The Song of the Cell

Every cell in a multicellular organism is surrounded by an oily membrane that separates it from other cells and from the extracellular fluid that bathes all cells. The cell surface membrane is permeable to certain substances, thereby allowing an exchange of nutrients and gases to take place between the interior of the cell and the fluid surrounding it. Inside the cell is the nucleus, which has a membrane of its own and is surrounded by an intracellular fluid called the cytoplasm. The nucleus contains the chromosomes, long thin structures made of DNA that carry genes like beads on a string. In addition to controlling the cell's ability to reproduce itself, genes tell the cell what proteins to make to carry out its activities. The actual machinery for making proteins is located in the cytoplasm. Seen from this shared perspective, the cell is the fundamental unit of life, the structural and functional basis of all tissues and organs in all animals and plants.

Besides their common biological features, all cells have specialized functions:

Liver cells, for instance, carry out digestive activities
Brain cells have particular ways of processing information and communicating with one another. These interactions allow nerve cells in the brains to form complete circuits that carry and transform information

From The Song of the Cell by Mukherjee

Introduction

To be living, an organism must have the capacity to:
- to reproduce
- to grow
- to metabolize
- to adapt to stimuli
- to maintain its internal miliau
Complex multicellular living beings also possess emergent properties, which emerge from systems of cells:
- to defend against injury or invasion
- organs with specialized functions,
- physiologic systems of communication between organs
- even sentience and cognition
It is difficult to imagine life without cells, or to imagine cells without life

A cell is an autonomous living unit that acts as a decoding machine for a gene. Genes provide instructions to build proteins, the molecules that perform virtually all the work in a cell. Proteins enable biological reactions, coordinate signals within the cell, form its structural elements, and turn genes on and off to regulate a cell's identity, metabolism, growth, and death. They are the central functionaries in biology, the molecular machines that enable life.
A cell thus transforms information into form, genetic code into proteins. A gene without a cell is lifeless. A cell brings materiality and physicality to a set of genes. But not only that.
Having unpacked the code by synthesizing a select set of proteins that is encoded in its genes, a cell becomes an integrating machine. It uses this set of proteins (and the biochemical products made by proteins) in conjunction with one another to start coordinating its function, its behavior (movement, metabolism, signaling, delivering nutrients to other cells, surveying for foreign objects) to achieve the properties of life. And that behavior, in turn, manifests as the behavior of the organism. The metabolism of the organism reposes in the metabolism of the cell, And the same for the reproduction, repair, survival, and death of the organism
Finally, the cell is a dividing machine. Molecules within the cell - proteins again - initiate the process of duplicating the genome. The internal organization of the cell changes. Chromosomes, where the genetic material of a cell is physically located, divide, and this division drives growth, repair, regeneration, and ultimately, reproduction, among the fundamental, defining features of life.

The Universal Cell

You have to think of a cell as a functional site for all physiological chemical reactions, as an organizing unit for all tissues, and as the unifying locus for physiology and pathology.
You have to move from a continuous organization of the biological world to a description that involves discontinuous, discrete, autonomous elements that unify the world:
- See past flesh (continuous, corporeal, visible)
- To blood (invisible, corpuscular, discontinuous)

Raspail - "A cell is a kind of laboratory" - it enables physiology
Virchow - "The body is a cell state in which every cell is a citizen."

Tenets of cell theory:

All living organisms are composed of one or more cells
The cell is the basic unit of structure and organization in organisms
All cells come from other cells
Normal physiology is the function of cellular physiology
Disease, the disruption of physiology, is the result of the disrupted physiology of the cell

The Pathogenic Cell

Germ theory - microbes are independent, living cells capable, in some cases, of causing human illnesses
Bacterial cells, Pasteur concluded, are carried in air and dust. Putrefaction or rotting was not caused by the inner decomposition of living creatures - or some visceral form of interior sin. Rather decomposition only happened when these bacterial cells landed on the broth.
Infections were invasions by microbes - single-celled organisms that entered other organisms and caused pathological changes and tissue degeneration

Antibiotics recognize some molecular component of hyman cells that is different from a bacterial cell. They are cellular medicines, drugs that rely on the distinctions between a microbial cell and a human cell.

