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

“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 the surrounding cells. A cell’s music. And their medical quest is to seek cellular therapies, to use the building blocks of humans to rebuild and repair humans.”

Here, Mukherjee succinctly summarizes the crux of his book. He documents the history of discovery of fundamental properties of life related to cells (e.g., reproduction). Once he tells these stories, he discusses how the discoveries transformed cellular technology. Each new discovery gets humans closer to understanding cells and thus what it means to be human. In addition, these discoveries are altering the view of humanness and how humans live.

“The basement of Paris’s hospital Hôtel-Dieu, where decaying human cadavers were dissected, was a dingy, airless, badly lit space with half-feral dogs roaming underneath the gurneys to gnaw on the drippings—a ‘meat market,’ as Vesalius would describe one such anatomical chamber. The professors sat on ‘lofty chairs [and] cackle like jackdaws,’ he wrote, while their assistants hacked and tugged through the body at random, eviscerating organs and parts as if pulling out cotton stuffing from a toy.”

One key focus of Mukherjee’s is to trace the history of medicine and the individuals that helped propel its advancement. Vesalius, a Flemish scientist and anatomist, was one such individual. He was extremely dissatisfied with the field of anatomy in the 16th century. He believed that anatomists didn’t know what they were doing and simply “hacked and tugged through the body at random” based on inaccurate and outdated anatomical teachings from the Roman era. Vesalius’s drawings of the human body helped revolutionize the study of anatomy.

“But tucked away among these images of parasites and pests was a relatively prosaic-seeming image that would quietly shake the roots of biology. It was a cross section of a plant stem—a thin slice of cork—that Hooke had placed under his scope.”

Robert Hooke’s study of thin slices of cork represents his most famous observation under a microscope. Through this study, he discovered plant cells, although he really just saw the cell walls. Based on this discovery, Hooke coined the term “cell,” from the Latin word cella, which means “small room.” However, Hooke didn’t understand the function of cells and didn’t recognize them as the building blocks of all living organisms.

“To locate the heart of normal physiology, or of illness, one must look, first, at cells.”

Cells are the building blocks of both health and illness. In Chapter 3, Mukherjee underscores the importance of not only determining where disease is located in the body but understanding which cells are responsible. M. K.’s case supports this assertion. Initially, M. K.’s illness puzzled Mukherjee because it didn’t act like it should. When Mukherjee examined the cells within M. K.’s blood, he realized that they’d misdiagnosed M. K. Once the team realized this, they could correct their course of treatment and cure M. K. Treatment of disease is possible only by pinpointing the exact cause. The cause can be determined only at the cellular level.

“It occurs to me, as I write this, how much this framework—germs, cells, risk—still scaffolds the diagnostic art in medicine. Each time I see a patient, I realize, I am probing the cause of his or her disease through three elemental questions. Is it an exogenous agent, such as a bacterium or virus? Is there an endogenous disturbance of cellular physiology? Is it the consequence of a particular risk, be it exposure to some pathogen, a family history, or an environmental toxin?”

John Snow, through his studies of cholera outbreaks in London, first proposed this framework. It united three different fields of medicine: epidemiology, germ theory, and cell theory. “Risk” refers to epidemiology: Snow realized the importance of understanding what risks people might be exposed to in their environments because these risks could impact their susceptibility to diseases. “Germs” refers to germ theory—to microbial invaders, or germs, causing infection. Cells refer to cell theory: The microbe is a cell capable of reproducing in the human body and causing it to malfunction.

“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.”

Mukherjee often uses analogies to help explain highly complex subjects. In this example, he uses the postal system to help illustrate cellular anatomy. Understanding the cellular system took decades of research on cellular anatomy, the dissection of various subcomponents of cells by researchers using novel techniques, and an understanding of what happens to these cellular subcomponents when they malfunction (i.e., their diseased state). This system is the most basic building block of human life. Without it, humans simply wouldn’t function.

“Unfortunately, Jean Purdy, who had performed the experiment, was not credited, consistent with the conventional practices of cutting women out of science.”

