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

by Siddhartha Mukherjee

“Each cell leads a double life,” Schleiden would write a year later, “an entirely independent one, belonging to its own development alone; and an incidental one, in so far as it has become part of a plant.”

And it brings us to the precipice of an uncertain future, in which “maverick” scientists (one of whom was jailed for three years and has been permanently disbarred from performing experiments) are designing gene-edited embryos, and using cell transplantation to blur the boundaries between the natural and the augmented.

Emily’s trial involved infusing her body with her own T cells. But these T cells had to be weaponized, via gene therapy, to recognize and kill her cancer.

The transformation of medicine made possible by our new understanding of cell biology can be broadly divided into four categories.

Some of these therapies, such as antibiotics and blood transfusion, have been so deeply entrenched in the practice of medicine that we hardly think of them as “cellular therapies.”

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.

the city of Oxford was always dimly lit (if cloudless Italy was a land made for telescopes, then foggy, dark England seemed custom-made for microscopes)—and

Akiko Iwasaki told me that 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.

In 1543, he published his anatomical works in seven volumes entitled De Humani Corporis Fabrica (The Fabric of the Human Body). The word Fabric in the title was a clue to its texture and purpose: this was the human body treated like physical material, not mystery; made of fabric, not spirit.

These two paragraphs—the first proposing the cell as a unit of life and physiology, and the second proposing the cell as the unit locus of disease—are pinned on a board in my office. In thinking about cell biology, cellular therapies, and the building of new humans out of cells, I inevitably return to them. They are, as it were, the twin melodies that ring throughout this book.

The link between microbial cells and human disease emerged from the answer to a question that had preoccupied scientists and philosophers for centuries: What is the cause of rot? Rot wasn’t just a scientific problem but also a theological one. In some Christian doctrines, the bodies of saints and kings were supposedly spared putrefaction, especially as they awaited the intermediate state between death, resurrection, and ascension to heaven. Yet when the decomposition rates of saints and sinners seemed no different, there was a theological reckoning to be had: whatever caused putrefaction apparently wasn’t behaving according to the laws of God.

The first, epidemiology, tried to explain the patterns of human disease in aggregate. As a discipline, epidemiology “hovered” above people—hence epi (above) the demos (people).

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.

Their location, organization, and orchestration are crucial. In short: a cell’s autonomy lies in its anatomy.

Not every cell is capable of reproducing: some cells, such as some neurons, have undergone permanent or terminal division and will never divide again.

The German scientist who discovered mitosis was a disillusioned, short-sighted military doctor seeking a new vision for biology. Walther Flemming,

It was an exhilarating result: no scientist before him had even faintly imagined that the cells of such diverse organisms would follow a nearly identical and rhythmic scheme during the division of their cells.

cells that opt out of the cycle altogether. They are permanently or semipermanently resting—quiescent, to use biology jargon.

division. It was an old biological trick: disrupting a physiological function in order to illuminate normal physiology.

We don’t reproduce like rabbits. Our eggs need a little more seduction.

At one medical conference, a distinguished gynecologist stood up and announced imperiously, “Laparoscopy is of no use whatsoever. It’s impossible to visualize the ovary.” Steptoe, soft spoken and reticent, had to rise up to defend his practice. “[You] are hopelessly wrong,” he replied. “The whole abdominal cavity can be inspected.”

The paper by Edwards, Steptoe, and Bavister, “Early Stages of Fertilization in Vitro of Human Oocytes Matured in Vitro,” was published in the journal Nature in 1969. Unfortunately, Jean Purdy, who had performed the experiment, was not credited, consistent with the conventional practice of cutting women out of science. Later, both Edwards and Steptoe made several attempts to acknowledge her contributions, for IVF was born in Purdy’s hands. In the lab, she created the first human embryo produced through IVF; in the hospital, she would later cradle the first IVF baby. In 1985, she died of melanoma at just thirty-nine years of age, never able to fully garner the scientific recognition due to her.

immediately. Attacks came from all sides at once. Some gynecologists did not consider infertility a disease. Reproduction, they argued, was not a requirement for wellness, so why define its absence as an “illness”?

If G2 were to arrest every mutation, catch every mistake, and rectify every error, mutants would never be generated, and evolution would come to a grinding halt. G2, then, must be a discerning guardian, knowing when to look and when to look away.