Every cell on earth belongs to one of three branches:

Bacteria - single-celled organisms that are surrounded by a cell membrane, lack particular cellular structure found in animal and plant cells and possess other structure that are unique to them.
- They are ferociously successfully and dominate the cellular world. Not just pathogens - our skin, guts, mouths are teeming with several billion bacteria that cause not disease whatsoever. Humans are just "nice-looking luggage to carry bacteria around the world".
- They live in the hottest and coldest parts of the world. They are autonomous, mobile, communicative, and reproductive
Eukaryotes - cells containing a nucleus, which is a storage site for chromosomes (bacteria are prokaryotes - before nuclei).
- We and other eukaryotes are feeble, finicky beings capable of living in vastly more limited environments and restricted ecological niches
Archaea - They look like bacteria, are tiny and lack some of the structures associated with animal and plant cells. Recently established as a separate domain, we know relatively little about them

The history of the cell:

The first cells arose on Earth some 3.5-4bn yeats ago, about 700m years are the birth of the Earth.
The simplest cell (a protocell) had to possess a generic information system that could reproduce itself. This was probably made of RNA.
Two RNA molecules were probably needed - a template and a duplicator - and they had to avoid separation, so some sort of structure - a spherical membrane, was likely needed to confine them. These three components may have been the first cell
At first the RNA would duplicate within the confines of the sphere, but at some point it would grow too big and split in two.
Then evolution would select more and more complex features of the cell, eventually replacing RNA with DNA as the information carrier.
Bacteria evolved out of that simple progenitor about 3bn years ago and they continue to evolve today. Archaea are probably at least as old as bacteria
About 2bn years ago, evolution took a strange and inexplicable turn, when a cell that is the common ancestor of human cells, plant cells, fungi cells, animal cells, and amoebal cells appeared on Earth.
This ancestor was recognizably a "modern" cell, with an exquisite internal structure and unprecedented molecular dynamism, all driven by sophisticated nanomachines encoded by thousands of new genes that are largely unknown in bacteria.
New evidence suggests that this "modern" eukaryotic cell arose within archaea, so that we are a relatively recent sub-branch of archaea.

The Organized Cell

The membrane:

Has two layers of lipids
Proteins are embedded in the membrane, like hatches or channels

The protoplasm/cytoplasm:

is a mind-bogglingly complex soup of chemical
It has a molecular "skeleton" that maintains the form of the cell and is called the cytoskeleton. It is made of actin and tubulin which form tubular structures and tethers components of the cell together.

The ribosome:

Is a massive macromolecular structure, a multipart assemblage.
It captures RNAs and decodes their instructions to synthesize proteins

Proteins:

Are the workhorses of the cell.
they create structural components, are receptors for signals from outside, form pores and channels across the membrane, and are the regulators that switch genes on and off in response to stimuli.
Building proteins is one of the cell's main tasks.

Organelles:

Are mini organs found inside cells

The mitochondria:

Are organelles that are the cells fuel generators - maybe originally microbrial cells that developed the capacity to produce energy via a chemical reaction involving oxygen and glucose, and which were engulfed or captured by other cells:
They are found in all cells, but are particularly dense in muscle cells, fat cells, certain brain cells, and other cells that need the most energy or regulate energy storage.
They are wrapped around the tails of sperm to provide swimming energy. They have no autonomous life and can live only within cells.
They produce energy through an aerobic reaction, breaking down sugar and feeding the result into a cycle of reactions to make ATP (adenosine triphosphate), which is the central currency of energy in virtually all living cells. There is a faster, but less efficient anaerobic production of ATP, which happens directly in the protoplasm.

The endoplasmic reticulum (ER):

Is an organelle that is a maze of winding, tortuous pathways.
Acts as a postal system. RNA is translated into a protein by the ribosome and then pushed into the ER, which sends it to the Golgi apparatus, which routes it to its final destination in the cell

The nucleus:

Is an organelle that is found in all plant and animal cells (but not in bacteria)
Is the storage bank for DNA, for the genome
Proteins enter through the pores of the nuclear membrane and bind to the DNA and turn genes on and off.
The set of on/off genes instructs a neuron to be a neuron and a white cell to be a white cell.
During the development of an organism, genes - or rather proteins encoded by genes - tell cells about their relative positions and command their future fates.
Genes are turned on and off by external stimuli such as hormones, which also signal changes in a cell's behavior.

Claude Bernard in the 1870 shifted physiology's focus from action to the maintenance of fixity. A major point of physiological activity, paradoxically, was to enable stasis. Don't just do something, stand there! - homeostasis.

The Dividing Cell

Every cell is the product of birth from another cell
Not every cell is capable of reproducing - some cells, such as neurons, have undergone permanent division and will never divide again
Mitosis (from the Greek for thread) is the process of dividing to produce new cells to build organs and tissues
Meiosis (from the Greek for lessening) is the birth of new cells, sperm, and eggs for the purpose of reproduction - to make a new organism

The lifecycle for a multicellular organism is a back and forth between meiosis and mitosis:

Humans start with 46 chromosomes in every bodily cell and produce sperm cells in the testes and egg cells in the ovaries via meiosis, each ending up with 23 chromosomes
When sperm and egg meet to form a zygote, the number of chromosomes is restored to 46
The zygote grows through cell division, mitosis, to produce the embryo, and then develops progressively mature tissues and organs - heart, lungs, blood, kidneys, brain - with cells that have 46 chromosomes each
As the organism matures, it eventually develops a gonad (testes or ovaries), with 46 chromosomes in each cell
When the cells in the gonads make male and female reproductive cells, they undergo meiosis, generating sperm and eggs with 23 chromosomes each
Fertilization restores the number to 46. A zygote is born and the cycle repeats. Meiosis, mitosis, meiosis. Halve, restore, grow. Halve, restore, grow.

