The Song of the Cell
Siddhartha Mukherjee (2022). The song of the cell: An exploration of medicine and the new human. Scribner, Simon & Shuster: New York
xv This book is the story of the cell … all organisms … are made of these “elementary particles.” … cooperative, organized accumulations of these autonomous living units … enable profound forms of physiology … Conversely, it is the story of what happens when cells become dysfunctional … And finally, it is the story about … the birth of transformational medicines
9 The transformation of medicine made possible by our new understanding of cell biology can be broadly divided into four categories.
The first is the use of drugs, chemical substances, or physical stimulation to alter the properties of cells …
The second is the transfer of cells from body to body …
The third is the use of cells to synthesize a substance …
And most recently, there is a fourth category: the genetic modification of cells, followed by transplantation
10-11 A cell is a unit of life … What is “life”? … Life’s definition … is akin to a menu. It is not one thing but a series of things, a set of behaviors, a series of processes, not a single property … one might define life as having cells, and cells as having life … It is difficult to imagine life without cells, just as it is impossible to imagine cells having no life … we need to understand cells to understand the human body
11-12 What is a cell, anyway? … a cell is an autonomous living unit that acts as a decoding machine for a gene …Genes … are physically located in … deoxyribonucleic acid (DNA), which is further packed in … chromosomes. As far as we know, DNA is present inside every living cell … a gene carries the code, a cell deciphers that code. A cell thus transforms information into form; genetic code into proteins … But a cell is not merely a gene-decoding machine. A cell uses this set of proteins … in conjunction with one another to start coordinating its function, its behavior … to achieve the properties of life … And finally, a cell is a dividing machine
19 True knowledge is to be aware of one’s ignorance. – Rudolf Virchow
19 The world of medicine … in the mid-1800s might have been divided into two halves – anatomy and pathology – one relatively advanced and the other still in a muddle, respectively
21-22 In 1543, he [Andreas Vesalius] published his anatomical works in seven volumes entitled De Humani Corporis Fabrica (The Fabric of the Human Body) … that would lay the foundation for human anatomical studies for centuries to come … Coincidentally, it was published the same year that … Nicolaus Copernicus … put out his … book The Revolutions (On the Revolutions of Heavenly Spheres) … that placed the Earth in orbit and the sun firmly at its center … There was no comparable book of pathology, and no common theory to explain diseases
24 Pathologists had long been divided into schools that argued for various sources of disease … the miasmists … the Galenists … and the “psychists,” … 1843
26 Modern genetics was launched by the practice of agriculture … Highbrow science was born from lowbrow tinkering
34 [early 1660s, Robert Hooke] searched for a name for them and finally decided on cells, from cella, a Latin word meaning “small room.”
37-38 In the history of biology, there are often valleys of silence that follow the peaks of monumental discoveries … Part of the explanation for this valley of science has to do with the time required to develop instruments and model systems to answer these questions … But perhaps an equal answer exists in the conceptual, or heuristic, changes required to switch from the description of an entity … and move toward understanding its universality, organization, function, and behavior
40 in the late 1830s … [François-Vincent] Raspail deduced that a cell performs chemical processes to make tissues and organs function. In other words, it enables physiology
41-43 at its moment of inception, cell biology happened to collide with two of the most contentious debates about life that were raging through seventeenth- and eighteenth-century European science … The first of the debates arose from the vitalists … that was convinced that living beings could not possibly be built out of the same chemicals that were pervasive in the natural world … Vitalists had no problem with cells per se … Their concern was the origin of cells … Counterposed against the vitalists, was a small, embattled group of scientists who argued that living chemicals and natural chemicals were one and the same, and that living beings came from living beings – not spontaneously, but through birth and development … The second debate that simmered through the early 1800s was preformation: the idea that the human fetus was already fully formed, albeit miniaturized, when it first appeared in the womb following fertilization … It was the demolition of the theories of vitalism and preformation – and their displacement by cell theory – that would firmly establish the new science and usher in the century of the cell
44-45 1838 … [Matthias] Schleiden and [Theodor] Schwann proposed the first two tenets of cell theory:
