Red blood cell

• 1. Introduction

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  Red blood cells carry roughly 270 million hemoglobin molecules each, and yet each cell is smaller than most other human cells. They circle the entire body in about 60 seconds. At any given moment, an adult human carries somewhere between 20 and 30 trillion of them, and they make up approximately 84% of every cell in the human body. Nearly half of the blood's total volume, between 40% and 45%, is nothing but these cells. The questions the rest of this documentary will explore are: how does something so small and so stripped down do so much, what exactly happens inside these cells at the molecular level, how did scientists come to understand them, and what goes wrong when they fail?

• 2. The Shape of a Workhorse

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  A typical human red blood cell measures roughly 6.2 to 8.2 micrometers across and no more than 2.5 micrometers at its thickest point. The shape is a biconcave disk, flat and slightly indented at the center, with a dumbbell-like cross section. That geometry is not arbitrary. It maximizes the surface area relative to the cell's volume, which speeds up the exchange of gases across the membrane.

  Mammals are unusual among vertebrates for producing red blood cells that, when mature, have no nucleus at all. During early development, the cells do carry a nucleus, but they eject it as they mature. The organelles go too: mitochondria, the Golgi apparatus, and the endoplasmic reticulum all disappear. What remains is essentially a flexible sack of hemoglobin wrapped in a specialized membrane. This extreme simplification is the trade-off that allows each cell to pack in more hemoglobin and still squeeze through capillaries less than half its own diameter.

  Not every mammal follows exactly this blueprint. Within the artiodactyl order, which includes cattle, deer, llamas, and their relatives, red blood cells take on a striking range of unusual forms: small and highly oval in llamas and camels, tiny and spherical in mouse deer, and fusiform, crescent-shaped, or irregularly polygonal in red deer and wapiti. These species appear to have evolved a substantially different path of red blood cell development from the standard mammalian pattern.

  The only known vertebrates to lack red blood cells entirely are the crocodile icefish of family Channichthyidae, which live in the oxygen-rich cold waters of the Antarctic. They transport oxygen dissolved directly in their blood plasma. Even so, remnants of hemoglobin genes persist in their genome.

• 3. Hemoglobin and Color

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  Hemoglobin constitutes about a third of the total volume of each red blood cell and is responsible for transporting more than 98% of the oxygen in the body. The remaining oxygen travels dissolved in the blood plasma. Each hemoglobin molecule carries four heme groups, and it is the iron ions within those heme groups that give blood its red color.

  The color is not fixed. When hemoglobin is bound to oxygen, the resulting compound, called oxyhemoglobin, is scarlet. When oxygen has been released, the resulting deoxyhemoglobin shifts to a dark red burgundy. Blood can appear bluish when seen through vessel walls and skin, but that is an optical effect, not a true change in the molecule. Pulse oximetry exploits the color difference between oxygenated and deoxygenated hemoglobin to measure arterial oxygen saturation directly.

  Hemoglobin binds carbon monoxide with very high affinity, forming a bright red compound called carboxyhemoglobin. Patients suffering carbon monoxide poisoning can present with flushed skin and a pulse oximetry reading of 100%, which makes the condition easy to miss without other clinical cues.

  The red blood cells of an average adult male store collectively about 2.5 grams of iron, representing roughly 65% of all the iron in the body.

• 4. The Membrane's Hidden Machinery

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  The membrane of a red blood cell is built from three layers. The outermost is the glycocalyx, rich in carbohydrates. Below it sits the lipid bilayer, composed of cholesterol and phospholipids in roughly equal proportions by weight. The innermost layer is a structural protein network called the membrane skeleton. Together, half the membrane mass in human red blood cells is protein; the other half is lipid.

  Cholesterol is evenly distributed between the inner and outer halves of the lipid bilayer. The five major phospholipids are not. Phosphatidylcholine and sphingomyelin cluster on the outer layer; phosphatidylethanolamine, phosphoinositol, and phosphatidylserine are confined to the inner layer. Maintaining that asymmetry requires active work. Proteins called flippases move phospholipids inward, floppases move them outward against a concentration gradient, and scramblases can move them in both directions simultaneously.

  That asymmetry has direct consequences for survival. Macrophages recognize and destroy red blood cells that expose phosphatidylserine on their outer surface; in healthy cells, that molecule is kept strictly inside. Premature destruction in thalassemic and sickle red cells has been linked to a disruption of this arrangement. When phosphatidylserine migrates to the outer surface, cells can also adhere to vascular endothelium, obstructing the microvasculature.

