuman,” endowed with augmented abilities and capacities that transcend the ones we currently possess. I mean a human rebuilt anew with modified cells who looks and feels (mostly) like you and me. A woman with crippling, recalcitrant depression whose nerve cells (neurons) are being stimulated with electrodes. A young boy undergoing an experimental bone marrow transplant using gene-edited cells to cure sickle cell disease. A type 1 diabetic infused with his own stem cells that have been engineered to produce the hormone insulin to maintain a normal blood level of glucose, the body’s fuel. An octogenarian who, following multiple heart attacks, is injected with a virus that will home to his liver and permanently lower artery-clogging cholesterol, thus reducing his risk of another cardiac event. I mean my father, implanted with neurons, or a neuron-stimulating device, that would have steadied his gait so that he might not have suffered the fall that led to his death.

we need to understand cells to understand the human body. We need them to understand medicine. But most essentially, we need the story of the cell to tell the story of life and of our selves.

we need to understand cells to understand the human body. We need them to understand medicine. But most essentially, we need the story of the cell to tell the story of life and of our selves.

molecules within a cell read certain sections of the genetic code, like musicians in an orchestra reading their parts of a musical score—the cell’s individual song—thereby enabling a gene’s instructions to become physically manifest in the actual protein. Or, put more simply, a gene carries the code; a cell deciphers that code. A cell thus transforms information into form; genetic code into proteins. A gene without a cell is lifeless—an instruction manual stored inside an inert molecule, a musical score without a musician, a lonely library with no one to read the books within it. A cell brings materiality and physicality to a set of genes. A cell enlivens genes.

molecules within a cell read certain sections of the genetic code, like musicians in an orchestra reading their parts of a musical score—the cell’s individual song—thereby enabling a gene’s instructions to become physically manifest in the actual protein. Or, put more simply, a gene carries the code; a cell deciphers that code. A cell thus transforms information into form; genetic code into proteins. A gene without a cell is lifeless—an instruction manual stored inside an inert molecule, a musical score without a musician, a lonely library with no one to read the books within it. A cell brings materiality and physicality to a set of genes. A cell enlivens genes.

the central pathology caused by SARS-CoV2 (severe acute respiratory syndrome coronavirus 2) was “immunological misfiring”—a dysregulation of immune cells. I had not even heard the term before, but its immensity hit me: at its core, the pandemic, too, was a disease of cells. Yes, there was the virus, but viruses are inert, lifeless, without cells. Our cells had awoken the plague and brought it to life. To understand crucial features of the pandemic, we would need to understand not just the idiosyncrasies of the virus but also the biology of immune cells and their discontents.

the central pathology caused by SARS-CoV2 (severe acute respiratory syndrome coronavirus 2) was “immunological misfiring”—a dysregulation of immune cells. I had not even heard the term before, but its immensity hit me: at its core, the pandemic, too, was a disease of cells. Yes, there was the virus, but viruses are inert, lifeless, without cells. Our cells had awoken the plague and brought it to life. To understand crucial features of the pandemic, we would need to understand not just the idiosyncrasies of the virus but also the biology of immune cells and their discontents.

This book is not about hunting for a cure or deciphering a code. There is no single adversary. Its protagonists want to understand life by understanding a cell’s anatomy, physiology, behavior, and its interactions with surrounding cells. A cell’s music. And their medical quest is to seek cellular therapies, to use the building blocks of humans to rebuild and repair humans.

This book is not about hunting for a cure or deciphering a code. There is no single adversary. Its protagonists want to understand life by understanding a cell’s anatomy, physiology, behavior, and its interactions with surrounding cells. A cell’s music. And their medical quest is to seek cellular therapies, to use the building blocks of humans to rebuild and repair humans.

It isn’t sufficient to locate a disease in an organ; it’s necessary to understand which cells of the organ are responsible. An immune dysfunction might arise from a B cell problem, a T cell malfunction, or a glitch in any of the dozens of cell types that comprise the immune system.

