3: Imagine your room filled with grains of rice. That will give you an idea of the billion or so cells that make up your fingertip.

4: An average protein, taken from any cell, contains about 5000 atoms. [C5H5N5O = guanine = 16 atoms. x3 = codon ~50 atoms per codon, 100 codons per protein]

5: The motions and the interactions of biological molecules are completely dominated by the surrounding water molecules… It bounces back and forth, always at great speed, but takes a long time to get anywhere. [but what about schroedinger’s point about energy & stability & snapping?]

6: “very fast and crowded places”. This is truly remarkable: this means that any molecule in a typical bacterial cell, during its chaotic journey through the cell, will encounter almost every other molecule in a matter of seconds.

9: Individual molecules are captured and sorted, and individual atoms in these moelcules are shuffled from place to place, building entirely new molecules. [Components for everything the same, and lying around. Like legos. Reusable parts.]

10: Cells do almost all of their work with six types of atoms — carbon, oxygen, nitrogen, sulfur, phosphorous, and hydrogen… Modern cells use four basic plans for combining atoms to make molecular machines… protein, nucleic acid, lipid, and polysaccharide.

“salt bridges”: Molecular machines also take advantage of two types of specific interactions: hydrogen bonds between a hydrogen atom and an oxygen or nitrogen atom, and salt bridges between atoms that carry opposite electrical charges.

16: These small chemical differences actually make a big difference in the functional of RNA. The extra oxygen atom makes RNA a bit less stable than DNA, so DNA is primarily used as the central storehouse of information and RNA is used for temporary information processing. [Why not use DNA for that too? The instability of RNA must mean it’s cheaper in some way.]

17: Proteins.. Some are built simply to adopt a defined shape, assembling into rods, nets, hollow spheres, and tubes… When proteins are placed in water, they perform a remarkable feat. They twist and fold, finding an optimal shape that will shelter the hyrophobic amino acids inside and display the charged amino acids on the surface…

19: If you make a protein with a random sequence of amino acids, chances are that it will form a gooey random tangle when placed in water…. Our own cells build about 30,000 different kinds [of proteins]… which has only 29 amino acids, to huge proteins like titin, which has over 34,000…

…lipid molecule aggregate to form huge waterproof sheets.. They are also used to build compartments inside cells…

20: Rhodopsin is the sensor of light in our retinas — it uses a colorful molecule of retinal to capture light. [How??] Insulin and glucagon are hormones that deliver opposite messages about blood sugar levels.

21: Collagen forms long, sturdy cables that support our organs and tissues, and is the most common protein in the human body.

23: Lipids also slide rapidly past one another, always staing in the sheet, but randomly migrating sideways.. Rips in the membrane rapidly heal and the membrane can quickly grow or shrink in size simply by adding or removing more lipid molecules.

Pure lipid bilayers, however, are rarely found in modern cells. After all, a perfect barrier would seal the cell away from food and nutrients, and seal in waste materials. To solve this problem, cells build a variety of specialize proteins that are inserted into the membrane. They act as pumps that transport materials across the sealed membrane, or messengers that form a line of commuincation from one side to the other.

In lucrative times, surplus sugar molecules are linked up into large granules of polysaccharide. In tougher times, these granules are broken down and the sugar is released.

25: This miexture of polysaccharide and water forms a gluey coat around the cell that acts as a protective barrier. To get an idea of wht this polysaccharide barrier is like, you only have to think of the last time you had a cold: mucus owes its distinctive properties to polyscchaide chains attached to its component proteins.

Cells are amazingly crowded, typically with 24-35% of the psace filled by large molecules such as proteins and nucleic acids. As you might imagine, thes emolecules get in the way of each other. This has two seemingly opposite effects on the function of molecules. First, larger molecules have more trouble diffusing throug hthe cellular environment, since they are consnttaly blocked by neighbors. This slows the mostion of each molecule, so it takes longer for two molecules to find each other. However, countering this effect, crowded environments tend to favor the association of molecules once they have found each other. Since they are constantly crowded teogether by the nneihboring molecules, they spend more time next to each other and are far more likely to find the prperi orientation for interaction.