1. All living organisms are composed of one or more cells.
2. The cell is the basic unit of structure and organization in organisms
50 [Rudolf] Virchow … refined Schwann and Schleiden’s cell theory by adding three more crucial tenets to the two founding ones …
3. All cells come from other cells …
4. Normal physiology is the function of cellular physiology.
5. Disease, the disruption of physiology, is the result of the disrupted physiology of the cell
50-52 Rudolf Virchow … Immersed within a society that was becoming progressively racist and anti-Semitic, he argued vehemently for equality among citizens … be began to witness in Germany the resurgence of a malignant form of radical nationalism that would eventually culminate in the Nazi state. The central myth of what would later be termed “Aryan” racial superiority … Volk who were blond, blue eyed and white skinned … 1876 … Only one in three Germans bore the hallmarks of Aryan superiority … and a full 11 percent of Jewish children were blond and blue eyed … He published the data in … 1886
52 These two … 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 … the twin melodies that ring throughout this book
53 B cells (white cells that make antibodies) and T cells (that kill microbially infected cells and help mount an immune response)
55 It isn’t sufficient to locate a disease in an organ: it’s necessary to understand which cells of the organ are responsible
56 It was germ theory – that microbes are independent, living cells capable, in some cases of causing human illness – that would first bring the cell … into intimate contact with pathology and medicine
57 In 1668, Francesco Redi … wrote. “All life comes from life.”
57 Louis Pasteur … Bacterial cells … are carried in air and dust … Decomposition and disease might have seemed superficially very different, but Pasteur made a crucial link between them
57-59 Robert Koch … In early 1876 … experimented with transferring disease from one organism to the next in a systematic, scientific manner … “In view of this fact … all doubts as to whether the Bacillus anthracis is really the cause and contagium of anthrax just fall silent.”
60 Pasteur intended to use attenuated anthrax as a vaccine … According to Koch, however, attenuation was nonsense … In time, both men would be proved correct
61-62 Ignaz Semmelweis … worked as an assistant in a Viennese maternity hospital in the late 1840s. The clinic was divided into two wards … Semmelweis noted a peculiar pattern: compared with the second clinic, the first clinic had a significantly higher rate of maternal mortality … the first clinic was run by surgeons and medical students who shuttled casually between the pathology department and the maternity ward … In contrast, the second clinic was run by midwives who had no contact with cadavers and never performed autopsies … He insisted that the students and the surgeons wash their hands … before entering the maternity ward … The impact was astonishing … Semmelweis was harassed and ridiculed … The idea that childbed fever was, in fact, a “doctor’s plague” … could hardly sit well with the professors of Vienna
62-64 In the 1850s … John Snow was tracking the course of a raging cholera epidemic in the Soho area of London … The source ... was … a specific pump on Broad Street … It was a piercing insight … Snow had, in essence, partially united three disparate theories and fields of medicine. The first, epidemiology … Germ theory, the second field … The third was the most audacious of all: cell theory
66 in 1864 … Joseph Lister … Even in ancient India and Egypt, physicians cleaned their instruments by boiling them. Yet in Lister’s time, surgeons paid little attention to the possibility of contamination by microbes
67 every antibiotic is a “cellular medicine” – a drug that relies on the distinctions between a microbial cell and a human cell
67-69 Every cell on Earth … belongs to one of three entirely distinctive domains, or branches, of living organisms. The first branch comprises bacteria … a second branch, or domain, called eukaryotes … contain a special structure called a nucleus … the third branch: archaea … this full branch of living beings remained undiscovered until about fifty years ago … In fact, we still know relatively little about them
75 To define an internal milieu is to define its edge … Without an edge, there is no self
76 Porosity … represents an essential feature of life – but also an essential vulnerability of living
78-79 the cell’s internal fluid, called either protoplasm, cytoplasm, or cytosol … through the protoplasm, you are certain to encounter … ribonucleic acid or RNA.