Mukherjee presents a balanced view of scientific discoveries, which includes noting when key contributors are left out of the accolades. Jean Purdy is one such example. A British nurse and embryologist, she worked with Robert Edwards and Patrick Steptoe to develop in vitro fertilization (IVF). She was the first to see the cells divide. However, only Edwards and Steptoe initially received credit for the success of IVF; they later tried to correct this and ensure that Purdy received credit. As Mukherjee notes, women scientists are routinely brushed over or forgotten. By acknowledging Purdy’s critical work on IVF, Mukherjee is trying to correct this trend.

“In his rush to be the first to make gene-edited humans, JK had, in essence, inverted virtually every principle that governs the ethical use of humans as subjects in clinical studies.”

Through the story of JK, a Chinese professor and biophysicist, Mukherjee illustrates the importance of maintaining strict codes of ethics in science. Like scientists before him, JK wanted to be the first. This desire warped his ethics, causing him to cut corners where he shouldn’t have. Scientists must obtain consent from their patients to perform any type of procedure or experiment, but JK likely didn’t get full consent (especially regarding the ethical tenet to inform them of the risks associated with implanting embryos that had undergone the gene editing process). In addition, JK didn’t seem to follow standard protocols for gene editing. Mukherjee emphasizes the importance of resisting the notion of being first because unethical conduct could set the field back and hurt the public’s view of science (as did JK and his gene editing experiment).

“A multitude of cells are affected, resulting in the dozens of diffuse congenital malformations that were caused by thalidomide. The effect is extraordinarily potent: a single 20-milligram tablet was found to be sufficient to cause birth defects. Tens of thousands of women across the world do not know if their child was miscarried, stillborn, or maimed by an irreversible congenital defect because of thalidomide.”

This passage depicts a particularly egregious crime. A German pharmaceutical company claimed to have developed a sedative and antianxiety medication for pregnant women. Instead, the drug caused birth defects and even death in fetuses because it stopped the breakdown of proteins. One of the only scientists who fought back against the drug’s approval by the FDA was its new commissioner Frances Kelsey. She was unconvinced by the data that the drug was safe for women. While the drug negatively impacted thousands of women and unborn children around the world, Kelsey helped save many more from giving birth to stillborn babies or babies with birth defects. However, despite the drug’s toll on women and families, the company was never charged. This example shows how important it is that pharmaceutical companies test products before releasing them to the public. Failure to do so can have far-reaching and horrendous consequences, as did thalidomide.

“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.”

While Mukherjee touches on many breakthroughs in biology throughout his book, arguably one of the most important is the discovery of blood types and its impact on the safe and successful transfusion of blood between two humans. The first safe and successful transfusion occurred only about 100 years ago, in 1907. Blood transfusions had a rocky start; all human patients died before the early 1900s because of blood type incompatibility. The identification of blood compatibility revolutionized transfusions. Imagine the world wars without blood transfusions. Both wars witnessed unimaginable death tolls. Without blood transfusions, however, these death tolls would have been even higher. Blood transfusions are crucial in many treatments today.

“It would be the ultimate feat of cellular reengineering for heart disease. The river of life (to use my preceptor’s favored phrase) would be cleansed forever.”

Mukherjee describes an experimental study that could prevent heart attacks from ever again occurring. This study is attempting to target the genes that create cholesterol-related proteins in the liver. The researchers hope to use gene editing to inactivate these genes, which, in turn, would free the human bloodstream (or “river of life”) from accumulating cholesterol. Heart disease is the leading cause of death in the US for both men and women. Most people know someone with heart disease or who has died of a heart attack. Because of the prevalence of heart disease, this example drives home the power of targeting specific cells to treat diseases. If the experimental study is successful, it will save the lives of millions of people in the US and around the world.

“I switched off the microscope and thought about the strange temple of Shitala—and of how long and how hard it has been to cool or heat innate immunity to make it an agent of our medical needs. Shitala, the cool goddess, is also known to have a tetchy side: anger her, and she might wreak havoc on the body with inflammation from poxes, fevers, plagues. Sometime in the near future, we will learn to pitch the innate immune system’s wrath against cancer cells; to calm it in the case of autoimmune diseases; to augment it to create a new generation of vaccines against pathogens.”