The division of cells goes in phases:

G0 - The resting cycle, quiescent. Some cells will never divide, they are post-mitotic. Most mature neurons are good examples
G1 - The cell decides to divide and prepares for division.
S - From synthesis of duplicate chromosomes. The chromosomes are duplicated
G2 - A second resting phase, a final checkpoint before division, where the cells checks the fidelity of its DNA replication. A cell showered with DNA-damaging radiation or chemotherapy might halt at this stage. Proteins called the Guardians of the Genome, including the p53 tumor suppressor, scan the genome and the cell to ensure its health before generating new cells
M - for mitosis. The nuclear membrane dissolves, the molecular apparatus to pull apart the duplicated chromosomes is fully assembled, they are separated and the cytoplasm of the cell is halved. The mother cell generates two daughter cells.

The Tampered Cell

In Down syndrom an extra chromosome - number 21 - is left over in the egg or sperm cell.
Gene editing - making directed, deliberate, and specific changes in a genome - is most commonly done using a bacterial protein called Cas9, which is introduced into human cells and then "guided" to a specific part of a cell's genome to make a deliberate alteration: typically a cut that usually disables the targeted gene. Bacteria use this system to chop up the genes of invading viruses, thereby inactivating the invader.
Cas9, when combined with a piece of RNA to guide it, can be directed to make a deliberate change in the human genome. It's like finding and erasing one word in one sentence on one page in one volume in an 80k book library. Recently, it has been modified to implement a vast array of potential changes in a gene, such as adding new information or making more subtle alteration.

Multicellularity is ancient. It evolved independently, and in multiple different species many, many times. Collective existence - above isolation - was so selectively advantageous that the forces of natural selection gravitated repeatedly toward the collective.
Specialization and cooperativity conserve energy and resources allowing new, synergistic functions to develop. One part of the collective can handle waste disposal, for example, while another acquires food. Multicellularity may have evolved to support larger sizes and rapid movement, allowing the organism to escape predation or to make faster coordinated movements toward weak gradients of food.

The Developing Cell

The zygote, floating in the womb, divides into two, then four, and so on until a small ball of cells is formed
Cells keep dividing and moving until the mass starts to hollow out within and become a blastocyst. The outer wall will attach to the maternal womb and become part of the placenta, the membranes around the fetus, and the umbilical cord. The inner wall will develop into the human fetus.
The inner cells mass starts to form two layers of cells, the outer ectoderm and the inner endoderm, and after three weeks a third layer lodges between them, the mesoderm. This three-layered embryo is the basis of every organ in the human body:
- The ectoderm will become the outer surface - skin, hair, nails, teeth, the lens of the eye
- The endoderm becomes the inner surface - the intestines and the lungs
- The mesoderm handles everything inbetween - muscle, bone, blood, heart.
Within the mesoderm, a series of cells assemble along a thin axis to form a rodlike structure called the notochord, which spans from the front of the embryo to its back. This becomes the GPS of the embryo, determining the position and axis of the internal organs as well as secreting proteins called inducers. Just above the notochord, a section of the ectoderm invaginates, folding inward and forming a tube, which will become the precursor of the nervous system - the brain, spinal cord, and nerves. It loses its function during childhood and its only remnant in the adult body is the pulp stuck between the skeletal bones - the notochord is trapped inside the bony prison of the very creature it has created.
Once the notochord and the neural tube have been generated, individual organs begin to form out of the three layers - the primitive heart, the liver bud, the intestines, the kidneys.
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.
The growth of an embryo is a process, a cascade. At each stage, preexisting cells release proteins and chemicals that tell the newly emerging and newly migrating cells where to go and what to become. They command the formation of other layers and, later, the formation of tissues and organs. And the cells within these layers themselves turn genes on and off, in response to location and their intrinsic properties, to obtain their self-identities. One stage builds upon signals emerging from a prior stage - the tumble of epigenesis that early embryologists had captured so vividly.

Thalidomide - a sedative medecine developed in the 1950s, caused sever congenital malformations - some babies were born with severely shortened or absent limbs. It bound to one or several of the proteins in the cells that directed the development of the embryo thus altering or destroying the instructions.