RNA strands are made of four subunits: adenine (A), cytosine (C), uracil (U), and guanine (G)
81-82 How does a cell generate energy? There are two pathways: one fast and one slow … anaerobic … aerobic
84-88 1960 … The twinning of two ways of seeing – microscopy and biochemistry – was synergistic
89 The nucleus … houses the organism’s genome, made of long stretches of deoxyribonucleic acid … DNA
93-94 the retina is uniquely privileged: along with a few other places in the body – the testes among them – it is not actively surveyed by an immune response and therefore highly unlikely to generate a severe reaction to an infectious agent
96-97 Conceptually speaking, cell division in animals might be broadly divided into two purposes or functions: production and reproduction … In humans and multicellular organisms, the process for the production of new cells to build organs and tissues is called mitosis – from mitos, the Greek word for “thread.” In contrast, the birth of new cells, sperm, and eggs for the purpose of reproduction – to make a new organism – is called meiosis, from meion, the Greek word for “lessening.”
97 Sight – real sight – requires insight
100 [mitosis] You start, say, with forty-six (the number of chromosomes in human cells); the chromosomes duplicate (ninety-two), and then each daughter cell gets half: back to forty-six
[meiosis] The genesis of sperm and eggs, then, must require first halving the number of chromosomes, twenty-three each, and then restoring them back to forty-six upon fertilization …
The life cycle for a multicellular organism, in short, could be reconceived as a rather simple back-and-forth game, between meiosis and mitosis
100-101 What controls the division of a cell? … the life cycle of a dividing cell could be divided into [four] phases [G1, S, G2, M].
Let us begin with cells that opt out of the cycle altogether. They are permanently or semipermanently resting – quiescent … G-zero, the G0 referring to the “gap,” or resting cycle …
When a cell makes a decision to enter the cycle of division, it moves into a new gap period, termed G1 … The phase that follows Gap 1 … is termed the S phase, from synthesis … The third phase … a second resting phase, called G2 … The final phase is M – mitosis itself
104 Urchin eggs … What the fruit fly had been to early genetics, the urchin would be to the study of the cell cycle
105 the role of Cyclins and CDK proteins in the cell cycle. The proteins act in concert to regulate the transitions in the phases of cell division
113 The paper by [Robert] Edwards, [Patrick] Steptoe, and [Barry] 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
129-130 Medical and scientific societies around the world are currently scrambling to establish rules and standards to govern human gene editing in embryos … there is no governing body with the power or authority to allow or disbar gene-editing experiments on human embryos
134 Under the right evolutionary pressure, single cells can become multicellular aggregates over a mere few generations … We can only generate theories and lab experiments about why single cells are so singularly drawn to form multicellular clusters
139 embryology … three-layered embryos … The ectoderm will give rise to everything that faces the outer surface of the body: skin, hair, nails, teeth, even the lens of the eye. The endoderm produces everything that faces the inner surface of the body, such as the intestines and the lungs. The mesoderm handles everything in the middle: muscle, bone, blood, heart
140 About three weeks after gestation, the heart will generate its first beat. A week later, one part of the neural tube will begin to protrude out into the beginnings of the human brain
140 (… perhaps a history of cell biology can be written through the lens of the history of glass.)
