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

by Siddhartha Mukherjee

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 find these “new humans”—and the cellular technologies used to create them—vastly more exciting than their imaginary sci-fi counterparts. We’ve altered these humans to alleviate suffering, using a science that had to be handcrafted and carved with unfathomable labor and love, and technologies so ingenious that they stretch credulity:

one might define life as having cells, and cells as having life.

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 Song of the Cell takes us on a very different journey: to understand life in terms of its simplest unit—the cell. 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.

True knowledge is to be aware of one’s ignorance. —Rudolf Virchow, letter to his father, ca. 1830s

Hooke’s interest in microscopy eventually dwindled. His peripatetic intellect needed to roam widely, and he returned to optics, mechanics, and physics. Indeed, Hooke’s interest in virtually everything may have been his critical failing.

“Cells have various means of choice, resulting in different proportions of water, carbon, and bases which enter into the composition of their cell walls. It’s easy to imagine that certain walls permit the passage of certain molecules,” Raspail continued, anticipating both the idea of a selective, porous cell membrane, the autonomy of a cell, and the notion of the cell as a metabolic unit.

Vitalists had no problem with cells per se. As they saw it, a divine Creator fashioning the entire repertoire of biological organisms over the course of six days may well have chosen to construct them out of unitary blocks (how much easier it is to build an elephant and a millipede out of the same blocks, especially if you have a rush order with just six days to deliver the goods).

“Every pathological disturbance, every therapeutic effect, finds its ultimate explanation only when it’s possible to designate the specific living cellular elements involved.”

Every cell on Earth—which is to say every unit of every living being—belongs to one of three entirely distinctive domains, or branches, of living organisms.

The first branch comprises bacteria: single-celled organisms that are surrounded by a cell membrane, lack particular cellular structures found in animal and plant cells, and possess other structures that are unique to them. (It is precisely these differences that are the basis for the specificity of the antibacterial drugs mentioned above.)

Bacteria are disturbingly, ferociously, uncannily successful. They domina...

An infectious disease specialist once told me that humans were just “nice-looking luggage to carry bacteria around the world.” He might have been right.

The abundance and resilience of bacteria stagger the mind. Some live in oceanic thermal vents where the water reaches near boiling temperature; they could easily thrive inside a steaming kettle. Some prosper within stomach acid. Yet others live, with seemingly equal ease, in the coldest places on earth,

We—you and me—inhabit a second branch, or domain, called eukaryotes.

contain a special structure called a nucleus (karyon, or “kernel,” in Greek). This nucleus, as we will soon learn, is a storage site for chromosomes. Bacteria lack nuclei and are called prokaryotes—that is, “before nuclei.”

Compared with bacteria, we are fragile, feeble, finicky beings capable of inhabiting vastly more limited environments and restricted ecological niches.

the third branch:...

Taxonomy wasn’t just missing the point, he insisted, it was missing a whole living domain. Archaea, Woese argued, were not “almost like” bacteria or “almost like” eukaryotes.

archaea are now classified as a distinct, third domain of living creatures. Superficially, archaea look like bacteria, for the most part. They are tiny and lack some of the structures associated with animal and plant cells. But they are indisputably different from bacteria, or from plant, animal, and fungal cells.

These, then, are among the first and most fundamental properties of the cell: autonomy, reproduction, and development.

To begin with, a bounded, autonomous living unit—a “closed unit” that bears the laws that govern its existence—must have a boundary. It is the membrane that defines the boundary; the outer limits of the self. Bodies are bound by a multicellular membrane: the skin. So is the psyche, by another membrane: the self. And so are houses and nations. To define an internal milieu is to define its edge—a place where the inside ends, and the outside begins. Without an edge, there is no self. To be a cell, to exist as cell, it must distinguish itself from its nonself.

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.

It’s simpler, perhaps, to imagine entering and exploring the interior of a cell as an astronaut might imagine exploring an unfamiliar spacecraft. From far away, you might see the spacecraft’s/cell’s outer contours: the oblong, gray-white sphere of an oocyte, or the crimson disk of a red blood cell. As you approach the cell membrane, you might begin to see its outer layer more clearly. Bobbing on that fluid surface are proteins. Some might be receptors for signals, while others might function like molecular glue for attaching one cell to another. Some of these might be channels. If you are fortunate, you might watch a nutrient or an ion slip through the pore and into the cell. And now, you, too, might “board” the craft. You would dive through the hull—that is, into the bilayer membrane, moving rapidly through the space between the two layers, only about ten nanometers thick, or ten thousand times thinner than a strand of human hair—and emerge inside. Look around and above: now the inner lamella of the cell membrane would hang above you like the fluid surface of the ocean as seen from below. You would also see the inner parts of the proteins dangling above you, like the underbellies of buoys.

protoplasm is a mind-bogglingly complex soup of chemicals. It is thick and colloidal in some places; watery in others.III It is the mother jelly that sustains life.

They form an internal system of organization. The cytoskeleton tethers components of the cell together, and is required for the movement of the cell.

Margulis argued that 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.”

Too radical, too early. On the streets of San Francisco and New York, it may have been the Summer of Love, with young men and women engulfing each other with ardor, but in scientific halls, Margulis’s engulfment theory was met with a barrage of skepticism. For her, the summer of endosymbiotic love turned into a long winter of ridicule and rejection—until decades later, when scientists began to note not just the structural similarities between mitochondria and bacteria but also their molecular and genetic commonalities.