  More than 50 membrane proteins are currently known, present in concentrations ranging from a few hundred to one million copies per cell. Around 25 of them carry blood group antigens, including the A, B, and Rh antigens. The normal zeta potential of the red blood cell, the net electrical charge at the outer membrane surface, is minus 15.7 millivolts. Removing the sialic acid residues that contribute most of this charge drops it to minus 6.06 millivolts.

• 5. Carrying Carbon Dioxide

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  Cellular respiration produces roughly as many molecules of carbon dioxide as it consumes of oxygen. That means the circulatory system faces just as large a carbon dioxide removal problem as it does an oxygen delivery problem. Most of the carbon dioxide in the blood travels not as a gas but as bicarbonate ion dissolved in the plasma, and it is the red blood cell that makes this conversion happen fast enough to be useful.

  Red blood cells contain a large number of copies of an enzyme called carbonic anhydrase on the inside of their membrane. This enzyme catalyzes the reaction between carbon dioxide and water to produce carbonic acid, which rapidly dissociates into bicarbonate ion and a hydrogen ion. Because it is a catalyst, carbonic anhydrase can process many carbon dioxide molecules without needing as many copies as hemoglobin requires for oxygen transport.

  The hydrogen ions released by this reaction reduce hemoglobin's binding affinity for oxygen, an effect known as the Bohr effect. The bicarbonate ions then leave the red blood cell in exchange for chloride ions from the plasma, facilitated by the band 3 anion transport protein in the cell membrane.

  Carbon dioxide also binds directly to the protein components of hemoglobin to form carbaminohemoglobin compounds. As oxygen is released in the tissues, more carbon dioxide binds to hemoglobin; as oxygen binds again in the lung, it displaces that bound carbon dioxide. This interplay is called the Haldane effect. Even though only a small fraction of total blood carbon dioxide is carried this way, changes in hemoglobin-bound carbon dioxide account for a disproportionately large share of the difference between venous and arterial carbon dioxide content.

• 6. Life, Death, and Recycling

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  Red blood cells develop from committed stem cells through a process called erythropoiesis, which takes about seven days. In adults, this occurs continuously in the red bone marrow of large bones. In the embryo, the liver serves as the main production site. The hormone erythropoietin, synthesized by the kidney, can stimulate production. Approximately 2.4 million new cells are produced per second in human adults.

  Just before and after leaving the marrow, the developing cells are called reticulocytes and make up about 1% of circulating red blood cells. Once mature, the cells circulate for about 100 to 120 days; in full-term infants, the lifespan is shorter, around 80 to 90 days.

  As cells age, changes in the plasma membrane mark them for destruction. Macrophages in the spleen, liver, and lymph nodes recognize these signals and engulf the old cells through a process called eryptosis, red blood cell programmed death. Eryptosis is elevated in a wide range of diseases, among them sepsis, malaria, sickle cell anemia, beta-thalassemia, and Wilson's disease.

  The breakdown is not wasteful. Heme is split into iron and biliverdin; the biliverdin is converted to bilirubin and carried to the liver bound to albumin. The iron is recirculated by a carrier protein called transferrin. Almost all red blood cells are cleared through this orderly process before they reach the point of rupturing on their own. Any hemoglobin that does escape into the plasma is caught by a protein called haptoglobin, which prevents it from being lost through the kidneys.

  In 2022, a human trial was conducted using blood cultured from stem cells obtained from donor blood, a step toward eventually supplying transfusions without relying solely on donated whole blood.

• 7. Discovery and History

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  Jan Swammerdam, a Dutch biologist, was the first person to describe red blood cells, examining frog blood under an early microscope in 1658. Anton van Leeuwenhoek, unaware of Swammerdam's work, published his own microscopic description in 1674. Leeuwenhoek was more precise, even estimating the cells' size as roughly 25,000 times smaller than a fine grain of sand.

  In the 1740s, Vincenzo Menghini in Bologna demonstrated the presence of iron in red blood cells by passing magnets over the powder left after heating them.

  In 1901, Karl Landsteiner published his identification of three main blood groups, which he called A, B, and C, later renaming C to O. He described the consistent patterns of reaction when serum was mixed with red blood cells from different groups, revealing which combinations were compatible and which caused clumping. A year later, two of his colleagues, Alfred von Decastello and Adriano Sturli, identified a fourth group: AB.

  In 1959, Max Perutz used X-ray crystallography to determine the structure of hemoglobin, finally revealing how the molecule that gives red blood cells their function is actually built.

  The oldest intact red blood cells ever found belonged to Otzi the Iceman, a natural mummy of a man who died around 3255 BCE. Those cells were discovered in May 2012, making them a record by a very wide margin.