142-145 In 1957, a German company called Chemie Grünenthal developed … thalidomide. Marketing was aggressive … misogyny … Its only hurdle was winning clearance from the US Food and Drug Administration (FDA) … partner … Wm. S. Merrell Company … Richardson-Merrell … in early 1960, the FDA had appointed a new commissioner, Francis Kelsey. The Canadian-born forty-six-year-old had earned a PhD and a medical degree from the University of Chicago … Kelsey … found herself unconvinced about its safety … Kelsey fired off a response that might well represent one of the most significant letters written in the history of the FDA: “The burden of proof that the drug is safe … lies with the applicant” … Kelsey dug in deeper … the FDA began to examine whether Merrell had broken the law … FDA lawyers listed twenty-four independent counts of legal violation … The case was closed … Thalidomide had been responsible for a crime of unfathomable proportions – but not a criminal was to be found
150 Multicellularity, the evolutionary transition that made single-celled organisms organize themselves into many-celled beings, may have been inevitable, but it wasn’t easy … multifarious requirements: self-defense, self-recognition, the movement of signals through the body, digestion, metabolism, storage, waste disposal … blood represents a model to describe how an entire system of cells achieves these functions
152 The purpose of a cell in a multicellular organism … is to serve the needs of the organism … “The cell is … a nexus,” Maureen O’Malley and Staffan Müller-Wille wrote in 2010
153 Normal white cells come in two main forms: lymphocytes and leukocytes
154 blood … is the central mechanism of long-distance communication, of transmission, in humans … It even speaks to itself: its three cellular components, red cells, white cells, and platelets
157 Blood transfusion, the first modern form of cellular therapy
158-160 1900 … Karl Landsteiner … eventually found that he could classify the blood from humans into four groups: A, B, AB, and O … (… published in 1936) … the four groups came to be known as A, B, O (universal donors), and AB (universal acceptors) … In time, the blood group system would undergo further refinement … such as Rh-positive (denoting the presence of an inherited protein called Rhesus-factor on the surface of the red blood cells) and Rh-negative … The real trial for blood transfusion … was … World Wars I and II
161 “… Spanish Civil War, World War II, and the Korean conflict.” Perhaps more than any other intervention, transfusion and banking – cellular therapy – stands as the most significant medical legacy of the war
165 Platelets are unusual in their biology right from their birth … megakaryocytes (massive, multi-nuclear-lobe-carrying cells) … broke up … into thousands of little shards – platelets … a healing cell (or, more accurately, cell fragment)
166 In parallel … there was a second, intersecting system in the blood to stop bleeding … a cascade of proteins that float in the blood … The two systems – platelets and clot-making proteins – communicate with each other, each amplifying the effect of the other to form a stable clot
167-168 as much as ancient humans may have desired a drug to activate platelets to heal their wounds, modern humans are in search of drugs that dampen platelet activity. Our lifestyles, lifespans, habits, and environments … have led … to the accumulation of plaques … When a plaque ruptures or breaks, it is sensed as a wound … Platelets rush in to plug that “wound” – except the plug, rather than sealing an injury, blocks the vital flow of blood into the heart muscle
168 “The modern epidemic of heart disease … started quite suddenly in the 1930s …”
168-169 1897 … aspirin, or ASA, short for acetyl salicylic acid … A senior executive at Bayer … almost stopped production … He preferred concentrating on the development of another drug – heroin … As a prevention mechanism for heart attacks, aspirin may well rank among the most important medicines of the past century
171 Many of the crucial proteins that enable the formation, trafficking, and circulation of so-called bad cholesterol are synthesized in the liver
173 “leukocytes,” or white blood cells. (They are “white” only in the sense that they are not “red.”)
174 immune cells moved toward the site of inflammation … impelled by … (… specific proteins, called chemokines and cytokines, released by cells upon injury.)