Cochlear implants can restore some hearing of speech, but, oddly, not music; what’s more, patients with implants typically require months of rehabilitation.

He Jiankui made terrible choices at every level: wrong gene, wrong patients, wrong protocol, wrong purpose.

“All happy families are alike; each unhappy family is unhappy in its own way.” For multicellular evolution, he told me, the logic is turned around: every single-celled organism that evolved toward multicellularity took a unique path. It became “happy”—or, rather, more evolutionarily fit—in its distinctive way. Single-celled organisms remained, well, similarly single-celled. It is, in Ratcliff’s words, “a reverse Anna Karenina situation.”

Some do take longer, however: in one experiment, unicellular algae became a multicellular agglomerate over 750 generations. That is no more than a blink, a ticktock, in evolutionary time, but 750 lifetimes for an algal cell.

Marketing was aggressive. The drug was targeted especially to pregnant women, who, given the casual misogyny of the time, were often considered “anxious” and “emotional” and therefore needed to be sedated. Thalidomide was soon approved in forty countries and was being prescribed to tens of thousands of women.

Frances Kelsey likely saved tens of thousands of lives by standing, like the final regulatory bulwark, against the relentless onslaught of a pharmaceutical giant. In 1962, she was awarded the Presidential Medal of Honor. This chapter serves to memorialize her service and tenacity.

It is, by far, the favorite time of my day at work. Number, color, morphology, shape, size. I move methodically.

Blood speaks to me—but only if I pay attention.

Immature blood cells, or blasts. The first signs of malignant white cells.

Blood transfusion, the first modern form of cellular therapy, would lay the basis for surgery, for treating anemia, for cancer chemotherapy, for trauma medicine, for bone marrow transplantation, for the safety of childbirth, and the future of immunology.

why does one need a cell to transport oxygen? Why not float hemoglobin as a free protein in the plasma and let it move in the body? It’s a conundrum that still remains unsolved and has to do with the structure of hemoglobin—a

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.

We—multicellular animals—have been at war with microbes for such a long time in evolutionary history that, like ancient, conjoined enemies, we’ve been defined by each other.

Although Jenner had breached virtually every boundary of ethical human experimentation (for instance, there is no record of informed consent, and the subsequent “challenge” with live virus might well have been lethal to the child),

Vaccination, more than any other form of medical intervention—more than antibiotics, or heart surgery, or any new drug—changed the face of human health.

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.

For centuries, the thymus has been an organ in search of a function. —Jacques Miller, 2014

And because antibodies cannot enter cells, how are they to identify one of these rogue cells masquerading as a normal cell? What, then, prevents any virus from using every cell in our body as a perfect microbial sanctuary?

the T cell cannot recognize the infected cell. It needs both the pathogen and the self—the picture and the frame.V

The matching of form and function is one of biology’s most beautiful ideas, first articulated centuries ago by thinkers such as Aristotle.

The inside is now outside. The cell has sent a sampling of its inner life, bound in the correct frame, to be surveyed by the immune system. When a CD8 cell comes by, sniffing the cell surface, it will find a large selection of peptides from the interior of a cell loaded on its surface—including, of course, the peptide from the virus. And only if that foreign peptide is presented by the self MHC (the altered self) will it trigger an immune response, killing the infected cell.

We typically think of AIDS as a viral disease. But it is also equally a cellular disease.

The pharmacopeia against the virus has increased year by year. There are drugs that prevent the virus from replicating efficiently, drugs that prevent the virus from duplicating its RNA or integrating into the host genome, drugs that prevent the virus from maturing into infective particles, drugs that prevent the virus from fusing to the vulnerable cells—five or six separate classes of drugs in all. Therapy with these medicines is so effective that patients with HIV can live for decades without any sign of the virus—undetectable, in the parlance of medicine. They are not cured, but so deeply controlled, with such vanishingly low viral loads, that they cannot infect others.

This cancer and HIV infection are weakly related. HIV-infected men and women have a high risk for certain lymphomas and a two-fold risk of acquiring AML,

Let’s make one fact clear: the world’s pandemic of HIV is not going to be solved by bone marrow transplantation with CCR5 delta 32 donor cells. The procedure is far too expensive, too toxic, and too labor intensive to be considered a practical option for a large swathe of the human population.

(Note that I specified blood, not just CD4 T cells. Macrophages, also derived from blood, for instance, are known to act as reservoirs for HIV.)