Throughout Chapter 11, Mukherjee highlights the importance of the innate immune system and how it has been exceedingly difficult for scientists to manipulate. Mukherjee is part of a team of researchers trying to do exactly this. They’re attempting to use a specific type of white blood cell (macrophages) to kill and eat a protein on a cancer cell. If this cell therapy is successful, it will eradicate cancer and result in “new humans” by allowing scientists to teach the innate immune system to attack specific cancer cells. As Mukherjee notes, the body’s soldiers (white blood cells) will then become assassins.

“‘Using cells to fight cells,’ he [Ron Levy] marveled. ‘We never thought about all that we could do when we raised that first antibody.’”

Immunologist Ron Levy was among the first scientists to use antibodies to fight cancer cells. He was especially interested in finding antibodies that targeted cancers of B cells (especially those that involve CD20-expressing cells). He helped create Rituxan, which did exactly this. Rituxan, when used in conjunction with chemotherapy, can treat and even cure aggressive B cell cancers. This type of cell therapy has revolutionized the ability to fight cancer. Most incredible is that this therapy uses one’s own cells (or antibodies) to fight other cells (i.e., cancer cells). As Levy underscores in this passage, such a feat wasn’t even thought possible when antibodies were discovered.

“Antigen processing and presentation to CD4 and CD8 cells—the mainstays of T cell recognition—are slow but painstakingly methodical processes. Unlike an antibody, a gunslinging sheriff itching for a showdown with a gang of molecular criminals in the center of town, a T cell is the gumshoe detective going door to door to look for perpetrators hiding inside.”

The immune system has a dual nature. On one hand, it includes the B cell and the antibody (the “gunslinging sheriff”), which doesn’t need a cellular context to recognize invading pathogens. On the other hand, the T cell (“the gumshoe detective”) requires foreign pathogens to be present in the cellular context to recognize and kill them. This duality enables the immune system to not only clear invading pathogens from blood but also eradicate them from infected cells.

“Checkpoint inhibitors did unleash T cells against his [Sam P.’s] melanoma, bringing its malignant growth under control. But they also unleashed an assault on his liver that we could never overcome. It was a medically induced form of horror autotoxicus. He was caught on the border between his cancer and his self. Eventually the tumor cells circumvented the border and survived. Sam was left behind.”

Mukherjee notes two particularly challenging features about cancer. The first is that it’s a rogue version of normal cells. The second is that it can make itself invisible to the immune system. Oncologists are still struggling to determine the best way to overcome these obstacles. One way that has shown some promise is to remove the innate T cell mechanism that prevents them from attacking foreign microbes. However, while this treatment can help patients battle cancer, it has an unintended consequence: It can unleash autoimmune disease, causing the T cells to start attacking normal cells. Sam P.’s story illustrates this point. While oncologists were able to help his cells fight the cancer, his cells also turned on his healthy cells. The team was unable to slow the destruction of his healthy cells, which is one of the reasons he died. While cancer treatments have come a long way, much more work is necessary.

“I cannot think of a scientific moment that has revealed such deep and fundamental shortcomings in our knowledge of the biology of a system that we had thought we knew. We have learned so much. We have so much left to learn.”

Before the COVID-19 pandemic, scientists thought they truly understood the human immune system. The pandemic illustrated that this wasn’t the case. While scientists created vaccines in record-breaking time, millions of people died (and continue to do so). The pandemic showed that science doesn’t fully understand the relationship between viruses and immune response. While scientists have come a long way through history in understanding this relationship, much is still left to learn.

“We might imagine the organ [the heart] as if it behaves, almost, as a single-minded cell.”

Chapter 16 represents a significant shift in Mukherjee’s narrative. In previous chapters, he focused on how the immune system fights microbial invaders. Here, though, he turns to how cells in organs work together to fulfill a common purpose. He starts with the heart. While numerous cells make up the heart, they all communicate and coordinate together to form heartbeats. As such, the heart almost functions as “a single-minded cell.”