[crowdedness = slowness but also nearness]

30: Think of the magnitude of this accomplishment. Many bacteria are able to build all of their own molecules from a few simple raw materials like carbon disoxide, oxygen, and ammonia. A single bacterial cell knows how to build several thousand types of proteins, including motors, girders, toxins, catalysts, and construction machinery.

[Versatility of a few parts]

33: [Transcription: DNA -> RNA… Translation: RNA -> protein] The enzyme RNA polymerase unrolls a section of the DNA double helix and, at a rate of about 30 nucleotides per second, builds a strand of RNA complementary to it.

35: …an average protein takes about 20 seconds to build… [1,000 nucleotides per gene… ]

[gene = protein? yeah, basically! see https://www.jain-foundation.org/what-relationship-between-gene-and-protein]

Mycoplasma genitalium has 580,000 nucleotides that together encode 517 genes… E coli: 4.7 million nucleotides and over 4500 genes. Human: 3 billion nucleotides, ~30,000 proteins.

[It’s not like the DNA (genome) is read (transcribed) all at once]

[Parellel processing.]

38: …when the gene is transcribed, the RNA copy must be edited to remove these segments, allowing many interesting variations and a whole extra level of control and regulation.

For instance, our own genome is only about 1% different from that of our nearest relative, the chimpanzee. However, if you start looking at the numbers of copies of each gene (Which will change how they are expressed), the ways genese are inserted into genomes or deleted from them, and the mysterious functions of vast tracts of non-coding DNA, the differences are actually far greater. THese differences have subtle but essential effects on development, shaping our bodies differently than the chimpanzee’s.

40: We need energy to control the chemical reactions in our cells, ensuring that only the proper reactions occur at exactly the time they are needed. [that activation energy graph]

[so cool:] The many surrounding chlorophyll molecules act as antennas that gather light and funnel the nergy into the center.

42: The combination of glucose and oxygen is a powerfully energetic process. We are all familiar with this because a similar reaction is occurring when we burn wood, which is largely composed of long chains of sugars like glucose… Cells manage their energy in small portions, breaking down gloucose molecules in many successive steps, each under perect control and each involving only smal changes in energy.

[this controlled harnessing of energy]

As with the breakdown of sugar, moleculear machines perform these energetic processes in small steps. Chemical energy is obtained through reactions of single molecules. Electrocehmical energy is stored by moving individual ions, light is captured one photon at a time, and electrons are moved one-by-one along a string of molecular electorn carriers. This allows a level of control, and efficiency, that is rarely seen in our familiar macroscale world.

[ATP = potential energy] Each of these phosphates carries a negative chage, so they strongly repel one another. This makes it difficult to construct ATP, but easy to break it apart.

43: ATP is unstable… The reaction shown here, with water breaking the bond bewteen two of the phosphates, is highly favorable and is used to power many processes i the cell… a gradient of hydrogen ions is used to pwer fhte production of most of our cell’se ATP.

44: [What is literally happening physically when the ATP is broken up to acause the reaction to actually happen / get over its activation energy barrier?]

47: [Fig 3.10 so crazy!] ATP synthaser is a molecule-sized generator that converts electrochemical energy into chemical energy…

49: Cells in our retina are filled with arrays of opsin proteins for sensing light, light that is focused by layers of eye lens cells packed full of clear crystalline proteins. [Everything is a protein.]

53: [Fig 4.1, Inside a Bacterial Cell]. Combine with p. 55, This is a really terrific picture, Fig 4.2

54: The most plentiful ingredient of a typical E coli cell is water, making up about 70% of the weight of the cell. [What’s the water for? What’s it do?].. For instance, egg whites are a gooey mixture of about 90% water and 10% protein.