The Restless Cell (Red Blood Cells)

Red cells, while cells, platelets
Normal white cells have two main forms: lymphocytes and leukocytes
Leukemia is a cancer of white blood cells.
Blood is the central mechanism of long-distance communication in humans. It transmits hormones, nutrients, oxygen, and waste products. It connects to and talks to every organ and allows communication between one organ and others.
90% of the wight of a red cell is hemoglobin, which carries oxygen (bound in iron). Its main purpose is to ferry oxygen to tissues in all the body's organs.
In addition to cells, plasma, the fluid component of blood, carries other materials crucial to human physiology: carbon dioxide, hormones, metabolites, waste products, nutrients, clotting factors, and chemical signals
Blood groups were worked out in the 1930s:
- A - Can accept from other As or from Os
- B - Can accept from other Bs or from Os
- O - Universal Donors. Can donate to anyone but can only accept from other Os
- AB - Universal Acceptors. Can accept from anyone but can only donate to other ABs

The Healing Cell (Platelets)

1912 - Coining of the term "heart attack" for when the artery bringing blood to the heart is blocked by a clot
1897 - invention of aspirin. In the 1960s, we learned that it blocks an enzyme that produces injury-sensing chemicals, and therefore decreases platelet activation and subsequent clots.

The Guardian Cell (White Blood Cells)

White blood cells do not contain hemoglobin, have nuclei, and are irregularly shaped
Inflammation and immune response - the recruitment of immune cells to the site of injury, and their activation once they have detected a foreign substance.
The immune cells move toward the site of inflammation autonomously (attracted by chemokine and cytokine proteins released by the injured cells)
Once there, they try to eat the infectious agent or irritant - phagocytosis - the engulfment and consumption of an infectious agent by the immune cell
Multicellular organisms have been at war with microbes throughout evolutionary history to such an extant that we have defined each other. Our first-responder immune cells carry pattern-recognition receptors that are inherently designed to latch on to molecules found in microbial cells or injured cells that are not specific to a particular pathogen, but are broadly present in all bacteria and viruses. They sniff around the body looking for patterns of injury and infection - substances that signal invasion and pathogenicity.
The "innate immune system" is the oldest part of the immune system, and some form of it is found in virtually all multicellular creatures.
We associate immunity with B and T cells or with antibodies, but without neutrophils and macrophages, we would meet the fate of the decomposing fly.

As early as AD 900, medical healers in China had realized that people who survived small pox did not catch the illness again, thus making them ideal caregivers for those suffering from the disease. It is as if the body retained a "memory" of the initial exposure.
Chinese doctors started to vaccinate children by harvesting some pox, grinding it up and blowing it in the child's nose. The dose had to be right - if too much then the child would simply catch the disease.
By the 1700s, the practice had spread throughout the Arab word and became known as "buying the pox".
In 1775, the term "immunity" is coined.
The term "vaccine" comes from cowpox, with vacca being latin for cow.

The Defending Cell (B Cells)

The terms "antitoxin" and "antibody" coined in 1890s. An antibody was a body - a protein - that locked on to another substance. And an antigen was a substance that generated an antibody.
Our bodies produce B cells primarily in the bone marrow, which then mature in the lymph nodes.
If the structure of antibodies was malleable then the genes that encoded them must also be malleable - by mutation.
In cell biology and genetics - in fact in most of the biological world - learning and memory typically happen by mutation, not instruction or aspiration.
When the connection is made, and a particular lymphocyte with a particular receptor is brought into the presence of the particular antigen, one of the greatest small spectacles in nature occurs. The cell enlarges, begins making new DNA at a great rate and turns into what is termed, appropriately, a blast. It then begins dividing, replicating itself into a new colony of identical cells all labeled with the same receptor. In the end, the dominant B cell clones, displaying the "right" receptor (the one that best binds the antigen) blast away, outgrowing all others. It is a Darwinian process, much like the finch with the right beak is "chosen" by natural selection.
These blasts now begin to secrete the receptor into the blood. Freed from the B cell's membrane and now floating in the blood, the receptor "becomes" the antibody. And when the antibody is bound to its target, it can summon a cascade of proteins to poison the microbe and can recruit macrophage to devour, or phagocytose, it. Decades later, researchers demonstrated that some of the activated B cells don't simply peter out. They persist in the body in the form of memory cells. The new cluster of cells stimulated by the antigen is a memory, no less. Once the fulminant infection has ceased and the microbe cleared, some of these B cells become more quiescent, but they persist - finches huddled in the cave. When the body encounters the antigen again, the memory B cell is reactivated. It arises out of dormancy into active division to mature into an antibody-making plasma cell, thereby encoding an immunological memory. The locus of immunological memory, in summary, is not a protein that persists. It is a B cell, previously stimulated, that bears the memory of the prior exposure.
Ultimately the B cell matures into a cell so single-mindedly dedicated to antibody production that its structure and metabolism are altered to facilitate the process. It is now a cell dedicated to making antibodies - a plasma cell. Some of these plasma cells also become long lived and retain the memory of the infection.