“‘And then it happened,’ Mayberg said. ‘As we hit the right spot, she [the patient] suddenly said: ‘What did you do?’ ‘What do you mean?’ Mayberg asked. ‘I mean you did something, and the void lifted.’ The void lifted. Mayberg turned the simulator off. ‘Oh, maybe I just felt something weird. Never mind.’ Mayberg turned it on again. The void lifted again.”

This passage describes neurologist Helen Mayberg using deep brain stimulation (DBS) on a patient. Mayberg hopes that DBS can cure forms of depression that are resistant to therapy. So far, her experiments have had mixed results. Some patients, like the one described above, feel relief. However, Mayberg and others are still trying to figure out the best part of the brain to target as well as for which patients DBS is right. If they can address these factors, DBS could be a new form of treatment. It could help regulate mood imbalances, transforming them.

“When not in the hospital or the lab, I spent my weekends in a house on a bluff that overlooked Long Island Sound. By the early light of morning with geometric crosshatches of sunbeams streaming across the lawn like rays of light coming out a prism, I would watch two ospreys that had come to nest there. They would fly up above the ocean, and then, miraculously, seem to sit still in midair—even while capricious gusts of wing might arrive from any direction.”

Mukherjee uses this description of ospreys in flight as a metaphor to describe how cells of the organs—particularly the liver, pancreas, kidney, and brain—work together to maintain homeostasis. Just as an osprey’s wing and tail feathers work together to help them glide in stillness against the wind, these organs work together to help adjust metabolism and other key functions in the body. When these adjustments are successful, the body maintains health. When these adjustments are blown off course, like what happens to ospreys in heavy wind, then the body is out of fixity and experiencing some pathology.

“And so it went. ‘We had one survivor from 1970. Three from ’71. And in ’72, we had a few. We didn’t have a lot of long-term survivors—but some of them did make it to twenty, thirty, and forty years. By the mid-eighties, we began to really see long-term survivors. Tens, twenties, dozens of them, living five, or ten years after the transplant.’”

Cell therapy for blood diseases today saves countless lives. However, it had a terrible start, as this passage describes. Early attempts at blood marrow transplants had few survivors. In speaking with nurses who helped with these early studies, Mukherjee illustrates how tough this period was. Nurses dealt with many failures that were punctuated by the occasional success story, although these successes were often short-lived. Not until nearly two decades after the start of blood marrow transplants did the odds change. Now some of the most deadly cancers of the blood are curable. Science is an iterative process. The road to a breakthrough is often filled with failure, despair, and death.

“But death isn’t a flying apart of organs. It is the withering grind of injury set against the ecstasy of healing.”

In Chapter 20, Mukherjee returns to the concept of homeostasis but in bones. Bones are constantly balancing decay with regeneration. An organism survives as long as regeneration keeps up with injury. When this fails, however, the entire system and the organism fail too. Death is absolute; there is no returning.

“There are mysteries beyond mysteries.”

This statement is especially sobering because it refers to scientific questions about a cell’s physiology that science simply hasn’t provided the answer to yet. These unknowns slow treatments for lethal diseases, including cancer. With cancer, one of the most mysterious questions is why some places in the human body attract cancer but not others. Scientists have many hypotheses and are slowly testing them. Given the iterative nature of science, an answer may come soon or in many years. Mukherjee seems hopeful that scientists are getting closer to unlocking more mysteries surrounding cancer cells.

“To build new humans out of cells, we need knowledge that is not just names, but the interconnectedness between names. Not addresses, but neighborhoods; not identification cards, but personalities, stories, and the histories that accompany them.”

In the penultimate chapter of his book, Mukherjee argues that scientists need to move away from an atomistic to a holistic worldview. He strongly believes that viewing cells as isolated units hinders the ability to craft even more novel drugs and treatments because of the lack of a fundamental understanding about how cells connect to each other, to organs, and to an organism overall. Mukherjee is in favor of creating “new humans.” By this, he believes that humans should use the power of science to reengineer cells to cure previously incurable diseases, reduce chronic pain, etc.