It isn’t sufficient to locate a disease in an organ; it’s necessary to understand which cells of the organ are responsible. An immune dysfunction might arise from a B cell problem, a T cell malfunction, or a glitch in any of the dozens of cell types that comprise the immune system.

But there is one question that we will not and, perhaps, cannot answer. The origin of the modern cell is an evolutionary mystery. It seems to have left only the scarcest of fingerprints of its ancestry or lineage, with no trace of a second or third cousin, no close-enough peers that are still living, no intermediary forms. Lane calls it an “unexplained void… the black hole at the heart of biology.”

Every such opening is an exception to the rule of integrity; after all, a doorway to the outside is also a doorway to the inside. Viruses or other microbes might use the routes of nutrient uptake or waste disposal to enter a cell. Porosity, in short, represents an essential feature of life—but also an essential vulnerability of living. A perfectly sealed cell is a perfectly dead cell. But unsealing the membrane through portals exposes the cell to potential harm. The cell must embrace both: closed to the outside, yet open to the outside.

complex organisms “did not evolve by ‘standard’ natural selection but by an orgy of cooperation, in which cells engaged with each other so closely that they even got inside each other.”

It was a ping-pong match in which both sides won. Microscopists would see subcellular structures; biochemists would assign functions to them. Or biochemists would find a function and then turn to microscopists to pinpoint the structure responsible for that function. Using this method, Palade, Porter, and Claude entered the luminous heart of the cell.

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.

The DNA double helix is elaborately folded and packaged around molecules called histones, and tightened and wound further into structures called chromosomes. 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.

If the insights revealed during this period seem “routine” today (some version of the phrase “The mitochondria are the cell’s energy factory” can inevitably be found in every high school science textbook), it’s because we’ve forgotten, as we often do, the spine-tingling awe that each of these discoveries generated in its time. I don’t think it’s hyperbolic to describe the transitions from the discovery of the cell to the revelation of its structural anatomy and, finally, to the elucidation of its functional anatomy as one of science’s most inspiring achievements.

specialization and cooperativity conserve energy and resources while allowing new, synergistic functions to develop.

It is impossible, in a few paragraphs, to capture the immense complexity of the cell-cell and the cell-gene interactions that allow the developing embryo to create each of its parts—organs, tissues, and organ systems—at the right time and in the right place in the body. Each of these interactions is a virtuoso act, an elaborate, multipart symphony perfected by millions of years of evolution.

Neutrophils live for just a few days after entering the circulation. But what dramatic days! Incited by an infection, the cells mature from the bone marrow and flood into blood vessels, hot for combat, their faces granulated, their nuclei dilated—a fleet of teenage soldiers deployed to battle. They have evolved special mechanisms to move quickly through tissues, squirming their way through blood vessels like contortionists. It is as if they are maniacally driven to reach sites of infection and inflammation—in part, because they so keenly perceive the gradient of cytokines and chemokines released by injury. They are lean, energetic, mobile machines built for immune attack. Professional killers—guardian cells—on a mission.

the story of vaccination is not the story of progressive scientific rationalism. Its hero is not Addison, who first found white blood cells. Nor is it Metchnikoff, whose discovery of phagocytes might have opened a door on protective immunity. Not even the scientists who discovered the innate response to bacterial cells merit being lauded as the heroes behind this medical milestone.III Rather, its history is one of veiled hearsay, gossip, and myth. Its heroes are nameless: the Chinese doctors who air-dried the first pox pustules; the mysterious sect of worshippers of Shitala who ground viral matter with boiled rice and inoculated it into children; the Sudanese healers who came to discern the ripest lesions.

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.

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.

Even a single breast tumor, then, is actually a collage of mutant cells—an assemblage of nonidentical diseases.

The relationship between cancer and stem cells, in short, is turning out to be far too uncomfortably close.

We can name cells, and even systems of cells, but we are yet to learn the songs of cell biology.

The human body functions as a citizenship of cooperating cells. The disintegration of this citizenship tips us from wellness into disease.