“The song of the cell” by Siddhartha Mukherjee: review

Book cover

Joel Eissenberg is Professor of Biochemistry and Molecular Biology at Saint Louis University School of Medicine. He is the author of the recent PT article, How humans lost their tails.

As a college junior, I took a course in microbial genetics. The text was Gunter Stent’s Molecular Genetics. I map the beginning of my career as a geneticist to that course. Stent’s book is a history of the origins of molecular biology, and in retrospect, I believe it was the combination of the history and the science that beguiled me. This potent combination is on offer in Siddhartha Mukherjee’s The Song of the Cell: An Exploration of Medicine and the New Human. I generally avoid popular science books in my field, but this book was a gift from my daughter. I had read and enjoyed Mukherjee’s The Emperor of all Maladies, so I was hoping for something special. I was not disappointed.

The factual information about cells and their roles in tissues and organs, and in disease were well established by the time most of us learned it in school, we mostly learned it by rote. Mukherjee uses the history of scientific discoveries about cells to show us not only each discovery, but also the context in which it was made and the impact it had on thinking at the time. Indeed, the book is chock-a-block with historical anecdotes. Many of these discoveries were controversial at the time, like germ theory as the basis for putrefaction and for disease. The esteemed evolutionary biologist Ernst Mayr mocked Carl Woese’s proposal of Archea as a third kingdom of life; Mayr was wrong and Woese was vindicated. Even today, the origins of eukaryotic cells are still controversial.

Mukherjee is a marvelous storyteller. For example, he tells the story that when lipids were extracted from a carefully measured number of red blood cells and spread out on a surface, the area was twice that necessary to contain that number of cells, pointing to a lipid bilayer, rather than monolayer. He is very effective at explaining how discoveries emerge at the confluence of scientific disciplines; e.g., the marriage of microscopy and biochemistry to define the functions of various organelles.

For the evolutionary biologist, Mukherjee discusses the evolution of multicellularity from free-living single cells. As a model, he describes experiments that selected for multicellular clusters of budding yeast. As the clusters grew larger and larger, a subset of cells appeared across the center of the cluster and underwent apoptosis (cellular suicide) to divide the single cluster into two smaller clusters. While certainly artificial, these experiments demonstrate how selection can result in the acquisition of a new property resembling multicellular cooperation.

This is a set-up for a discussion of the community of cells we call embryos. There is a lovingly detailed description of the Spemann-Mangold discovery of the early embryonic “organizer.” The narrative then pivots to describe the infamous case of the anti-anxiety drug thalomide and its teratogenic side effects. The hero of that story was Frances Kelsey, Chief of the Division of New Drugs when Merrell sought to market thalidomide in the US as a sedative. She stood as the lone bulwark against the approval of thalidomide, thus preventing unnumbered birth defects, miscarriages, and stillbirths.

Mukherjee is a hematologist, so blood cells enjoy pride of place in this book. Blood transfusion was the first cellular therapy. It advanced modern surgery, safe childbirth, and cancer chemotherapy. There is an interesting history of blood clotting and the discovery of its role in heart attacks. The topic of immunology is launched with the ancient history of inoculation for smallpox (a.k.a., variolation) and its western descendant, Jenner’s vaccine. Until I read this book, I didn’t know that the history of antibody discovery began with Paul Ehrlich, who coined the word antibody, and immunity to snake venom.

The problem of how antibody diversity arises was a vexed one for decades, and Mukherjee has an amusing digression on the topic involving Linus Pauling. (A bit of personal history: the problem of antibody diversity was still unsolved when I was a microbiology major in college, and resulted in my aborted infatuation with immunogenetics. Fortunately, the mechanism was worked out by Susumu Tonegawa before I got too far into the weeds, and I went in a different genetics direction.) The complex cell biology of the immune response can be overwhelming, but Mukherjee brings the narrative within grasp using metaphors, engaging anecdotes and lively turns of phrase, while either eliding distracting details or relegating them to footnotes.