175 phagocytosis: the engulfment and consumption of an infectious agent by an immune cell … The human versions of the phagocytic cells … macrophages, monocytes, and neutrophils – are among the first cells to respond to injuries and infections
176 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
177 neutrophils, macrophages … “innate immune system.” Innate, in part, because it exists inherently in us, with no requirement to adapt to, or learn, any aspect of the microbe that caused the infection
178 innate immunity has proven difficult to manipulate medically
178 the word vaccine would be coined centuries after vaccination itself was being practiced widely across China, India, and the Arab world
179 As early as AD900, medical healers in China had realized that people who survived smallpox did not catch the illness again … To harness this idea, Chinese doctors harvested a smallpox scab from a patient, ground it into a dry, fine powder, and used a long silver pipe to insufflate it through a child’s nose … By the 1700s, the practice had spread throughout the Arab world
181 the underappreciated fact of vaccination is that it is, at first, a manipulation of the innate immune system … the first step in vaccination is the activation of the first-responder cells: macrophages, neutrophils, monocytes, and dendritic cells
181 the central conundrum of immunology: if you disable the … nonadaptive innate system … you also disable the adaptive B and T cells
182 Vaccination, more than any other form of medical intervention … changed the face of human health. (A close contender might be safe childbirth.) … its history is one of veiled hearsay, gossip, and myth. Its heroes are nameless
183-184 what if we armed these cells with genes that, rather than detecting general patterns of infection, were attuned to a specific protein present only on the surface of, say, a cancer cell? … 2022 – the very first patient, a young woman in Colorado with a deadly cancer of T cells, is being infused with this experimental therapy … It will be months before we know whether the treatment worked
184 Delhi … The monsoons would hit the city in July and August
186 snakebites and smallpox haunted seventeenth-century India … (India still reports eighty thousand snakebites a year, the largest number in the world.)
190 An antibody was a body – a protein – that locked on to another substance. And an antigen was a substance that generated an antibody
190 antibody-making cells were called B cells, after the word bursa … humans … produce B cells primarily in the bone marrow (thankfully, another B), which then mature in the lymph nodes
190-191 two distinct functions of the antibody – antigen binder and immune activator, are combined in one molecule
191-192 In 1940 … Linus Pauling, proposed an answer – an answer so wrong that it would eventually point to the truth … Pauling’s colleagues … by reasoning through what was wrong with the proposal, and why it couldn’t be correct … often found that they could arrive at the real mechanism, the truth
192 In cell biology and genetics – in fact, in most of the biological world – learning and memory typically happen by mutation, not instruction or aspiration
194 B cell … This is not natural selection, but clonal selection: the selection of an individual cell capable of binding an antigen
195 The locus of immunological memory … is a B cell, previously stimulated, that bears the memory of the prior exposure
196 it’s the B cell that makes antibodies, and these antibodies are typically responsible for long-term immunity. (… T cells also contribute to this.)
203 the thymus … the site of maturation for a different kind of immune cell: not a B cell, but a T cell (T for thymus) … T cells were discovered only about fifty years ago … these cells would become the epicenter of one of the defining epidemics in human history
204 [footnote] T cells can recognize only pieces of viral proteins – peptides – loaded on a molecule known as major histocompatibility complex, abbreviated MHC
205 “To understand T cell virology, learn to think like a virus,”
206-207 What do T cells do during an infection? … there are two pathological worlds of microbes. There is an “outer” world of a bacterium or a virus floating outside the cell, in lymph fluid or blood, or in tissues. And there is an “inner” world of a virus that is embedded and living within a cell … what if a virus has taken residence within a cell? … And because antibodies cannot enter cells, how are they to identify one of these rogue cells masquerading as a normal cell? … the cell that could … discern a virus-infected cell from an uninfected one … the … T cell
207 T cells can recognize virally infected cells only if they come from your body, not someone else’s
208 T cells had evolved to recognize self, but an altered self that happens to harbor an infection … Using … a set of molecules called MHC class I
212 The T cell receptor looks like two outstretched fingers. Parts of the two fingers touch the self – that is, the raised hinges of the MHC molecule around the sides of the peptide. And parts of it touch the foreign peptide carried in its groove. Both the self and foreign are recognized simultaneously
213 How do viruses and bacteria present outside the cell activate a T cell response?
214 Once phagocytosed, targeted to the lysosome and degraded, bacteria and viruses are chopped into peptides. And just as the class I MHC molecule frames and presents a cell’s internal peptides to T cells, a related class of proteins – called class II MHCs – presents mostly external peptides to T cells
215 the immune response diversifies … The internal peptides, presented by class I MHCs … are detected by a set of T cells called CD8 killer T cells … In contrast, a majority of peptides derived from pathogens outside the cell … are presented by class II MHCs. These are detected by a second class of T cells, called CD4 T cells.
