Pathologists and microscopists in the 1800s discovered that “human blood carried minuscule fragments of cells—tiny, shorn-up pieces, barely visible but always present” (164). These tiny fragments became known as platelets, a term coined by Italian scientist Giulio Bizzozero. Platelets are created in the bone marrow. Aided by clot-making proteins, platelets help form blood clots to slow and stop bleeding and help heal wounds. Because platelets perform this task, Mukherjee refers to them as the healing cells.

Numerous genetic disorders result from platelet malfunction. Investigating these disorders helped scientists better understand the relationship between platelets and clot-making proteins. The most well-known disorder is heart disease, which often results in an event known as a heart attack. The first documentation of a heart attack occurred in 1912 when a banker collapsed. Obituaries show that the incidence of heart attacks massively increased in the 1950s and 1960s.

Modern lifestyles, including a diet rich in fatty foods, limited exercise, obesity, and smoking, contribute to the accumulation of plaques. Plaques are “inflamed, calcified, cholesterol-rich blobs that hang on the walls of the arteries” (167). When plaques break, the platelets and clot-making proteins respond as they would to a wound. In doing so, the healing platelets switch to deadly platelets because they block blood from flowing into the heart, which induces a heart attack.

Pharmacologists have worked to find drugs that dampen platelet and clot-making protein activity. Effective drugs include aspirin, Lipitor (which reduces cholesterol), clot-dissolving drugs, and platelet-inhibiting drugs. These drugs must be taken every day. However, this situation might change. Verve Therapeutics, a biotech company based in Boston, is trying to develop gene-editing technology that eliminates cholesterol proteins in the liver. A person would undergo this procedure only once (if it turns out to be effective).

Because of the red color of blood, scientists didn’t notice the existence of white blood cells (also known as leukocytes) for many centuries. French pathologist Gabriel Andral discovered this blood cell type in the 1840s. In comparison to red blood cells, white blood cells lack hemoglobin, possess nuclei, and have irregular shapes. Since their discovery, scientists have believed that they play a critical role in helping defend against infection and inflammation.

To discover the connection between white blood cells and immunity, zoologist Elie (Ilya) Metchnikoff conducted experiments on starfish. Because starfish are semi-transparent, Metchnikoff deduced that he could watch the cells move around in their bodies. When Metchnikoff stuck thorns in starfishes’ feet, he saw immune cells accumulate and activate at the site of injury. He noted “that the immune cells moved toward the site of inflammation autonomously as if impelled by a force or attractant” (174). Scientists eventually realized that upon injury, cells release proteins (chemokines and cytokines), which then send white blood cells to the site of injury. Metchnikoff extended his experiments to other living beings and described the relationship between them and the invaders as a struggle, or (in German) Kampf.

Neutrophils, a type of white blood cell produced in bone marrow, are the first line of defense for human immune systems. Although short-lived, neutrophils are critically important. As Mukherjee notes, they “are intrinsically armed with receptors that recognize proteins (and other chemicals) found on the surface or the interior of some bacterial cells and viruses” (176). These receptors highlight that human cells have been fighting microbes (invaders) for millennia. As a result, scientists began to describe neutrophils as the “‘innate immune system’” (177). All multicellular creatures have this type of immune system, illustrating the key role of neutrophils in immunity.

Vaccines are one way that scientists can manipulate this innate immunity. Humans have been practicing vaccination for hundreds of years. For example, priests in India 250 years ago rubbed cuts on children’s skin with pus from smallpox blisters (a process known as variolation). Variolation helped children develop immunity to smallpox. Likewise, healers in China from at least 900 AD realized that the best caregivers of people with smallpox were those who already had smallpox. This exposure to the disease gave the individuals immunity. Similar practices continued in Asia and the Middle East through the early 18th century. Beginning in the 1700s, scientists attempted to make variolation safer by using less severe forms of smallpox. In addition, these scientists realized that “some factor produced in the body must be able to counter the infection and also retain a memory of the infection over multiple years” (181).

The innate immune system in all multicellular organisms is critically important to survival. Disabling it has extremely negative consequences. For example, humans that lack a functional innate immune system often are severely immunocompromised and less responsive to vaccines.

Starting in this chapter, Mukherjee turns to the second part of the innate immune system, which includes B cells, T cells, and antibodies. Interest in this second wing began with a snakebite. While traveling in India in the late 1800s, German physician and scientist Dr. Paul Ehrlich encountered a man who claimed to be immune to snake bites. The man told Ehrlich that “he survived the first snake attack, and with each subsequent bite, the symptoms became milder and milder” (187).

This story sparked Ehrlich’s interest in determining the mechanism that helped cells render immunity to some diseases. Alongside another scientist, Ehrlich created the first antitoxin. In addition, he coined the term “antibody.” Ehrlich was convinced that “an antibody was an actual chemical substance: a ‘body’ produced to defend the body” (188). Furthermore, he believed that antigens generated antibodies. While some aspects of Ehrlich’s theory are wrong, the term “antibodies” is still in use today.

Mukherjee describes antibodies as proteins that latch onto another substance. Antigens are in fact a substance that creates antibodies. Studies on birds in the 1940s demonstrated that B cells, a type of white blood cell, are “the antibody-making cells” (190). The antibody serves two purposes. The first is that it acts as an antigen binder, and the second is that it activates the immune response to an invader. B cells acquire their unique antibodies through mutation. Without antibodies produced by B cells, humans would be unable to acquire long-term immunity. Vaccines would be rendered useless. Ehrlich argued that B cells could be the source of a magic bullet in the fight for immunity. If scientists could target B cells to attack and kill specific pathogens, “it would be a medicine like none other” (196). Studies suggest that Ehrlich’s magic bullet theory might have merit.