The history of César Milstein’s invention of hybridomas—fusions of B-cells (a type of white blood cell) and tumor cells—and the resulting monoclonal antibodies at Cambridge University is a riveting one, intimately bound up with the lethal politics of Argentina at the time. Mukherjee notes that the UK government failed to patent this transformative technology in the belief that it would have no immediate practical application.

An aspect of immunology that I’ve always found daunting is T-cell biology. T-cells are another type of white blood cell, and Mukherjee does a superb job of simplifying this branch of immunology without dumbing it down. Key to the cell-cell communication that underpins immunity is distinguishing self from non-self. The puzzle of how this works was solved through a combination of genetics, cell biology, and structural biology, and it makes for engrossing reading. Mukherjee shows how this knowledge is now being harnessed for new anti-cancer therapies.

Our immune system is in an ongoing arms race with pathogens. How this arms race played out with the SARS-CoV-2 virus in the early stages of COVID-19 pandemic is dramatically narrated. In some patients, the infection triggered a massive cellular over-reaction in the form of a cytokine storm—a hyperactive and dysfunctional inflammatory response that killed patients. As someone who enrolled in the Phase III Moderna trial, I remember hoping I’d be in the vaccine wing of the blinded trial. I was.

From blood, the narrative shifts to organs. How the heart muscle contracts and how it coordinates the contractions are designed into its cells. The cellular organization of neurons in the brain was only beginning to be understood at the end of the 19th century, a testament to advances in histological staining and microscopy. That nerves were conduits for electrical impulses became clear by the 1930’s. But detailed histology showed that nerve cells were not physically joined like wires, but separated by small gaps. Mukherjee describes the simple but elegant experiments that led to the discovery of acetylcholine as a chemical neurotransmitter that bridged the gaps between these cells. He speculates on how a system of wires modulated by chemicals might have evolved. In addition to neurons, our brains have glial cells that perform several roles, among them sculpting the connections between neurons. Mukherjee then tells a personal story of his bout of clinical depression to connect us personally with the role of serotonin in regulating mood.

The section on the pancreas includes a cinematic description of the original dog experiments by Banting and Best; these led to the discovery of insulin, which is secreted by the pancreatic beta cells. After decades of work, clinical trials using stem cells forced to differentiate into beta cells are proving therapeutic in Type I diabetics.

Stem cells get their own chapter. Mukherjee begins poignantly by describing the victims of the Hiroshima atom bomb who survived the initial blast and the radiation sickness, only to sicken and die of anemia and loss of immune cells due to death of the stem cells in the bone marrow. Interest in stem cells began in the 19th century, but by the early 20th century it had given way to other aspects of cell biology. It was radiation biology that revived stem cell research in the 1950’s. From studies of bone marrow transplantation in irradiated mice emerged the unexpected finding that all blood cells originated from a single rare—one in ten thousand—precursor cell in the marrow. By 1960, the first successful human bone marrow transplant, and thus the first stem cell therapy, had been performed. In this case, the donor was an identical twin, and it took many years and many patient deaths to work out how to use unrelated donors successfully.

Mukherjee points out that cancer cells have properties shared with stem cells. He discusses evidence that stem cells can become cancer cells, and that some cancers contain “cancer stem cells” that renew the cancer after chemotherapy in analogy to the way that healthy stem cells renew organs and tissue during our lifetimes.

But why are we built from cells? Mukherjee says,

Recall that unicellular organisms evolved into multicellular organisms—not just once but many independent times. The driving forces that goaded that evolution, we think, were the capacity to escape predation, the ability to compete more effectively for scarce resources, and to conserve energy by specialization and diversification. Unitary blocks—cells—found mechanisms to achieve this specialization and diversification by combining common programs (metabolism, protein synthesis, waste disposal) with specialized programs (contractility in the case of muscle cells, or insulin-secreting capacity in pancreatic beta cells). Cells coalesced, repurposed, diversified—and conquered.

I can’t do justice in this review to a book that so effectively and seamlessly melds science, history, and philosophy. Science is more than collecting facts. It is a human endeavor of experience and interpretation. While I was well acquainted with most of the factual content in this book, the writing revitalized this familiar territory as a charming and engaging new synthesis, like listening to fresh improvisations on familiar jazz standards. Song of the cell indeed!