The CD4 T cell isn’t a killer … Rather, this T cell is an orchestrator
216 Antigen processing and presentation to CD4 and CD8 cells – the mainstays of T cell recognition – are slow but painstakingly methodical processes. Unlike an antibody … Unlike the B cell … There is a duality in the immune system: one recognition system needs no cellular context (B cells and antibodies), while the other is triggered only when the foreign protein is presented in the context of a cell (T cells)
218 acquired immunodeficiency syndrome, acronymed AIDS … was “the first human disease to be characterized by the selective loss of a specific T cell subset, namely, CD4+ T helper/inducer cells.”
219 the new virus caused AIDS. It was christened human immunodeficiency virus, or HIV
219 the CD4 cell … is the central bridge between innate immunity and adaptive immunity – between all the cells of the immune system. The collapse of CD4 cells thus cascades rapidly into a collapse of the immune system in total
222 HIV treatment … is so effective that patients with HIV can live for decades without any sign of the virus – undetectable … They are not cured, but so deeply controlled, with such vanishingly low viral loads, that they cannot infect others
225 HIV … the immune system can be taught to recognize this most devious of pathogens
226 What is the self? … What stops cells from transiting … from one human to another?
226-227 what mechanism exists to ensure that a T cell does not attack its own body? And second … How does a T cell know that a frame carrying the peptide – the MHC molecule – came from its own body, and not from another?
231 H genes, for histocompatibility genes – histo from tissue and compatibility because of the capacity to render foreign tissue to be accepted as self … If organisms showed the H genes, you could transplant tissue from one organism to another … (In humans, they are mostly found on chromosome 6.) … H genes … Most of them turned out to encode functional MHC molecules – the very molecule, recall, that had been implicated in how a T cell recognizes its target… every cell in your body expresses a set of histocompatibility (H2) proteins that are different from the proteins expressed by a stranger’s cells
232 H2 (or HLA) molecules serve two linked purposes. They present peptides to a T cell so that a T cell can detect infections and other invaders and mount an immune response. And they are also the determinants by which one person’s cells are distinguished from another person’s cells, thereby defining the boundaries of an organism
233 rejection … Self and Not-Self … The basis for this tolerance was that T cells that reacted against “self” cells – immune cells that attacked our own … where somehow deleted or removed from the immune system during infanthood or prenatal development … It is one of the philosophical enigmas of immunity that the self exists largely in the negative – as holes in the recognition of the foreign
234 T regulatory cell (T reg) … T cells and T reg cells are anatomically indistinguishable. And yet they are functionally complimentary. Immunity and its opposite are twinned
235 “But there are mountains beyond mountains,” the Haitian proverb runs … there are backup systems beyond backup systems
237 Could a human T cell response be directed against cancer?
238 Cancers, varied as they are, share some common features – among them, their invisibility to the immune system
241 A new class of drugs grew out of this work: antibodies to inhibit CTLA4 and PD-1 among them … Yet these therapies had their limitations
246 2020 … almost a fifth of all human drugs being discovered had something to do with the immune system
246 SARS-COV2
249 Akiko Iwasaki … coronaviruses similar to SARS-COV2 had circulated through human populations for millennia, but none caused this kind of devastation. Some cousin viruses, like SARS and MERS, were deadlier than COV2, but they had been rapidly contained
250 Asymptomatic/presymptomatic transmission. Exponential growth … third … unpredictable, mysterious deadliness
250-251 the medical mysteries of the Covid-19 pandemic … demands … an autopsy of our knowledge about cell biology … TLR7
252 the most severe cases of SARS-COV2 infection … typically men
253-254 Pandemics teach us about epidemiology. But they also teach us about epistemology: how we know what we know … Our understanding of the true complexities of the immune system has been partially shoved back into its black box
255 The pandemic energized immunology, but it also exposed gaping fissures in our understanding … We have learned so much. We have so much left to learn
259-260 For months, during the early, deadening days of the pandemic … What preoccupied me was the collapse of infrastructure and of homeostasis
262 Beyond metaphors, the heart is actually an organ where the belonging and citizenship among cells is of crucial importance … the heart will beat more than two billion times over an average person’s life … The heart is an model of cellular cooperation, citizenship, and belonging
