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

by Siddhartha Mukherjee

But perhaps

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.

The acuity of their insight was in the proposition that a deep unity of organization and function ran through living beings.

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

Cell division is what drives growth, repair, regeneration, and, ultimately, reproduction, among the fundamental, defining features of life.

“Omne vivum ex vivo,”

Life came from life, he proposed—just a step away from the idea that cells came from cells.

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

“All happy families are alike; each unhappy family is unhappy in its own way.”

Since Yamanaka’s discovery, for which he won the Nobel Prize in 2012, hundreds of labs have started working on iPS cells. The allure is this: you take your own cell—a skin fibroblast, or a cell from your blood—and you make it crawl backward in time and transform it into an iPS cell. And from that iPS cell, you can now make any cell you’d like—cartilage, neurons, T cells, pancreatic beta cells—and they’d still be your own. There would be no problem with histocompatibility.

When mice got arthritis, we reasoned, the OCHRE cells would try to regenerate the lost cartilage—much like stem or progenitor cells act in other tissues when the tissue is depleted or injured. Osteoarthritis was the forme fruste—the frustrated form—of a tissue trying to repair itself, but failing.

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. And so we have a theory to answer the fourth age-old mystery: Why doesn’t cartilage in joints get repaired, just as a bone fracture does, in adults? Because the repairing cells die during the injury. Injury and repair share a border—except, as we age, injury, and the weariness of regenerative capacity, keeps infiltrating, creeping over the hedge. Osteoarthritis is a degenerative disease that arises from a regenerative disease. It is a flaw in rejuvenative homeostasis.

Cartilage in the joints—as Dan, Jia, and Toghrul discovered—sits somewhere in between. Fully mature cartilage cells in the joint are largely post-mitotic in adult mice. But in young mice, there is a reservoir of cells that can generate cartilage; it diminishes radically with age and injury, until it vanishes altogether.VI

a furious battle between a rate of decay and a rate of repair, with each rate unique for every individual cell, and individual organ.

But cancer is, in a sense, a disorder of internal homeostasis: its hallmark is that cell division is dysregulated. The genes that control these accelerators and brakes are broken—i.e., mutated—such that proteins that they encode, the regulators of cell division, no longer function in their appropriate contexts.