PDF Summary:The Song of the Cell, by Siddhartha Mukherjee

In The Song of the Cell, physician and biologist Siddhartha Mukherjee dives into cell biology, examining its history, its use in modern medicine, and its radical possibilities for the future, from curing cancer to genetic engineering. An expert in oncology and a celebrated pop science writer, Mukherjee expands on his previous works on cancer, DNA, and medicine to consider the all-encompassing role cells play in our understanding of illness and the body.

This guide will explore Mukherjee’s explanations of cell biology, how cellular therapy has transformed medicine, and what new, cell-based approaches scientists have devised as treatments for various illnesses. We’ll also discuss additional views on cell classification and evolution, new developments in the field, and the ethical questions surrounding some of the most cutting-edge procedures.

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3) White Blood Cells: White blood cells, or leukocytes, are responsible for coordinating the body’s immune response, fighting off disease or infection by consuming and destroying antigens (a molecule or substance that triggers an immune response), dead cells, and tumor cells. Phagocytic cells ingest antigens and break them down into their harmless chemical components, while lymphocytes recognize and target specific antigens. Mukherjee describes lymphocytes as the “adaptable immune system,” responding to a unique antigen with a unique immune response, versus the one-size-fits-all behavior of phagocytic cells. While phagocytic cells can act more quickly, they may fail to destroy stronger antigens.

(Shortform note: In addition to the body’s natural defenses, doctors may prescribe antibiotics (a generic term for various chemical compounds that attack microorganisms like bacteria) in an effort to kill or neutralize a disease. The discovery of the first antibiotic, penicillin, in 1928 is considered to have revolutionized medicine by reducing the deadliness of many bacterial infections (antibiotics aren’t effective against viral infections). However, some doctors argue that overusing antibiotics may actually weaken your immune system by damaging white blood cells, worsening your health long-term.)

Mukherjee explains that there are two types of lymphocytes; B cells and T cells. B cells produce antibodies—proteins designed to bind with and neutralize specific antigens. Each B cell is capable of producing only one type of antibody, and the correct B cell is only activated once it “recognizes” an antigen by bonding with it. B cells remain in the blood even after the antigen has been eliminated, enabling a faster immune response if you’re exposed again. This is the main principle behind vaccines—by introducing your body to an antigen in a small, controlled amount, the relevant B cells are activated and are prepared to respond to a later, more serious infection.

Types of Vaccines

While the intent of a vaccine is to train your immune system, particularly your B cells, to respond to a particular antigen, not all vaccines are “live virus” vaccines that contain a weakened form of that antigen. While it’s theoretically possible for a person to become infected with chickenpox or measles by receiving the related vaccine—which does contain a live virus—the odds are extremely low, and generally only immunocompromised and pregnant people are considered at risk. Despite being the subject of many conspiracy theories, none of the Covid-19 vaccines available in the US are live virus vaccines, and so cannot transmit the disease.

Other types of vaccines include “inactivated” vaccines, which contain material from a dead or inactive antigen (such as the polio vaccine), and “toxoid” vaccines, which contain a toxin made by the virus, teaching your body to resist the harmful effects of the infection rather than the infection itself (such as the tetanus vaccine). There are also “biosynthetic” vaccines that contain man-made materials that mimic the effects of the antigen (like the Hepatitis B vaccine) and mRNA vaccines that train your cells to make proteins associated with the antigen, thus triggering the production of the relevant antibodies (several Covid-19 vaccines are this type).

Mukherjee says that antibodies can’t enter cells, so T cells alone are responsible for detecting and destroying cells that have been infected or become cancerous. He stresses that the T cell’s most important function is to recognize cells that belong to the shared body of the organism versus those that are foreign. It does this through a combination of recognizing the cells’ genes (the “self”) and recognizing proteins that are produced only by a virus or an infected cell (the “nonself”). Having recognized an invader, T cells will attack the infected cell with toxic chemicals until it dies. However, this ability of T cells to recognize foreign materials also makes them responsible for complications in medical transplants of skin, bones, and organs.