57: [I think what I want is to see a video at multiple scales of the creation and growth of a single E coli bacterium]

[All these gizmos jammed in there.]

58: Many important antibiotics, such as penicillin, kill bacterial cells by attacking the enzymes taht build the peptidoglycan layer. [when they explode, they stop multiplying and all their resources go elsewhere.]

59: The tiny mechanosensory McsL protein senses the tension of the cell membrane. If the pressure inside the cell rises too high, this protein opens like an iris and temporarily relieves the pressure. [wow!]

62: For example, the lac repressor binds at the beginning of a region that encodes four proteins that are used in lactose metgabolism. When lactose is scarce, the lac repressor binds to the DNA and blocks the genes. But when lactose becomes available, it induces a change in teh shape of lac repressor, and it falls off. Then the gene is granscribed and the cell makes the proteins needed to utilize the lactose.

[An example of gene regulation. How proteins are constantly being transcribed in response to cell conditions.]

65: Cells live in a world of thick, viscous water, almost oblivious to gravity. When moving from place to place, most of their energy is spent trying to push through the gooey liquid.

66: [gradient descent] Then it swims in a random rdirection, and measures the level of nutrients there. If the levels are increasing, it keeps swimming in that direction, since things are getting better.

71: Each of our cells, however, i smuch larger and far more complex than a bacterial cell. Where bacteria are built to be fast and efficient, our cells are made to perform complex and specific tasks, and they are made to last and perform these tasks for years.

72: [compartments as the major breakthrough] The new compartmented cells gave rise to all other forms of life, including protozoa, fungi, plants, and animals.

Surprisingly, when we look under the microscope, some of these compartments look similar to whole caterial cells.

[MITOCHONDRIA as symbiotes]… These remarkable similarities have prompted a theory of the origin of mitrochondira (and cholorplasts) that is now widely accepted. It is thought that a bacterial cell took to living inside another cell in the distant past, perhaps entering as a paraiste or pheraps survign the process of beaing eaten.

Each of our cells is filled with hundreds of compartments.. This allows for a much larger cell, with more direct control of hte processes happening from moment to moment, and more sophisticated mechanisms fof perfecption and protection.

[Why exactly are compartments so good for control? Is it that there’s too much random bouncing around when everhtyhing’s in one jumbled space? So in the same way that enzymes bring reaction cofactors physically together, compartments bring components of pathways near to each other so that favorable reactions occur?]

75: Fig 5.3. Much of the DNA is wrapped around histone proteins to form small nucleosomes (A) that compact and protect the DNA.

76: Fig 5.4. Endoplasmic Reticulum. [super-complicated! and this is just one little part of the factory]

79: Fig 5.5. [wow! This is wild. how much of this does Justin understand?]

84: Our cells make their specialized proteins on top of this necessary overhead: lymphocytes make antibodies for export into the blood; nerve cells make chemical sensor protiens and electrical insulation; red blood cells make so much oxygen-carrying hemoglobin that there is not room for much else; muscle cells forge a protein engine composed of actin and myosin.

[Cells share machinery but specialize with their own proteins]

This diversity createsa an informational problem not encountered by simpler organisms. Since all of the cells in the human body are created from a single fertilized egg cell, the single copy of DNA from each parent must hold all of the information needed by every type of cell.

[That is such a crazy fact.]

The DNA encoding these unneeded proteins is put into storage and packed in the dusty corners of the nucleus. [Chromatin structure. Justin’s work]

Embryonic stem cells are the most general of all. They can divid and choose any specialty, becoming skin cells or msule cells or nerve cells acording to their placement in the developing embryo. [Chemical gradients.]

85: [How much of the body is not cells?].. When assembled, they may be used in the most strenuous structural tasks, but at the same time, they may be quickly disassembled and reassembled lesewhere to meet the changing needs of the cell. [Shape-shifting LEGOs. A proteomic programming model]

86: Most of ourcells, however, do not need to crawl around inside our bodies. They reamin fixed in tissues and organs… cadherin proteins… These proteins also extend into the cell, binding to actin filaments inside. In this wsay, the junction links the cytoskeletons of the two cells, strengthening entire tissues. [cool]

..but to build large structures like muscles and organs… These structures are built outside cells, surrounding and supporting them.

