Divisional Danger

“Beyond Inheritance

 

By Roxanne Khamsi

 

Riverhead, 304 pages, $30

 

Rudolf Virchow, a 19th-century Prussian pathologist, considered organisms a kind of "cellular democracy," a harmonious republic of cooperating cells. Wilhelm Roux, who studied under Virchow and later absorbed Charles Darwin's influence, saw something darker: a "struggle of the parts," with individual cells vying fiercely for resources and dominance. As Roxanne Khamsi explains in "Beyond Inheritance," her accessible if disquieting study of our inconstant genomes, we are now, more than a century later, starting to appreciate the prescience -- and wrestle with the consequences -- of Roux's unsettling vision.

 

We begin our lives as single fertilized eggs, which repeatedly divide and sequentially specialize into the 30 trillion or so cells that make up the adult body.

 

Each division requires duplication of the original DNA, a process that is high-fidelity but not perfect. Occasionally, small genetic changes -- mutations -- are picked up along the way. Many of these alterations are benign; some are not. Modern analytic tools, in particular methods introduced in 2009 to sequence the genetic material of individual mammalian cells, have revealed how pervasive these changes are.

 

"They are constantly happening within your body," Ms. Khamsi writes, noting that we may "acquire trillions of new mutations a day," distributed across our tissues.

 

Over time, the glitches in individual cells add up; a single white blood cell from a 100-year-old, we learn, typically contains more than 3,000 mutations.

 

Sometimes these mutations lead to cancer. Peter Nowell, a pathologist, argued in 1976 that cancers arise from a single mutant cell and then evolve, as offspring acquire new mutations and compete for dominance -- a prediction that single-cell sequencing has dramatically confirmed.

 

An advanced tumor, Ms. Khamsi says, "might harbor thousands upon thousands of mutations," including some that may render the cancer less susceptible to whatever medication an oncologist plans to use.

 

Therapy may destroy most cells, but those with protective mutations can quickly take over.

 

Recognizing this, some oncologists have begun administering drugs with restraint rather than abandon, aiming to keep the cancer in check rather than creating conditions that predispose to the rapid growth of resistant cells.

 

Even short of cancer, mutations can cause trouble. Patients may appear healthy, but as they age, Ms. Khamsi explains, there are "populations of abnormal cells taking hold in their bodies." Consider clonal hematopoiesis of indeterminate potential, or CHIP, in which blood cells harbor mutations often seen in blood cancer, giving them a growth advantage over their well-behaved neighbors. The condition turns up in 10% to 20% of people in their 70s, and predisposes them to blood cancer and, surprisingly, heart disease, likely driven by the inflammation these rogue cells provoke. A similar dynamic may be emerging in the brain, where researchers have found that in Alzheimer's patients, a striking proportion of microglia -- immune cells that scan for pathogens and injury -- carry cancer-associated mutations, hinting that clonal expansion could contribute to cognitive decline as well.

 

But not all mutations are menacing.

 

Mutagenesis, Ms. Khamsi explains, is also the "engine of antibody diversity," an idea first proposed in 1957 by Macfarlane Burnet, an Australian immunologist, and elucidated by Susumu Tonegawa in the mid-1970s, work for which Mr. Tonegawa was awarded a Nobel Prize.

 

Patients who lack the ability to access this diversity-generating process -- including those suffering from a condition known as hyper IgM -- remain dangerously vulnerable to infection and often require antibody infusions for life. Even a functional mechanism can lead to problems if it generates antibodies that react against the body's own tissues. Autoimmunity, as one researcher puts it, is "the price we pay" for diversity.

 

Germ cells, the cells that form the sperm and the egg, are also subject to mutations, which can be particularly consequential since such changes can be passed along to the next generation. New mutations arise more frequently than researchers once believed; a 2025 study of four generations of a Utah family revealed around 150 new genetic changes per generation.

 

Ms. Khamsi notes that while most discussion of reproductive risk tends to focus on eggs, "children inherit four times as many new mutations from their dads than their moms," simply reflecting math: Cells forming eggs undergo about 22 rounds of division in the womb, then hold steady until ovulation, while cells that generate sperm divide continuously throughout life.

 

(Maternal age remains the dominant risk factor in reproduction, but for a distinct reason: not genetic typos but errors in chromosomal sorting, which become more common in older eggs.)

 

The accumulation of mutations with age turns out to be remarkably consistent across the animal kingdom. Scientists studying rapidly dividing cells in the folds of the intestine found that, across species, roughly 3,200 mutations accumulated in these regions over the course of a lifetime, whether that lifetime lasted two years (mice), 80 years (humans) or 200 years (the bowhead whale). Shorter-lived creatures simply mutate faster.

 

Whether aging reflects the sheer accumulated damage or the specific character of the mutations remains an active debate. But one conclusion is inescapable. "The genome you are conceived with," a researcher explains, "is very different from the genome you die with."

 

The author seems almost apologetic for the decidedly dismal message she carries. "It can feel overwhelming to contemplate all the messiness," Ms. Khamsi acknowledges. Perhaps to spare readers even more dismay, she reserves her critical scrutiny for cells, chronicling their nasty competitive struggles in vivid detail, while largely overlooking these same inconvenient realities in science. Here, she tends to describe a largely peaceable kingdom populated by earnest researchers thoughtfully pursuing nature's questions in a collaborative environment of inquiry and wonder. Like Virchow's vision of a cellular republic, it's a charming ideal.

 

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Dr. Shaywitz is the chief medical scientist at Lore Health, a lecturer at Harvard Medical School and an adjunct fellow at the American Enterprise Institute.” [1]

 

1. Divisional Danger. Shaywitz, David A.  Wall Street Journal, Eastern edition; New York, N.Y.. 21 Apr 2026: A13.