(Shortform note: Immune rejection refers to the body’s rejection of transplanted organs (such as kidneys or livers), skin grafts, or bone marrow. “Acute” rejection occurs when T cells recognize transplanted material as being foreign and usually occurs within the first few days or weeks after a transplant. However, a patient can also suffer ”chronic” rejection, which can occur months or years after the transplant as the foreign organ or material slowly ceases to function and is broken down by the patient’s immune system. Chronic rejection isn’t as well understood as acute rejection, though it’s more common in patients who recovered from acute rejection through the use of immunosuppressant medication.)

Bone Cells

Bone cells are distinguished by their ability to gain size or change shape, allowing the skeleton to grow, heal from a fracture, or dissolve pieces that aren’t functioning properly. Mukherjee also highlights cartilage cells, which connect bones together, osteoblasts that deposit calcium to thicken or extend an existing bone, and osteoclasts, which degrade existing bone that’s become too thick or is restricting bone marrow. Several diseases are associated with the activity of these cells, such as osteoarthritis (underproduction and loss of existing cartilage) or osteoporosis (resulting from overactive osteoclasts, especially later in life when the body is no longer producing much new bone).

(Shortform note: Both osteoarthritis and osteoporosis are common in adults (particularly women) over the age of 55, affecting close to a fifth of the population worldwide. While treatment plans often emphasize better eating habits (particularly anti-inflammatory foods or those rich in calcium and vitamin D) and regular exercise, some people also seek out surgery to replace the damaged tissue with prosthetics or “regenerative medicine,” which aims to reverse the loss of cells by stimulating tissue growth or implanting newly grown cells.)

Stem Cells: For Mukherjee, the most significant characteristic of bones is their high quantity of adult stem cells. Found in bone marrow, stem, or “undifferentiated,” cells are capable of evolving into any other cell type—blood cells, muscle cells, skin cells, and so on—and in fact are the original cell from which every other cell in the body develops during pregnancy. Embryonic stem cells produce all the needed organs and tissues as a zygote grows into an embryo and then a fetus, while adult stem cells are responsible for growth, repairing the body, and the production of blood cells. Each stem cell is capable of producing billions of daughter cells, including identical copies of itself and mature cells of other types.

(Shortform note: Some biologists believe that the future of medicine may lie in regular transplants of lab-grown, cultivated stem cells to replace diseased, damaged, or cancerous tissue. However, adult stem cells have a limited capacity for differentiation, and embryonic stem cells are hard to come by. They can be isolated from a human embryo, but the embryo is usually destroyed in the process. Embryonic stem cell extraction and stem cell cloning have proven controversial, as critics argue that both embryos and fetuses are forms of human life that are entitled to protection from medical experimentation.)

Mukherjee describes how bone marrow transplants have been used to treat cancers like leukemia, allowing recipients to produce new, healthy blood cells. Within the bone itself, skeletal stem cells, or OCHRE (osteo, chondro, and reticular) cells, can differentiate into cartilage cells and osteoblasts, creating new bones or lengthening existing ones. These stem cells are most active in children and adolescents, and their populations shrink over time, slowing or stopping the growth of the skeleton in adults. With the loss of stem cells, it becomes more difficult for the body to maintain bone thickness or repair bone in the event of a fracture or break.

(Shortform note: Because adult stem cells can be extracted from a patient without harming them, their use has been less controversial than experimentation with embryonic stem cells. Even so, the hematopoietic stem cell transplants Mukherjee describes (using donations of bone marrow or blood) are the only form of stem cell therapy currently in widespread use. Research is still being done on the possibility of using adult stem cells or bone grafts grown from stem cells to repair bone breakage or decay, particularly in older patients.)

Cell Pathology in Medicine

Moving beyond his descriptions of cells, Mukherjee considers how new practices like cellular therapy and cellular engineering can advance medicine. He’s particularly interested in the prospect of manipulating cells to cure cancer, eliminate disease, and even alter the human genome—though he acknowledges how little is still known, the potential to do harm, and the ethical considerations. Above all, he emphasizes that nothing in the body works in isolation. Cells are constantly communicating with one another, and while this enables many of the body’s most complex and impressive functions, it also means that any disruption to the system could have unexpected consequences.