265 “venous” blood … pours into the … right atrium. It then passes through a valve and is moved into … the right ventricle … the right ventricle pumps the blood to the lungs … blood, now … collects in the left atrium … It is then pushed into the left ventricle … that ejects the blood forcefully … to the body, and to the brain
267 there were two systems of interconnected fibers inside a muscle cell: actin and myosin … every heart cell and muscle cell is chock-full of mitochondria to supply the energy required for the two fibers to slide (… it is the release of actin from myosin – not the binding of the fibers – that requires energy. When an organism dies, and the source of energy is lost … The body hardens and contracts into a permanent clasp of death – the phenomenon that we call rigor mortis)
267 [footnote] There are three fundamental kinds of muscle cells in the human body: cardiac muscle … skeletal muscle … and smooth muscle … All three muscles use variants of the actin/myosin system along with a smattering of other proteins, for contractility
268 In its resting state, the heart cell has low levels of calcium. When it is stimulated to contract, calcium floods into a heart cell, and it instigates contraction
270 If the heart is single-minded, then the brain is many-minded
271 the neuron – the most essential unit of the brain’s whole
273-274 It is one of [Santiago Ramón y] Cajal’s legacies that he never performed a single experiment in cell biology … he learned by just seeing … drawing as thinking: an astute observer and draftsman could generate a scientific theory as much as an experimental interventionist … “drawing a conclusion” – illuminates the connection between thinking and drawing
274-275 (… Alessandro Volta, fascinated by [Luigi] Galvani’s experiment, found that the real source of electricity was … the contact between the two metals [iron and bronze] submerged partially in the dead frog’s fluids. In time, Volta would use this idea to devise the first primitive battery)
275 squid … happens to possess one of the largest neurons in the animal kingdom
278 “It takes a courageous person,” the poet Kay Ryan once wrote, “to leave spaces empty”
281 the synapse
282 electrical, chemical, electrical, chemical, electrical
283 “If a subject […] has a glamorous aura, if its practitioners are prizewinners who receive large grants,” the biologist E.O. Wilson once advised, “stay away from that subject.” … exploring the brain, the neuron … and … The glial cell, or glia
284 We are hardwired not to be hardwired, and this anatomical plasticity may be the key to the plasticity of our minds
284-285 Beth Stevens … Ben Barres … In 2007, they … found that glial cells were responsible for this pruning of synaptic connections in the visual system … 2012 … microglia … are the brain’s “constant gardeners,”
286 schizophrenia … Alzheimer’s disease … multiple sclerosis … autism … It’s hard to locate an aspect of neurobiology that doesn’t involve the glial cell
288 [Paul Greengard] … We might … divide the pathologies of the brain into those that affect the “fast” signals (the rapid electrical conduction of neuronal cells), those that affect “slow” signals (the biochemical cascades that are altered in nerve cells), and those that fall somewhere in between … “Depression is a slow brain problem,”
297-298 an organism cannot depend on local communication alone … some signal, or impulse, must move between cells, informing them of the global “state” that the body is inhabiting. The signals move from one organ to the next, carried by blood … We call those signals “hormones,” from the Greek hormone – to impel, or to set some action into motion. In a sense, they impel the body to act as a whole
299-300 1848 … Claude Bernard … coined the concept of “homeostasis” … In 1856 Bernard published … his idea that the pancreas released these juices to enable digestion
301-306 1920, Frederick Banting … Toronto … discovered … insulin … John Macleod … Charles Best … James Collip … They licensed the purified substance to the university and set up a lab to produce more of it to treat patients … In 1923 … Banting and Macleod were awarded the Nobel Prize for the discovery of insulin … The discovery is now widely attributed to Banting and Best
306 Virtually every tissue responds to insulin
306 Type 1 diabetes … Without insulin, the body cannot sense the presence of sugar … It is one of the defining metabolic crises of the human body – cellular starvation in the presence of plenty
309 the pancreas – the central coordinator of metabolism, the maker of the hormone to which all tissues respond
310-311 the kidney … serves as a large filter … one of the strange strategies often used by cells: we generate excess, and then pare it back to restore normalcy
311 Liver cells … have evolved dozens of mechanisms to detoxify and dispense waste
312 The liver, pancreas, brain, and kidney are four of the principal organs of homeostasis
314 Old age … is a maceration – the steady grind of injury upon injury, the unstoppable decline of function into dysfunction, and the inexorable loss of resilience.