The Discerning Cell (T Cells)

The thymus is a gland that sits above the heart.
What do T cells do during an infection? There are tow pathological worlds of microbes, an outer world of a bacterium or a virus floating outside the cell, in lymph fluid or blood, or in tissues, and an inner world of a virus that is embedded and living within a cell.
This is what viruses do. They go native and because antibodies cannot enter cells, we need a cell that can discriminate the self from the nonself.
T cells can't get inside cells.
The job of the helper T cell is to bridge the innate and adaptive immune system - macrophages and monocytes on one end, and B and T cells on the other.
Unlike an antibody, a gunslinging sheriff itching for a showdown with a gang of molecular criminals in the center of town, a T cell is the gumshoe detective going door to door to look for perpetrators hiding inside.
In the immune system there is a recognition system that 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). So viruses and bacteria are not just cleared from the blood by antibodies but are also cleared from infected cells where they could otherwise be harbored safely, by T cells.

On June 5, 1981, AIDS was first recorded in a CDC report. It was named in July 1982. It attacks cellular immunity, killing the very system designed to kill it. The virus is called Human Immunodeficiency Virus (HIV).
The CD4-positive T cellls is the central bridge between innate immunity and adaptive immunity.

The Tolerant Cell (T Cells II)

Every cell in your body expresses a set of histocompatibility (H2) proteins that are different from the proteins expressed by a stranger's cells.
Graft rejection (likely important for primitive organisms) and invader recognition (important for complex, multicellular organisms) are thus combined into a single system. Both functions repose in the T cell's capacity to recognize the MHC peptide complex, or the altered self.
The self is defined, in part, by what is forbidden to attack it. Biologically speaking, the self is demarcated not by what is asserted but by what is invisible: it is what the immune system cannot see.
T cells are born in the bone marrow as immature cells and migrate to the thymus to mature.
T cell deletion in the thymus - a mechanism called central tolerance because it affects all T cells during their central maturation - isn't enough to guarantee that immune cells don't end up attacking the self. There is a further phenomenon called peripheral tolerance; here tolerance is induced once the T cells have left the thymus
The Tcell, which confers active immunity and incites inflammation, and the regulatory T cell, which dampens these processes arise from the same parent cells: T cell precursors in the bone marrow. Immunity and its opposite are twinned: the Cain of inflammation conjoined with the Abel of tolerance.
There are multiple safety switches to prevent T cells attacking normal cells.

Cancers are invisible to the immune system. Cancer is a distorted version of our normal selves. To attack a cancer, one has to make it re-visible to the immune system and that system must find some determinant in the cancer that can enable an attack, without concomitantly destroying the normal cell.

Blood. A cosmos of cells:
- The restless ones: red blood cells.
- The guardians: multilobed neutrophils that mount the first phases of the immune response.
- The healers: tiny platelets - once dismissed as fragmentary nonsense - that redefined how we respond to breaches in the body.
- The defenders, the discerners: B cells that make antibody missiles, T cells, door-to-door wanderers that can detect even the whiff of an invader, including possibly, cancer.
It is a conglomerate of organs, a system of systems.
It has built training camps for its armies (lymph nodes), highways and alleys to move its cells (blood vessels).
It has citadels and walls that are constantly being surveyed and repaired by its residents (neutrophils and platelets).
It has invented a system of identification cards to recognize its citizens and eject intruders (T cells) and an army to guard itself from invaders (B cells).
It has evolved language, organization, memory, architecture, subcultures, and self-recognition. Perhaps we might think of it as a cellular civilization

The Pandemic

The gene TLR7 (Toll-Like Receptor 7) is one of the key detectors of viral invasion.
The virus was most deadly when it infected a host whose early antiviral response had been functionally paralyzed - like a raider that had come into an unlocked house. The pathogenicity of SARS_COV2 perhaps lay precisely in its ability to dupr cells into believing that it is not pathogenic.

If you mount a robust innate immune response during the early phase of infection, you control the virus and have a mild disease. If you don't, you have uncontrolled virus replication in the lung that fuels the fire of inflammation leading to severe disease.

Cellular specialization and citizenship - the hallmark of the cell biology of an organ - result in the profound "emergent" properties of human physiology - ie properties that can only emerge when multiple cells coordinate their functions and work together. A heartbeat. A thought. And the restoration of constancy - the orchestration of homeostasis.

The Citizen Cell (Heart)

The heart will beat more than 2bn times over an average person's life.
The heart is two pumps:
- The right-sided pump (veins to heart to lung) collects blood from the veins of the body. Exhausted and depleted, having delivered oxygen and nutrients to the organs, "venous" blood (often darker red than bright crimson) pours into the upper right chamber called the right atrium. It then passes through a valve and is moved into the pumping chamber, the right ventricle. A powerful heave from the right ventricle pumps the blood to the lungs.
- The lungs, having received blood from the right side of the heart, oxygenate the blood and clear the carbon dioxide. Replete with oxygen and cleansed, blood, nos a vivid crimson, moves to the left side. It collects in the left atrium of the heart. It si then pushed into the left ventricle. It is this left ventricle, perhaps the most tireless muscle in the body, that ejects te blood forcefully into the wide arc of the aorta, the major blood vessel that carries oxygenated blood to the body, and to the brain.