Tenet 3: Cells Work Together in Complex Systems

Mukherjee refers back to 19th-century descriptions of cells as a kind of community, able to function independently but constantly working in tandem to reproduce, exchange chemicals and proteins, and enable the body’s more complex processes. Cells work together not only within an organ or system, but across the body as a whole. For example, the circulation of blood involves not just blood cells but those of the heart, the lungs, the bones, the pancreas , and the kidneys . Understanding health and homeostasis requires a global view of cells.

Mukherjee stresses that just as the body’s normal, healthy functions are complex and diffuse, so is the breakdown of those functions in the form of injury or disease. Though he believes that all illness has a cellular cause, he says that identifying that cause is often difficult, as a patient can display many unusual cellular behaviors without a clear cause or effect. For example, a patient may have a low T cell count due to an infection of the bone marrow, or the bone marrow infection may be a result of a low T cell count failing to fight the disease. Therefore, understanding illness and dysfunction requires a holistic approach.

(Shortform note: The interconnectedness of cells means that cancer cells can spread throughout the body, requiring a holistic approach to treatment. In recent years, “multidisciplinary” treatment plans have become standard in oncology—rather than a cancer patient relying on a single doctor for treatment or having to seek out multiple experts (a cardiologist for heart disease, a radiation oncologist for radiation therapy, and so on), a team of physicians come together to work on the case. This gives the patient access to a variety of treatment options and recommendations, and it helps to prevent misdiagnosis or a doctor prescribing the patient something that may conflict with other aspects of their care.)

Tenet 4: Disease and Death Result From a Breakdown of Cell Relationships and Activity

According to Mukherjee, cellular biology is closely related to germ theory, the now-dominant belief in medicine that disease occurs on a microscopic level with cells being invaded and made dysfunctional by foreign agents. Having entered a cell, bacteria may produce toxins that kill the cell outright, impair or destroy the organelles responsible for energy production, and consume needed proteins and chemicals. Likewise, viruses can “hijack” the cell nucleus to produce many copies of themselves and viral proteins, spreading the infection further. Altogether, Mukherjee argues that disease can be understood as a disruption in cellular activity, whether this means the cessation of activity, impaired activity, or overactivity.

(Shortform note: Germ theory was as revolutionary for medicine as the discovery of the cell. Understanding that disease begins at the cellular level and is spread by specific organisms enabled doctors to study the exact causes of sickness and how they spread. Today, working as a physician means knowing not just the symptoms of an illness but which bacteria or virus causes it, how it enters the body, and what effects it has on the cell. For example, malaria is caused by the bacteria Plasmodium falciparum, which bypasses the skin and enters the bloodstream through a mosquito bite, whereas polio spreads through the body when poliovirus uses the membrane of its host cell to replicate its own RNA.)

How Cancer Cells Work

As an oncologist, Mukherjee is particularly interested in cancer cells, which are distinguished by their relentless growth. A cancer cell is unable to properly interpret the signals that start and stop cell reproduction, thus dividing endlessly and mutating along the way, sometimes forming a mass called a tumor. Because cancer cells are not foreign material and do not produce proteins that indicate the presence of disease, they can go unrecognized by the immune system. In a sense, Mukherjee suggests, cancer cells are not impaired so much as they perform their function too well, damaging and potentially killing their organism.

(Shortform note: The US’s National Cancer Institute considers a capacity for endless replication and invisibility to the immune system to be characteristics common to all cancer cells. In his previous best seller The Emperor of All Maladies, Mukherjee describes several other characteristics, including cancer cells’ ability to travel through the bloodstream and attach to other areas of the body, as well as their ability to hijack blood vessels to create a self-sustaining tumor with its own source of oxygen and nutrients. Despite the fact that cancer has likely existed as a form of illness since the beginning of human history, many of these characteristics were only firmly defined in the late 1990s and early 2000s.)

Imbalance in Cell Activity

Mukherjee notes that illness or death can also be caused by an imbalance between the activity of two types of cells. Sometimes, the cells that work to destroy or remove tissue are simply working faster than the cells that work to create or repair it. This is the cause of degenerative illness like osteoporosis (loss of bone mass) and Alzheimer’s (loss of brain cells). It’s also the case with radiation sickness—though many of a patient’s blood cells may die as a result of radiation exposure, death occurs most often because damaged bone marrow is unable to produce new, healthy blood cells. Even death from old age, Mukherjee states, is ultimately the result of the natural processes of decay outpacing those of rejuvenation.

