Provides some cell biology background for subsequent discussion.
A Brief Overview of Cell Biology
To understand subsequent chapters, the reader needs some comprehension of the structure and chemistry of the human cell and of the irregular terminology with which I have chosen to model it. Keep in mind that life is an organic process and, as such, produces exceptions to any generalizations one makes about it, including mine. Also in a complex organic process, you can probably find anything you look for. Numbers must be attached to any theories or findings to view them in perspective and distinguish the significant from the insignificant.
Matter is, of course, composed of atoms. Atoms can be bound to each other in clumps called molecules. Cells are composed of molecules of atoms of the elements oxygen, carbon, hydrogen, nitrogen, calcium, sulfur, phosphorous, and a few others. Oxygen alone comprises over 60% of the human body by weight.
At minimum a cell is a generally microscopic drop of liquid termed cytoplasm enclosed in a membrane. Most importantly it is alive, meaning that it constructs and repairs itself and reproduces its own kind. It achieves all this ultimately by manufacturing molecules called proteins. Basically a cell is a protein factory. It contains DNA, a long polymer of four types of molecules called nucleotides. The cell constructs polymers from 20 types of molecules called amino acids in sequences that mirror the sequence of nucleotides in the DNA, three nucleotides corresponding to one amino acid (with some redundancy). The amino acid polymers so produced are the proteins that form the bulk of the cell and catalyze its chemical processes. They then convert molecules drawn from the cell’s environment into the other chemical types (fats, sugars, etc) of which the cell is composed.
The cytoplasm is, of course, much more than just a drop of liquid. Cells have motion and hold and change shape, and solid structures must be constructed to support these activities and to move things around. The cell lays down a virtual railroad composed of filaments called microtubules. Upon these rails, specialized locomotive proteins drag other proteins and even larger structures to their destinations within the cell. Each protein displays a ticket (a particular amino acid sequence usually) that identifies its destination.
The cell is the smallest autonomous unit of all life-forms. Even the largest whale was at one time a single cell. All free-living life-forms have bodies composed of cells. Most have only one cell in their body. A single cell is generally invisible to the naked eye so any visible plant or animal must be composed of many cells. For instance estimates for the number of cells in the human body range between 10 and 100 trillion (million million)! For the typical adult body, the range is 50 to 75 trillion2.
A meter is a little more than a yard in length. A typical bacterial cell is about 3 to 5 millionths of a meter (micrometers) in diameter. For a globular human cell the diameter is about 50 micrometers3, at least 10 times greater. This means that the volume of a human cell can be over a thousand times greater than a bacteria’s volume (10x10x10).
Some human cells are much larger than average. A nerve cell though only 50 micrometers tall and wide can be as much as a meter long. That could be 20,000 times the volume of a globular cell and 20 million times the volume of a bacterial cell.
Independent life forms come in two flavors cell-wise: bacteria and everybody else. As noted bacteria cells are small and typically contain their DNA in a ring floating in the cytoplasm of the cell. They are unicellular. Despite their size bacteria form the vast bulk of living mass on Earth.
The cells of everybody else including yeast, fruit flies, mice and humans are, as mentioned, much larger. The DNA is kept in a separate membrane-bound compartment of the cell called the nucleus in special structures called chromosomes The cells even contain so-called organelles called mitochondria that evolutionarily are themselves captive bacteria with their own membranes, DNA and protein-synthesis machinery.
In subsequent chapters we will focus on nerve cells and mitochondria and this might be a good point at which to ponder the idea that a single nerve cell could harbor hundreds of thousands of them.
The mechanics of the cell seem extremely cumbersome and inefficient from our macro perspective. Mostly protein molecules wait around for the right molecule to bump into them at just the right angle. In the complex way that proteins are made, for example, it seems it would take forever for one little chain. Yet ribosomes spit out polypeptides at the rate of 20 amino acids per second4. You have always to keep in mind that, when you move from the macro to the micro, time speeds up and what takes a day to work out in our macro models may happen in the cell in a microsecond.
Oil and Water
When oil and water are shaken together, they quickly separate when the shaking stops. The oil being less dense rises to the top. This happens because the water molecule, though its net electrical charge is zero, is slightly positively charged on one end and negatively charged on the other. Opposite charges attract and water molecules align to satisfy this attraction. Oil molecules do not have this charge separation and are squeezed out of the water semi-crystal formed by these so-called hydrogen bonds..