The buildng blocks of this extracellular matrix are built inside cells, then exported out of the cell and assembled in place. The major component of the extracellular matrix is collagen — it is so common that rouhgly one-fourth of the protein in your body is collagen.

87: Each of the connexon proteins in the gap junction has a tiny pore connecting the two cells. Normally, the gap junction watches tover a busy traffic of small moleceules back and forth between the cells, but they can be closed in emergencies. For instance, if the calcuim level of one cell rises charply — often a signal that the cell is sick or damaged — the connexons snap closed and quarantine the unhealthy neighbor. [cells line up and exchange molecules.]

95: Finally, the cell makes the ultimate sacrifice. It concentrates all of its normal molecular machinery — mitochondria, nucleus, ribosomes — into one corner and ejects it all from its body. The mature red blood cell, now a directionless automaton, is then placed into the bloodstream where it carries oxygen through the blood for about 4 months. [woah, is it even alive like the other cells?]

99: The blood-clotting cascade begins with the tissue factor, a protein found on the surface of cells that surround blood vessels, but not on cells normally in direct contact with blood. It is the signal that a tissue has been injured: if the blood reaches a cell that has tissue factor, that means that the blood has leaked out of the vessel… Second, each of these proteins has a very short lifespan. They are highly unstable once they are activated, so they can diffuse only a short distance from the site of injry, creating a localized clot in the proper place. [so clever.]

100: The use of hormones as messengers, however, is limted to these basic messages, beacuse hormones are so costly to develop. For each new message, an entirely different molecule must be created, as well as a new set of molecular machinery to recieve it at the target cells.

101: The nerve initiates the signal by letting the sodium back across the membrane at the beginning of the axon. This reduces the voltage difference across the membrane. Teh channels in the local area sense this difference and all open up, letting even more sodium flow back into the axon. This triggers channels further down the axon to open, letting their local charge of sodium enter the axon. [video of this? lots when googling “axon action potential”]

[how does myelin help signals go faster? with myelin, you don’t need a bunch of action potentials one after the other; you have them spread out every so often (at the ravines), and in between, the signal is transmitted via the myelin.. how?]

107: The end of the axon is shown at the top, with two vesicles full of neurotransmitters inside the axon terminal. [Why do we have synapses and not a connected reticulum? What do they allow?]

127: Viruses have a particularly simple way of creating new viruses, a way that requires only a minimal investment of molecular machinery. All they need to do is get a copy of a viral messenger RNA into a cell.

128: Most viruses don’t bother to encode any machinery to synthesize proteins from the viral RNA — they simply co-opt the ribosomes and transfer RNA molecules that are already there in the cell.

They inject a viral RNA into the cell, which contains instructions for making a special RNA-dependent RNA polymerase. This viral polymerase builds RNA strands using the viral RNA strand as the template. Thus, they don’t need DNA at all — the viral RNA is copied directly to make more viral RNA.

[when did we discover how viruses work? must have been very exciting.]

129: They are blind assailants, inert until they bump into the side of an unlucky cell.

[What else has Goodsell written?]

The protein capsid of poliovirus is perfectly stable in the acid environment of the stomach, so it inefects there and can then spread through the lymph to distant parts of the body rhinovirus, on the other hand, is destroyed by acid and therefore infects primarily the throat and nose, which are not as acidic.

The genomes of the poliovirus and rhinovirus are so small that only a few proteins may be encoded. These include four protiens that otgether make up the capsid, two proteases that cut the viral proteins into the proper lengths, a special RNA-dependent RNA polymerase that makes new RNA strands based on the viral RNA, and a few small proteins to assist the proces. [<10 proteins]

132: [Viruses are parasites.]