(Shortform note: Some scientists theorize that the key to immortality, or at least extending the human lifespan, will come from finding a way to keep cells regenerating permanently. For example, in Lifespan, biologist David Sinclair argues that aging is not a natural process but a disease affecting DNA; there’s no reason why our DNA shouldn’t be able to direct the body to respond to damage or illness as aggressively in old age as it does in youth. Similarly, in The Telomere Effect, biochemist Elizabeth Blackburn suggests that preserving or lengthening our telomeres—repetitive DNA sequences that “cap” and protect the ends of our chromosomes—could prevent DNA degradation, keeping cells active and reproducing longer.)

Tenet 5: Cells Will Play a Role in the Future of Medicine

Mukherjee describes four major types of cellular therapy that arose out of cell biology, including some that are already an accepted part of medicine—such as antibiotics, blood transfusions, and vaccines—and others that are still experimental but may play a role in treating or eliminating cancer. These include altering the properties of cells using drugs, chemicals, or physical stimulation; transferring cells between two bodies, or extracting cells from a person and then reimplanting them; using cells in a laboratory setting to synthesize a useful substance, like insulin; and genetically modifying cells to give them—or the larger organ or organism—new properties.

(Shortform note: Even “accepted” forms of cellular therapy are still prone to controversy in the modern day. Some people refuse vaccination, blood transfusions, or any medication on religious grounds, suspicious of medical science’s ability to “alter” the body outside of God’s design. Others question the potential side effects and health risks of new vaccines or connect them to anti-government conspiracies. In the case of blood donation, LGBT+ advocates in the US fought for decades against the Food and Drug Administration’s ban on gay and bisexual men donating blood, calling the practice discriminatory. The ban was overturned in 2023.)

Genetic Engineering to Fight Disease

When the cells in a person’s body are not behaving properly—for example, if their bone marrow is unable to produce healthy blood cells—a transfer of healthy cells from another person can treat the disease, though this requires finding a close enough match. As an alternative, Mukherjee describes how cellular engineering could allow cells from a patient’s body to be extracted, genetically modified, and reimplanted so that they can function properly again. In another approach, healthy cells could be grown from scratch in a lab, or cells could be altered without removal.

Diabetes

Diabetes is caused by a dysfunction of the pancreas in which it’s either unable to produce sufficient insulin (type 1) or is no longer producing as much insulin as it used to (type 2). Insulin is needed for the body to break down and absorb energy from sugars in food, and current treatments often require the patient to inject insulin into their bloodstream at least once a day. Mukherjee suggests that a more dramatic treatment, or even a cure, could come in the form of growing healthy pancreatic cells in a lab and implanting them into the patient. While some of these cells have been successfully grown from stem cells, implantation is still being tested.

(Shortform note: Transplantation of pancreatic cells, or even of an entire pancreas, has been attempted in the past with some success, but this treatment is generally limited to people with type 1 diabetes, which make up around 5% of all diabetes patients. This is because type 2 diabetes isn’t just a dysfunction of the pancreas; it also involves cells failing to absorb insulin, so merely restarting insulin production wouldn’t be a cure. Transplantation is also limited due to a shortage of healthy donor pancreases. Mukherjee’s suggestion of using lab-grown pancreatic cells could solve this problem, but this is not yet widely practiced.)

Cancer

Modifying the patient’s cells is the basic principle behind T cell therapy, which trains the patient’s immune system to recognize and attack cancer cells. T cells are extracted or grown in a lab and then genetically modified to recognize proteins unique to the otherwise normal-appearing cancer cells. Mukherjee states that T cell therapy has been somewhat successful in treating leukemia, as in the famous case of Emily Whitehead, the first person to undergo this type of treatment at the Children’s Hospital of Philadelphia. But it can also backfire, causing an immune response so violent it kills the patient—Whitehead herself had to be hospitalized for severe inflammation while receiving treatment.