There are two systems of interconnected fibers inside a muscle cell: actin and myosin
Each muscle cell has thousand of ropes - bands of actin in parallel with bands of myosin. As the ropes, lines side by side, slide against each other - clutch, pull, release - the edges of the cell are also yanked, and the cell is dragged into a contraction. The process requires energy, of course, and every heart cell and muscle cell is chock-full of mitochondria to supply the energy required for the two fibers to slide.
There are three fundamental types of muscle cells:
- cardiac muscle
- skeletal muscle (that moves your arms on command)
- smooth muscle (that moves involuntarily, but consistently, allowing say liquid in the intestines to keep moving
Heart cells are connected to each other through minuscule molecular channels, called gap junctions. Every cell is inherently designed to communicate with the rest. Although many, they behave as one. When a stimulus to contract is generated in one cell, it automatically travels to the next cell, resulting in its stimulation, and ultimately resulting in contraction in unison.

The Contemplating Cell (Neuron)

Neurons possess a cell body - the some - from which sprout dozens, hundreds, or even thousands of branch-like projections called dendrites. And they possess an outflow tract - an "axon" - that extends to the next cell, which is separated from the second neuron by an intervening speace - the synapse. The nervous system is wired, but the wires consist of cells connected to cells connected to cells with intervening spaces between them.
Information travels unidirectionally. The dendrites receive the impulse, which is then moved through the cell body, out through the axon, through the synapse to the next nerve cell
Nerve cells chatter with each other - collecting inputs via dendrites and generating outputs via the axon, and this intercellular chatter gives rise to the profound properties of the nervous system: sentience, sensation, consciousness, memory, thinking, and feeling.
Chemical transmitters are stored in vesicles (membrane-bound sacs) at the end of the axon.
The synapse can not just excite the neuron to fire, but can also be an inhibitory synapse, making the next neuron less prone to excitation. A single neuron can thus have positive inputs and negative inputs from other neurons. Its job is to integrate these inputs and his integrated total of excitatory and inhibitory inputs determines whether a neuron will fire or not.

Glial cells are present all over the nervous system - in about the same number as neurons. They don't generate electrical impulse but they are extraordinarily diverse in structure and function.
Synaptic pruning is thought to involve the paring back of structures, eliminating the synaptic connection at that site - akin to removing, or cutting the soldering joint between two wires. Our brains make connections in vast excess, and then we pare back the excess
The secret of learning is the systematic elimination of excess. We grow mostly by dying. We are hardwired not to be hardwired, and this anatomical plasticity may be the key to the plasticity in our minds.
Specialized cells known as microglia - spidery and many-fingered - had been seen crawling around the brain, scrounging for debris, and their role in eliminating pathogens and cellular waster had been known for decades. But they are also found coiled around synapses that have been marked for elimination. They nibble at the synaptic connections between neurons and pare them away. They are the brain's constant gardeners.
Microgiglia use proteins and processes to mark synapses to be nibbled and ingest the bits of a neuron involved in the synaptic connections. The very proteins and pathways that are used to clear pathogens in the body have been repurposed to fine-tune connections between neurons. Microglia have evolved to "eat " pieces of our own brain.
Synapses compete against each other and the strongest synapse wins.
Dysfunctions in glial pruning may be related to schizophrenia - a disease where pruning doesn't occur appropriately. Maybe also Alzheimers, multiple sclerosis, and autism.

An electrical impulse arrives at the end of the neuron - the axon terminal - and causes the release of chemical neurotransmitters into the synapse. These chemicals, in turn, open channels in the next neuron, and ions surge in, reinitiating the impulse. This is the fast electrical brain.
But the chemical signals also create a cascade of slow signals in the neuron. Neuronal signaling instigates profound biochemical and metabolic changes in the recipient cell causing alterations in metabolism, in gene expression, and in the nature and concentration of chemical transmitters that are secreted into the synapse. And these slow changes in turn alter the electrical conduction of an impulse from nerve to nerve.
We might divide the pathologies of the brain into those that affect the fast electrical signals, those that impact the slow biochemical cascades, and those that fall in between
In the 1950s, there was the idea that depression was caused by a lack of serotonin in the synapse so that the electrical circuits don't get enough stimulation. But not everyone responds to SSRIs.
The Brodmann area 25 (BA25) is an area of the brain that seems to regulate emotional tone, anxiety, motivation, drive, self-reflection, and sleep - all of which are dysregulated by depression.
When this area is stimulated with Deep Brain Stimulation (DBS) patients spontaneously reported acute effects including sudden calmness or lightness, disappearance of the void, sense of heightened awareness, increased interest, connectedness and sudden brightening of the room. One woman described her illness as a complete incapacity to feel emotional, or even sensory connections.
When we turn the DBS on, patients want to move again, but the activities that they want to do involve cleaning out rooms. Taking the trash out of the kitchen. Washing dishes.