Beginning in 1975, doctors attempted to use antibodies to target particular cancer cells. One of the first cases was an American man with lymphoma. Although the treatment was unsuccessful (the man died), researchers continued to search for antibodies that could help fight cancer. Rituxan, approved by the FDA in 1997, represents one of “the first monoclonal antibodies against cancer” (201).

In the 1960s, scientists realized that the thymus, “a human organ that most scientists had long forgotten” (202), produced T cells, another type of white blood cell. As a graduate student, Mukherjee examined why the immune system, particularly T cells, couldn’t destroy some chronic viruses. One of his mentors was an Italian postdoc named Vincenzo Cerundolo, who told Mukherjee, “‘To understand T cell virology, learn to think like a virus’” (205). Their relationship blossomed from mentor/mentee to colleagues and friends. Vincenzo died from lung cancer in 2020.

Mukherjee turns his attention to describing the two things that T cells do during infection. First, they attack cells that have been infected by an invading microbe. This is why they’re known as killer T cells. T cells have a protein on their surface called CD8, which helps them “recognize viral infections only in the context of the self” (207). T cells recognize cells that have been infected only if they come from the individual’s body. They don’t recognize virally infected cells from another person’s body. Moreover, T cells only kill infected cells from the same body.

The MHC class I protein helps T cells recognize the “infected ‘self’” (208) by sending out samples of a cell’s inside. A cell loads peptides from its interior onto its surface. CD8 cells check cell surfaces for peptides from viruses and, if it detects foreign peptides on a cell, triggers an immune system response.

So far, Mukherjee has described the CD8 T cell response after a virus is detected within the cell. However, this raises a question about the T cell response when pathogens are found outside cells in the human body. The discovery of class II MHC proteins, which are related to class I MHC proteins, answers this question— and represents the second thing that T cells do during infection. The class II MHC protein “presents mostly external peptides to T cells” (214). Another class of T cells called CD4 cells detect the foreign peptides presented by class II MHCs. In this case, the T cells don’t kill the pathogen. Instead, the T cells help B cells create antibodies. T cells act as helper or coordinator cells. Understanding the T cell’s immune response was critical in recognizing and fighting AIDS because this cellular disease results in the collapse of CD4 cells, which, in turn, causes the collapse of the immune system. Scientists are attempting to develop cellular therapies that might cure AIDS, including “alternating the cellular reservoir of HIV in the blood” (224) through bone marrow transplants. The story of Timothy Ray Brown is one example of an attempt to use this cell therapy to cure AIDS.

In this chapter, Mukherjee investigates how “T cells know its altered self” (226), or how they know to target foreign microbes rather than healthy cells in the same human body. Scientists were especially interested in understanding how to get the human body to accept skin grafts during World War II. Doctors and nurses wanted to use skin grafts to treat wounded soldiers and civilians. Skin graft experiments were often unsuccessful because the body rejected the transplant. Scientists soon realized that T cells, alongside multiple genes, played a role in the rejection.

Researchers at Jackson Laboratory in Bar Harbor, Maine searched “for the mysterious compatibility genes that defined self versus nonself” (230) throughout the 1930s. They bred generations of mice to produce offspring that would accept and reject grafts from each other. These experiments paid off. Researchers realized that histocompatibility genes, or H genes, determined whether the body would accept grafts from someone else. Mukherjee notes that H genes “turned out to encode functional MHC molecules—the very molecules […] that had been implicated in how a T cell recognizes its target” (231). Humans also have H genes (called H2 or HLA) that help the immune system check inside cells for foreign microbes.

Mukherjee turns his attention to how a T cell recognizes “that the frame carrying the peptide—the MHC molecule—came from its own body, and from another” (227). Studies of placenta-sharing twin cows suggested that something in the immune system of both animals learned to tolerate the other. Scientists found that T cells that tried to attack cells from their body were removed from the immune system during prenatal development and infanthood. These self-reactive cells were called “‘forbidden clones’—forbidden because they had dared to react to some aspect of a self peptide and were therefore deleted from existence before they could be allowed to mature and attack the self” (233). The deletion occurred in the thymus (a process called central tolerance).

In addition to central tolerance, there is a process called peripheral tolerance, which induces tolerance once T cells have left the thymus. Regulatory T cells (T reg) control this process by suppressing the immune response to sites of injury or inflammation. T reg thus helps prevent autoimmunity and minimizes chronic inflammatory diseases.

Autoimmune disease occurs when the immune system mistakes healthy cells for foreign invaders and attacks them. The body essentially poisons itself. Ehrlich called this phenomenon “horror autotoxicus.” As Mukherjee emphasizes, “Horror autotoxicus—autoimmunity—comes in so many manifestations and forms that there is not a single horror but rather a multitude” (235).

Although autoimmune disease negatively impacts the daily lives of many people, it raised the important question of whether this process might be turned on cancer cells. Initial studies yielded mixed results. Human cancers challenge the immune system because “the proteins that cancer cells make are, with a few exceptions, the same ones made by normal cells, except cancer cells distort the function of those proteins and hijack the cells toward malignant growth” (238). In addition, through evolutionary processes, some cancer cells remain hidden from the immune system. Recent studies have helped immune systems see previously invisible cancer cells and attack them. However, these treatments also cause autoimmune responses in which T cells start attacking normal cells, which is part of the reason that Sam P.’s treatments were unsuccessful.