(Shortform note: Leukemia, or cancer of the blood cells, is the most common cancer affecting children under the age of 15. Whitehead received CAR-T cell therapy when she was six years old, and it effectively cured her leukemia (she remains in remission over a decade later). Her success story has inspired others to seek similar treatment, though many also suffer the same violent immune reaction—known as cytokine release syndrome—in the course of therapy. As of 2022, six varieties of CAR T-cell therapy have been approved for general use, all in the treatment of various blood cancers.)

Mukherjee writes that another difficulty comes in finding a unique aspect of cancer cells that T cells can target. Unlike bacteria or viruses, cancer cells generally produce the same proteins as healthy cells, but direct them toward unhealthy growth. There is no foreign agent for the T cell to detect, and training a T cell to attack cells that are of its own body may lead to it to view the entire body as foreign, giving the patient an autoimmune disease. Cancer cells also mutate over time, meaning that they may effectively evolve out of the characteristic that made them vulnerable to T cell therapy.

(Shortform note: In The Emperor of All Maladies, Mukherjee mentions The Cancer Genome Atlas (TCGA), a project begun in 2006 that works to sequence the genomes of various cancer cells and thus identify common mutations that could be targeted by T cell therapy or other cancer treatments. While Mukherjee notes that the diversity of cancer cells means that sequencing all of them could take years, the TCGA has successfully characterized 33 cancer types (as of 2021) and made their data publicly available to researchers, advancing treatment options for patients suffering from cancers like mesothelioma, leukemia, and some sarcomas.)

Modifying Non-Human Cells

In addition to treatments using the patient’s own cells, foreign or infectious cells can also be used to fight disease. Mukherjee describes a treatment for Leber hereditary optic neuropathy (LHON), a condition that causes vision loss, which involves genetically modifying a virus and injecting it into the patient’s eye. The virus takes over the patient’s mutated cells and rewrites their mitochondria to make them behave normally. While this treatment is still being tested and is only effective for patients in the early stages of the disease, Mukherjee says it has many upsides—namely that the virus infects the patient without causing acute disease and is injected in such small amounts that it’s unlikely to trigger an immune response.

(Shortform note: The treatment for LHON that Mukherjee discusses is particularly desirable, as there are currently no known cures for the disease and only a few treatment options. Similar tactics of using “oncolytic” cancer-destroying viruses have been explored for the treatment of liver cancer, head and neck cancer, and cervical cancer, though only a few have moved past the laboratory testing stage. Viruses may also play a role in treating cancer through the development of “cancer vaccines” which, like other live virus vaccines, could expose the immune system to a small amount of cancerous material and train it to target any similar material created by the body.)

Genetic Engineering to Prevent Disease

All of the cellular therapies Mukherjee has described so far involve modifying cells’ genes to treat disease in an existing person. The more controversial options involve editing cells and DNA in the womb, or in the lab prior to IVF implantation, to create a new kind of human: one resistant to disease, without any unwanted mutations, and potentially longer-lived than humans today. While Mukherjee is excited about the possibility of eliminating disease, he expresses caution toward the idea of the genetically engineered human, noting that interfering with DNA could have unexpected consequences and that the idea of genetically “improving” people is inextricably tied to racism and eugenics.

Genetic Engineering and Eugenics

The eugenics movement began in the late 19th century and aimed to improve the genetic quality of the human population through selective breeding. The movement frequently overlapped with scientific racism—claims that people of color were inherently biologically inferior to whites—as well as the systematic oppression and exclusion of disabled people. It was also foundational to Nazi ideology. When put into practice, eugenicist policies have resulted in systems of segregation, compulsory sterilization, and mass murder.

While the types of genetic engineering Mukherjee describes could meaningfully improve the lives of many people, the idea of creating a new, superior human through gene editing has been called “new eugenics,” the argument being that society’s concept of what makes a person “superior” remains largely racist, sexist, and ableist. Critics argue that the true aim of new eugenics is not just to eradicate disease but to wipe out large swaths of human diversity.