The viral capsid has a network of pockets that reocgnize these cellular receptors, attaching the virus to the surface of the cell This triggers a change int he structure of the viral coat, causing it to inject the RNA through the membrane and into the cell. [What is literally happening here?]

The new viral polymerase quickly beings making new copies of the viral RNA, using the cell’s reservoir of neucleotides.. One of the viral proteases seeks out a particular initiation factor used by the cell, and cuts it in half. .. so all normal protein syntehsis stops… the viral RNA is designed so that it doesn’t need this initation factor to start protein syntehsis, so the ribosomes devote al ltheir energy to making viral proteins. AS the number of viral RNA molecules rises and increasing numbers of capsid proteins are made from them, new viruses spontaenously begin to assemble. Each one contains a new RNA molecule packaged in a coat of newly built proteins… Finally, the cell ruptrues and new virsues swarm out to infect other cells, and the cycle begins again. [Yikes.]

133: This segmented genome is the innovation that makes influenza so successful… If an avian virus infects a pig at the same time as a human virus, the two viruses can exchange RNA strands and create entirely new viruses.. The lipid membrane is not made by the virus: it is stolen from the cells that it infects.

134: …of DNA using the viral RNA as a template. Then, the integrase takes this piece of viral DNA and splices it into the cell’s normal DNA. This has terrible consequences. Once the viral DNA is spliced into the DNA, it is virtually indistringuisahble from the normal genes. It is duplicated along with the genome when the cell divides…

137: The first polio vaccines were created by Salk and Youngner by inactivating purified poliovirus with formaldehyde.

Because its reverse transcriptase makes lots of errors, HIV mutates very rapidly… The virus is also resistant to the antibodies that normally provide protection because the proteins on the viral surface are coated with non-descript polysaccharides and the unique binding sites are hidden away in grooves too small for antibodies to reach .[big flaw!]

142: The first one that was characterized, thiamine, gave vitamins their name: amines that are vital for life.

For instance, amino acids are colorless, so in order to build a protein that senses light, a colored molecule is needed. Vitamin A, also known as retinal, is the perfect candidate for this job. [??]

But more importantly, when it absorbs the light energy, it changes shape from bent to straight (Fig 9.2.). This change in shape is easily sensed by the protein rhodopsin, which launches a nerve signal telling the brain that it has just captured a photon.

151: When engulfed in concentrated alchohol, bacterial proteins unfold and are inactivated.

Fig 9.8… A chemically unstable ring of four atoms in penicillin attacks a serine amino acid in the protein, gluing the drug in the active site and blocking its action. [It’s all shapes!]

153: Fig. 9.9. Drug resistance in HIV… [woah: evades by changing the shape.] In the mutant enzyme, this amino avid has been changed to smaller alanine, weakening the contact just enough to make it ineffective as a drug. [presmuably the mutant still does its job for HIV?]

154: In addition, drug therapy is most often temporary. Our natural detoxification machinery, such as cytochrome P450, destroys the circulating drugs within a few hours, so daily doses must be taken to give a consistent therapeutic result. [Right. Is “gene therapy” the process of changing DNA so that effects are permanent? see https://en.wikipedia.org/wiki/Gene_therapy. would using a retrovirus to introduce foreign DNA into a person’s cells possibly cause those changes to be heritable, if the retrovirus found its way to the sperm cells?]

Plants and fungi are especially adept at making poisons that attack the nervous system, since they have no nerves themselves.

155: These poisons act by blocking the binding of acetylchorline to the receptor, so the muscle never gets the signal to contract. If you have ever had your eyes examined at the ophthalmologist, you have probably bneen posined by atropine. A small dorp of the poison in each eye temporariliy paralyzes the muscles that close the iris, dialting the pupils and allowing the doctor to see inside.

156: We are coming to understand when and where and how these machines are built, under the control of a resilient system of nanoscale information storage where errors are actually turned into evolutionary advantages.