Author’s rendition of a cell, showing its various substructures,

The trio of scientists won the 2013 Nobel Prize for this work on the intracellular trafficking of proteins). At almost each point in their journey, some of the proteins are modified: they can be clipped short, chemically modified by the addition of a sugar, or twirled around and bound to another protein (the signals to make these modifications are typically contained in the sequence of the protein itself). 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. (a) Endoplasmic reticulum (ER) in human fetal adrenal

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.

Membrane. Protoplasm. Lysosome. Peroxisome. Nucleus. The subunits of the cell that we’ve met are vital to its existence; they perform specialized functions that allow a cell to possess and maintain an independent life. Their location, organization, and orchestration are crucial. In short: a cell’s autonomy lies in its anatomy.

A cell, as noted before, is not just a system of parts sitting next to parts, just as a car is not a carburetor sitting next to an engine. It is an integrating machine that must amalgamate the functions of these individual parts to enable the fundamental features of life.

But the retina is a special site. Not only is a raindrop’s worth of virus sufficient to infect the cells, but also the retina is uniquely immune privileged: along with a few other places in the body—the testes, among them—it is not actively surveyed by an immune response and therefore highly unlikely to generate a severe reaction to an infectious agent.

Conceptually speaking, cell division in animals might be broadly divided into two purposes or functions: production and reproduction.

The life cycle of a snowflake yeast. The snowflake forms evolved from single-celled yeast cells by selecting for larger clusters. Over time, they maintain these large cluster forms and do not revert to single cells—i.e., they have been evolutionarily selected for multicellularity. New cells are added to the growing branches, increasing the size of the cluster. Initially, the snowflakes were split by the physical strain of their size, like a branch of a tree that has grown too long to remain attached. Over generations, though, specialized cells have now evolved that commit deliberate, programmed suicide to create a cleavage site that fractures to facilitate the division of one cluster into another.

“Oh, we’ve already seen the emergence of new properties,” he replied with a faraway look, as if imagining the future of this new Being. “The clusters are now twenty thousand times larger than the single cells. And the cells have evolved a kind of entanglement with each other. Now it’s hard to break them apart, until the furrow of dead cells forms. And some of them have started dissolving the walls between them. We’re trying to see if they’re beginning to form some sort of channel of communication to deliver nutrients, or signals, across these large clusters.

Once a single sperm has penetrated an egg, a wave of ions diffuses out from within the egg, initiating a host of reactions that prevent other sperm from entering. We are, after all, monogamous in the cellular sense.

Lewis Thomas wrote in his collection of essays The Medusa and the Snail: More Notes of a Biology Watcher, “at a certain stage there emerges a single cell which will have as all its progeny the human brain. The mere existence of that cell should be one of the great astonishments of the earth.”

How do these cells and organs know what to become? 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.

FDA lawyers listed twenty-four independent counts of legal violation. And yet, in 1962, Herbert J. Miller, the assistant attorney general at the US Department of Justice, chose not to prosecute the company, arguing, with tragicomical absurdity, that it had distributed the drug to “physicians of the highest professional standing” and that only “one malformed baby” had been definitively proven to be harmed. Both claims were untrue. It concluded that “criminal prosecution is neither warranted nor desirable.” The case was closed.

When a plaque ruptures or breaks, it is sensed as a wound. And the ancient cascade to heal wounds is activated and released. Platelets rush in to plug that “wound”—except the plug, rather than sealing an injury, blocks the vital flow of blood into the heart muscle. The healing platelet now turns into a deadly platelet.

Scientists at Verve have devised ways to insert catheters into the arteries leading to the liver. (The dexterity that Sek learned from decades of practice in cardiology helped.) These catheters will deliver gene-editing enzymes, loaded inside tiny nanoparticles, to the organ. Once these particles off-load their cargos inside the liver cells, the gene-editing enzymes will change the scripts of genes that aid and abet cholesterol metabolism, thereby drastically decreasing the amount of circulating cholesterol in the blood—in essence, activating the LDL metabolizing pathways. It’s a one-and-done infusion. Once the genes have been altered, they are altered for life. If successful, Verve’s gene therapy would transform you into a human with permanently lowered cholesterol level, permanently protected from coronary artery disease, permanently safe from myocardial infarction.

the word vaccine carries the memory of Jenner’s experiment: it is derived from vacca, Latin for “cow.”

(India still reports eighty thousand snakebites a year, the largest number in the world.)

Susumu Tonegawa showed that B cells also acquire their unique antibodies through mutations, albeit a precisely regulated form of mutation that occurs in these cells, not in sperm and eggs. B cells rearrange a set of antibody-making genes, mixing and matching genetic modules, like articles of clothing. The analogy oversimplifies the process, but it is important.

The distinctive genetic arrangement in every mature B cell allows it to display a particular receptor on its surface. When an antigen binds to it, the B cell gets activated. It switches from displaying the receptor on its surface to secreting it, in the form of an antibody, into the blood.

Ultimately, the B cell matures into a cell so single-mindedly dedicated to antibody production that its structure and metabolism are altered to facilitate the process. It is now a cell dedicated to making antibodies—a plasma cell. Some of these plasma cells also become long lived and retain the memory of the infection.

the ultimate activity of a vaccine depends on the adaptive system: it’s the B cell that makes antibodies, and these antibodies are typically responsible for long-term immunity.