IVF

Mukherjee notes that in vitro fertilization (IVF) was an extremely controversial practice when it was first introduced in the late 1970s, with critics expressing anxiety about the “artificiality” of fertilization taking place in a lab and the fact that some zygotes are destroyed in the process of creating a viable embryo. What remains controversial is the prospect of using IVF to genetically modify embryos before implantation. Currently, doctors can screen embryos to identify the sex and the presence of hereditary mutations that could lead to Down syndrome, muscular dystrophy, and cystic fibrosis. While these embryos are not modified in any way, the parents can choose not to implant them based on this information.

(Shortform note: Though IVF is increasingly popular—thousands of people use it to conceive each year in the United States—the prospect of screening embryos to “select” certain characteristics has proven controversial. Both disability rights and women’s rights advocates have argued that the systematic devaluing of girls and people born with disabilities would lead to a significant reduction in those populations. This would seem to be supported by the widespread infanticide of disabled infants and the aftermath of the “one-child policy” implemented in China in 1979, which led many parents to abort female fetuses or give girls up for adoption in favor of raising a son.)

Gene Editing

Scientists have long considered the possibility of gene “editing,” in which undesirable mutations are excised or new mutations are introduced as a way to produce a healthy organism or one with specific characteristics. Mukherjee notes that this practice has been carried out on mice, sheep, and cows to make them more resistant to disease or to carry proteins in their milk or their meat that are good for humans. However, he warns that DNA is so complex that even a minor change may damage the whole in unexpected ways.

Gene-Edited Food

Gene editing has already been implemented on a wide scale in the form of genetically modified organisms, or GMOs, which are fruits, vegetables, and meat products that have been genetically altered to be more desirable for human consumption. For example, cash crops like corn or soybean may be modified to grow in larger quantities, be more resistant to pests, and take longer to rot. Genetically modified animals are more rare, but some breeds of salmon have been modified to mate more often and grow to full size in a shorter period of time.

Although GMOs must be approved by food safety authorities, such as the US’s Food and Drug Administration, some people avoid GMOs out of fear that there are unknown safety risks. Because gene editing often involves incorporating genetic material from another organism, some people believe that consuming GMOs could trigger unexpected allergic reactions. Others fear that consuming GMOs could have a long-term impact on our own genetic material, or that GMOs could cross-breed with unmodified organisms and change the characteristics of entire species. However, the current scientific consensus argues that GMOs are no more dangerous than unmodified food products.

Mukherjee provides a real-world example of the dangers—both medical and ethical—of gene editing in the case of He Jiankui, who in 2017 claimed to have genetically modified two female twins in China to prevent the transmission of HIV from their father. He attempted to recreate the natural genetic mutation “delta 32,” which gives some people resistance to HIV. Critics argued that he failed to properly inform the parents of the risks, as his edits (which were not identical to the delta 32 mutation) may have permanently damaged the twins’ immune systems. Also, the children were never in danger in the first place, because the IVF process “washes” sperm cells of HIV before fertilization, making transmission impossible.

He Jiankui’s actions were widely condemned, and he was ultimately sentenced to three years in prison. However, Mukherjee notes that other biologists are pursuing similar experiments, such as the Russian biologist Denis Rebrikov, who proposes modifying DNA to prevent deaf adults from having deaf children. Some medical authorities have proposed establishing a ban on gene editing, but they lack the power to enforce it, while others argue that humanity has a responsibility to use science to reduce suffering, even if the definition of what qualifies as “suffering” remains unclear. Mukherjee does not come down firmly on either side, though he believes the adoption of gene editing into medical practice may be inevitable.

The Future of Gene Editing

He Jiankui was released from prison in 2023 and has stated that he hopes to continue his work, despite the Chinese government banning him in 2019 from doing any further research related to gene editing for “reproductive purposes.” He argues that despite the current controversy, gene editing will eventually become an accepted medical practice. Indeed, while Denis Rebrikov’s research also triggered backlash, it did not result in legal action—possibly because, unlike He, Rebrikov has yet to put his ideas into practice.

Even so, pop culture shows us that most people are still resistant to the idea of gene editing. Science fiction that explores the possibility of creating “transgenic” organisms tends to condemn it, arguing that the motivation for doing so is immoral (Star Trek), the results are unexpected and dangerous (Jurassic Park), and doing so will lead us to devalue humans who aren’t modified (Gattaca).)