Humans counter this decline by two overlapping processes – repair and rejuvenation
316 Macabre as it was, the bombing of Hiroshima provided proof that the human body possesses cells that continuously generate blood
317 stem cells are … a biological paradox. Their two principal functions seem, at face value, to be precisely opposed to each other. On one hand, a stem cell must generate functional “differentiated” cells … But on the other hand, it must also divide to replenish itself – i.e., a stem cell
319-320 In the mid-1950s, two Canadian researchers, Ernest McCulloch and James Till, launched a collaboration to understand the physiology of blood cell regeneration after radiation exposure … they … would open a new frontier in stem cell biology
322 Irving Weissman … “… Till and McCulloch proved … The red cell ‘mother’ and the white cell ‘mother’ and platelet ‘mother’ cell … all arose from the same stem cell … The effect on the field of bone marrow transplantation was extraordinary …”
326 Dottie Thomas … “the mother of bone marrow transplantation.”
329 bone marrow transplants are … now one of the mainstays of cellular therapy
330 more than any other type of stem cell, the two that remain the most fascinating, and most controversial, perhaps, are the embryonic stem cell (ES cell) and its even stranger cousin, the induced pluripotent stem cell (iPS cell)
330-331 “human embryonic stem cells,” or h-ES cells. One of these cells, called H-9 – a “female,” with XX chromosomes – has become the standard ES cell
334 Kazutoshi Takahashi … [Shinya] Yamanaka … The fibroblasts had turned into stem cells … It was as if – presto! – he had turned biological time backward … the field termed these induced pluripotent stem cells, or iPS cells – “induced” because they had been changed, using genetic manipulations, from mature fibroblasts into induced pluripotent cells … Yamanaka … won the Nobel Prize in 2012
335 the Greek story of the Delphic boat. The boat is built of many planks. Bit by bit, the planks decay and are replaced by new ones, until all of them are new. But has the boat changed? Is it even the same boat?
337 the skeleton turns out to represent one of the most elaborately complex of cellular systems
339 The dynamic balance between osteoblasts and osteoclasts – bone makers and bone chewers – is one mechanism by which bone maintains homeostasis … bone begins, in early development, as a matrix of glutinous cartilage. Then it deposits calcium and hardens into the structure that we recognize as bone and begins to grow longer
351 One astonishing feature of cancer is that any individual specimen of cancer has a permutation of mutations that is unique to it
353 The peculiar thing about the rebirth of a cancer cell is that the genetic programs that enable cancer cells to sustain malignant growth are shared, to some extent, with stem cells … (making it … nearly impossible to find a drug that will kill cancer but spare stem cells)
366-368 Rudolf Virchow … His founding tenets of cell biology have expanded into at least ten …
372 Michael Sandel … challenged the human quest for enhancement, basing his argument , ultimately, on what the late theologian William May called “an openness to the unbidded.”
The “unbidded” – the vagaries, or gifts, of chance – Sandel argues, is essential to human nature
373 In 2004, Sandel consolidated his ideas in an essay, “The Case Against Perfection,” which he soon expanded into a book … “… Parents are supposed to cultivate children through unconditional as well as conditional love. Selecting a baby’s sex betrays that relationship.”
373 I used to find Sandel’s argument persuasive – but as the combined forces of genetics and cell engineering extend their reach to touch new depths of the human body and personhood, the “moral landscape” has changed radically