The electrical force, like gravity, operates 24/7, and though ever so slight, organizes life forms as much as gravity, though ever so slight, organizes the cosmos. Molecules in the cell that have charge separation can likewise attract water and remain in the aqueous water phase. Molecules without charge separation are pushed aside and accumulate in oil droplet ghettos in the cell.
Some large molecules have charge separation on one end but lack it on the other. They can move within the cell on their own to end up on the surface of an oil droplet with their so-called hydrophilic (water-loving) end in the aqueous phase and their so-call hydrophobic (water hating) end in the oil (lipid) phase forming structures called micelles like this:
|Fig. 1 & 2 (public domain image)|
Except for in some specialized fat storage cells, most oil-type molecules in the cell also have aqueous ends. There is very little purely hydrophobic oil to surround and so, as more of these molecules are recruited into the micelle, it tends to flatten out into a sheet like this:
This sheet can wrap around itself as shown in two dimensions as follows
This forms the so called liposome with an aqueous phase totally enclosed by a lipid membrane:
Note that these structures tend to self assemble and, with a little guidance, can be made to form functional ‘organelles’ for life purposes. For example proteins or protein complexes with the right arrangement of hydrophilic and hydrophobic parts can embed themselves in the liposome and pump water and other selected molecules into the liposome to enlarge and to specialize it. Or they may pump hydrogen ions into it to create an acid interior.
In actuality most liposome structures in the cell bud off from existing liposome structures rather than arising de novo as outlined here, but the dynamics remain the same.
Liposome structures within cells are called ‘vesicles’. Terms for specialized vesicles include ‘vacuoles’, ‘peroxisomes’, ‘endosomes’, ‘phagosomes’, ‘autophagosomes’, ‘lysosomes’ and arguably ‘mitochondria’, ‘nuclei’ and the cell itself.
The cell itself is like a vesicle containing vesicles, some of which contain their own vesicles. Protein structures embedded in the vesicle walls control the flow of materials in and out of the vesicles and, in this way, the cell is divided into compartments and the compartments specialize to serve different cell functions.
Endocytosis and Exocytosis
Liposomes can be formed from the outer membrane of the cell as well as from internal membranes. When this happens, the process is called ‘endocytosis’. It is used by cells to take in nutrients or to clean up extra cellular materials. The reverse of endocytosis, ‘exocytosis’, is used to dump liposome contents outside of the cell.
This separation of oil and water not only acts between molecules but within large molecules as well, in particular, proteins. Proteins are long single-chain polymers of small molecules called amino acids. 21 different types of amino acids are used to make human proteins, some of which are hydrophobic and others hydrophilic. The same forces as organize micelles organize the protein to produce its functional configuration. Generally for soluble proteins, hydrophilic amino acids occupy the outside of the protein that is exposed to the cytoplasm. Proteins that embed in membranes have hydrophobic amino acids where the protein interfaces with the lipids.
Hydrophobic amino-acids generally occupy the core of most protein molecules and give them their structure. Acids can be a threat to this structure. By definition, solutions are ‘acid’ in proportion as hydrogen ions are abundant. Positively charged hydrogen ions, just protons with no electron shell, are effectively so small compared to other molecules that they can navigate into the core of proteins and disrupt the charge arrangements between the atoms of the protein. This usually causes the protein to change its configuration irreversibly to a non-functional form, a process called denaturation. A similar thing happens when you boil an egg. It cannot be unboiled. The body uses acid to denature proteins at two levels, in the stomach and in a cell vesicle called the lysosome. In both there are proteins that are specifically designed to be unaffected by the acid and continue to serve their intended functions. Indeed they cannot function without it. There can also be accidental aggregates of protein that can resist this denaturation as well. Some of these aggregates and the diseases they may cause are a central topic of this narrative.
When any two or more proteins form an attachment, it can be said that they have formed an aggregate. Now there any number of aggregate forms. Some are soluble, others insoluble, Some contain water and are like gels. Others have excluded water and can appear as solid objects. In some, the constituent molecules are free to come and go. In others, they are permanently bound. In this book, I am referring to soluble labile aggregates as ‘aggregates’ and insoluble fixed aggregates as ‘condensates’. This distinction is important since the aberrant proteins that underlie neurodegenerative diseases are toxic in solution or in soluble labile aggregates but inert in condensates. The argument as to whether or not the aggregation is responsible for the disease often depends on this distinction.