The Orchestrating Cell (Pancreas, Kidney, Liver + Hormones)

There must be a means for one part of the body to "meet" a distant part of the bodfy. We call these signals "hormones" from the Greek hormon - to impel, or to set some actions into motion. In a sense, they impel the body to act as a whole.
Hormones are molecules that are produced by endocrine glands, including the hypothalamus, pituitary gland, adrenal glands, gonads, (i.e., testes and ovaries), thyroid gland, parathyroid glands, and pancreas.
The pancreas is a gland that releases juices into the digestive system, where they break down complex food molecules into simple ones. It contains the islets of Langerhans, which produce a range of hormones, including glucagon, somatostatin, and ghrelin.
Insulin is the master regulator of sugar metabolism. It is synthesized in the pancreatic beta cells, and its secretion is stimulated by the presence of glucose in the blood. It then travels all over the body. Virtually every tissue responds to insulin: the presence of sugar means that the extraction of energy, and everything that flows from energy - the synthesis of proteins and fats, the storage of chemicals for future use, the firing of neurons, the growth of cells - can proceed. It is, perhaps, among the most important of the "long range" messages that acts as a central coordinator and orchestrates metabolism all through the body.
Type 1 diabetes is a disease in which immune cells attack the beta-islet-cells of the pancreas. Without insulin, the body cannot sense the presence of sugar. The cells in e body, imagining that the body has no sugar, begin to scramble around for other forms of fuel. The sugar, meanwhile, spikes threateningly in the blood, and spills into the urine - cellular starvation in the presence of plenty.
The pancreas is the central coordinator of metabolism, the maker of the hormone to which all tissues respond.

After dinner at a pizzeria:

The carbohydrates from the bread and rigatoni are digested into sugars - ultimately into glucose. The glucose is packed up from the intestines, absorbed into blood and moved into circulation. When the blood reaches the pancreas, it sense the spike in glucose, and sends out insulin. The insulin, in turn, moves the sugar from the blood into all the cells of your body, where it can be stored, if needed, or used for energy, as needed. The brain is the ultimate recipient of these signals: if the sugar drops too low, it reacts by sending out converse signals. Yet other hormones, secreted by different cells, send signals to release stored sugars into the blood. The stores come from liver cells, which respond, at least transiently, by releasing their stockpiles of stored glucose to restore equilibrium.

The kidney contains the nephron, which is the site where the blood and kidney cells meet, and the first drops of urine are generated. The circulation of blood carries the excess salt, dissolved in plasma to the kidneys.
The excess sodium causes a hormonal system, regulated by the kidney and the adrenal gland, which sits just above the kidney, to decrease its signal. The cells in the tubule respond to these changes by excreting the excess sodium into urine, thereby discarding the salt and returning the sodium level to normal. The salt is also detected by specialized cells in the brain that monitor the overall concentration of salts in the blood, a property called osmolality.*
The non-waste products? The sugar and other essential products are reabsorbed into the body by the cells in the collecting duct through special channels. We generate excess, and the pare it back to restore normalcy.

The alcohol is treated by the cells of the liver - hepatocytes. Liver cells are specialized for both storage and waste disposal, secretion, protein syntheses, etc.
We think of metabolism as a mechanism to generate energy. But it's also a mechanism to generate waste. The kidney dispenses some of this through urine, but the kidney is not a detoxifying plant: its master plan for waste is to merely wash it away down a sewer.
Liver cells, in contrast, have evolved dozens of mechanisms to detoxyfy and dispense waste. Alcohol is detoxified in a series of reactions, until it is broken down into a harmless chemical

The pancreatic cell maintains metabolic constancy, the kidneys salt constancy, the liver chemical constancy.
The liver, pancreas, brain, and kidney are four of the principal organs of homeostasis. The pancreatic beta cells control metabolic homeostasis through the hormone insulin. The kidney's nephrons control salt and water, maintaining a constant level of salinity in the blood. The liver, among many of its functions, prevents us from being soused in toxic products, including ethanol. The brain coordinates this activity by sensing levels, sending out hormones, and acting as a master orchestrator of balance-restoration.

The Renewing Cell (Stem Cells)

On the one hand, a stem cell must generate functional "differentiated" cells; a blood stem cell, for instance, must divide to give rise to the cells that form the mature elements of blood - white cells, red cells, platelets. But it must also divide to replenish itself, ie a stem cell
A totipotent cell can give rise to all types of cells
A pluripotent cell can five rise to nearly all cell types
A multipotent cell can give rise to all cell types in a particular kind of tissue.
A single stem cell can produce billions of mature red and white cells - and an entire organ system of an animal.
Human embryonic stem cells (h-ES cells) come from embryos discarded from IVF procedures.
In 1998, James Thomson extracted cells from inside these embryos and grew five human cell lines - three "males" and two "females". One of these, H-9, a female, has become the standard ES cell, grown in thousands of incubators in undreds of labs around the planet, and subject to tens of thousands of experiments.
In 2001, Bush restricted federal funding to research involving ES cells that had already been derived (such as H-9)
There are now iPS cells (induced pluripotent stem cells) changed, using generic manipulations, from mature fibroblasts into induced pluripotent cells. The ides is you take your own cell, from your skin or blood and make it crawl backward in time and transfom it into an iPS cell, from which you can make any cell - cartilage, neurons, T cells, pancreatic beta call, without any problems of histocompatibility, because they are your own cells.

