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

by Siddhartha Mukherjee

A life within a life. An independent living being—a unit—that forms a part of the whole. A living building block contained within the larger living being.

Animals and plants—as seemingly different as living organisms could be. Yet, as both Schwann and Schleiden had noticed, the similarity of their tissues under the microscope was uncanny. Schwann’s hunch had been right. That evening in Berlin, he would later recall, the two friends had converged on a universal and essential scientific truth: both animals and plants had a “common means of formation through cells.”

The transformation of medicine made possible by our new understanding of cell biology can be broadly divided into four categories. The first is the use of drugs, chemical substances, or physical stimulation to alter the properties of cells—their interactions with one another, their intercommunication, and their behavior. Antibiotics against germs, chemotherapy and immunotherapy for cancer, and the stimulation of neurons with electrodes to modulate nerve cell circuits in the brain fall in this first category. The second is the transfer of cells from body to body (including back into our own bodies), exemplified by blood transfusions, bone marrow transplantation, and in vitro fertilization (IVF). The third is the use of cells to synthesize a substance—insulin or antibodies—that produces a therapeutic effect on an illness. And most recently, there is a fourth category: the genetic modification of cells, followed by transplantation, to create cells, organs, and bodies endowed with new properties.

Life’s definition, as it stands now, is akin to a menu. It is not one thing but a series of things, a set of behaviors, a series of processes, not a single property. To be living, an organism must have the capacity to reproduce, to grow, to metabolize, to adapt to stimuli, and to maintain its internal milieu.

What is a cell, anyway? In a narrow sense, a cell is an autonomous living unit that acts as a decoding machine for a gene. Genes provide instructions—code, if you will—to build proteins, the molecules that perform virtually all the work in a cell. Proteins enable biological reactions, coordinate signals within the cell, form its structural elements, and turn genes on and off to regulate a cell’s identity, metabolism, growth, and death. They are the central functionaries in biology, the molecular machines that enable life.I

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.

And finally, a cell is a dividing machine. Molecules within the cell—proteins, again—initiate the process of duplicating the genome. The internal organization of the cell changes. Chromosomes, where the genetic material of a cell is physically located, divide. Cell division is what drives growth, repair, regeneration, and, ultimately, reproduction, among the fundamental, defining features of life.

Tucked away as an epigraph in an 1825 manuscript, Raspail formulated the Latin aphorism Omnis cellula e cellula: “From cells come cells.”

“The body is a cell state in which every cell is a citizen,” Virchow would write. “Disease is merely the conflict of the citizens of the state brought about by the action of external forces.”

All cells come from other cells (Omnis cellula e cellula). Normal physiology is the function of cellular physiology. Disease, the disruption of physiology, is the result of the disrupted physiology of the cell.

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.”

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

About three weeks after gestation, the heart will generate its first beat. A week later, one part of the neural tube will begin to protrude out into the beginnings of the human brain. All of this, remember, emerged from a single cell: the fertilized egg.

How does the self know itself? Because every cell in your body expresses a set of histocompatibility (H2) proteins that are different from the proteins expressed by a stranger’s cells. When a stranger’s skin, or bone marrow, is implanted into your body, your T cells recognize these MHC proteins as foreign—nonself—and reject the invading cells.

In short, H2 (or HLA) molecules serve two linked purposes. They present peptides to a T cell so that a T cell can detect infections and other invaders and mount an immune response. And they are also the determinants by which one person’s cells are distinguished from another person’s cells, thereby defining the boundaries of an organism. Graft rejection (likely important for primitive organisms) and invader recognition (important for complex, multicellular organisms) are thus combined into a single system. Both functions repose in the T cell’s capacity to recognize the MHC peptide complex, or the altered self.

Harold Varmus, the Nobel-winning cancer biologist, called cancer a “distorted version of our normal selves.” And so they are: the proteins that cancer cells make are, with a few exceptions, the same ones made by normal cells, except cancer cells distort the function of these proteins and hijack the cells toward malignant growth. Cancer, in short, may be a rogue self—but it is, indubitably, a self.

the most severe cases of SARS-COV2 infection, he found, occurred in patients—typically men—who lacked the ability to elicit a functional type 1 interferon signal after infection.

(The neurobiologist Carla Shatz, who discovered these waves of spontaneous activity, wrote, “Cells that fire together, wire together.”)

There must be a means for one part of the body to “meet” a distant part of a body. We call these signals “hormones,” from the Greek hormon—to impel, or to set some action into motion. In a sense, they impel the body to act as a whole.

It is the acrobatic balance between self-preservation and selflessness—self-renewal and differentiation—that makes the stem cell indispensable for an organism, and thereby enables the homeostasis of tissues such as blood.

But cancer is, in a sense, a disorder of internal homeostasis: its hallmark is that cell division is dysregulated.

Stem cells can change the programs of identity; as I said before, they balance selfishness (self-renewal) with self-sacrifice (differentiation). The cancer cell, in contrast, is trapped—imprisoned in a program of perpetual rebirth. It is the ultimate selfish cell.