The Repairing Cell (Bone)

The skeleton grows to a point, and then knows when to stop growing. It heals itself continuously throughout adult life and repairs itself acutely after injury. It responds with sensitivity to hormones; it potentially even synthesizes its own hormones.
It might look like a chunk of hardened calcium, but bone is in fact made of a multiplicity of cells:
- Cartilage cells - chondrocytes
- Osteoblast - deposits calcium and other proteins to form a calcified matrix in layers, and then get trapped in its own deposit to form new bone. It is the bone-making, bone-depositing cell.
- OSteoclast -are large cells with multiple nuclei that are bone eaters. They chew away on the matrix, or puch holes in it, removing and remodeling bone like constanly pruning gardeners
There are cells at the ends of a bone - but not in its middle - that generate new cells that lengthen it.
How does bone grow during adolescence? A special population of cells, sitting at the growth plate at the two ends of bone, shoots off cartilage and osteoblasts that allows bone to lengthen. And why does it stop growing? Because this population diminishes over time, until early adulthood, when very few are left.
Why doesn't cartilage in joints get repaired, just as a bone fracture does, in adults? Because the repairing cells die during the injury.
There are other organs where damage, once done, is permanent. Neurons in the brain and the spinal cord, once they've stopped dividing, don't divide to regenerate neurones (they are post-mitotic, ie no longer able to divide).

The Selfish Cell (Cancer)

A cut on your hand shows homeostasis at work. Blood leaks out. Platelets and clotting factors, induced by the tissue damage, gather around the wound. Neutrophils, sensing a danger signal, accumulate at the site as first responders to infection. They stand guard to ensure that pathogens don't get a chance to breach the boundaries of the self. A clot forms, and the wound is temporarily plugged.
Then the healing begins. If the wound is shallow, the two ends of skin appose against themselves. If the wound is deep, fibroblasts from under the skin, crawl in to deposit a protein matrix underneath the wound. And then skin cells proliferate over the matrix to cover the wound, occasionally leaving a scar. Once they touch each other, the cells stop dividing. It takes a host of cells to coordinate this process. The wound has healed.

In cancel, cell division is dysregulated - jammed accelerator genes and snapped brakes. The cars speed through the traffic jam, piling up on each other and causing tumors. Or they frantically move into alternate routes, causing metastasis.
The jammed accelerators are called oncogenes. The snapped brakes are called tumor suppressors
Any individual specimen of cancer has a permutation of mutations that is unique to it.
The genetic programs that enable cancer cells to sustain malignant growth are shared, to some extent, with stem cells
A tiny fraction of the bulk of leukemia cells in the marrow are capable of regenerating the whole leukemia from scratch.

The Songs of the Cell

All cells come from cells.
The first human cells gives rise to all human tissues. Every cell in the human body can be produced, in principle, from an embryonic cell (or stem cell)
Although cells vary widely in their form and function, there are deep physiological similarities that run through them.
These similarities can be repurposed by cells for specialized functions. An immune cell uses its molecular apparatus for ingestion to eat microbes; a glial cell uses similar pathways to prune synapses in the brain.
Systems of cells with specialized functions, communicating with each other through short and long-range messages, can achieve powerful physiological functions that individual cells cannot achieve - for example, the healing of wounds, the signaling of metabolic states, sentience, cognition, homeostasis, immunity. The human body functions as a citizenship of cooperating cells. The disintegration of this citizenship tips us from wellness to disease.
Cellular physiology is thus the basis for human physiology, and cellular pathology is the basis for human pathology.
The process of decay, repair, and rejuvenation in individual organs are idiosyncratic. Specialized cells in some organs are responsible for consistent repair and rejuvenation (blood rejuvenates through human adulthood, albeit at diminished rates), but other organs lack such cells (nerve cells rarely rejuvenate). The balance between injury/decay and repair/rejuvenation ultimately results in the integrity or defeneration of an organ.
Beyond understanding cells in isolation, deciphering the internal laws of cellular citizenship - tolerance, communication, specialization, diversity, boundary-formation, cooperation, niches, ecological relationships - will ultimately result in the birth of a new kind of cellular medicine.
The capacity to build new humans out of our building blocks - cells - lies very much within ghe reach of medicine today. Cellular reengineering can ameliorate, or even reverse, cellular pathology.
Cellular engineering has already allowed us to rebuild parts of humans with reengineered cells. As our understanding grows, new medical and ethical conundrums will arise, intensifying and challenging the basic definition of who we are, and how much we wish to change ourselves.