Sunday, December 16, 2007

Fahrenheit -459.67

Molecules need to be on the move to react with each other. Inspired by his observations on the thermodynamics of gas molecules, the Irish scientist Lord Kelvin conceived it useful to set to zero the temperature, at which molecular motion must come to a standstill. Today, his idea is recognized in the international system for measures, and units of temperature have been named in his honor. Extrapolation from experimental observation has pegged -459.67° Fahrenheit to zero degrees Kelvin. At this temperature, the molecules reach the state of lowest kinetic energy and greatest stability.

However, at higher temperature, molecules are in motion and chemical reactions occur. As a result, energy may be set free. Although this energy can be used to fuel other chemical reactions, some will dissipate unused. The loss is called entropy. Entropy commonly increases with the multitude and the complexity of the reactions, summarily advancing our universe toward Lord Kelvin's endpoint.

Life is an effort to stem this progress. In order to survive, living things need to preserve energy like surfers tirelessly weaving up and down the face of a wave. Every descend fuels the next ascend. Organisms as a whole as much as the cells they are built from have to meet this challenge. This is our lot in life.

In the battle against entropy, nothing lasts forever. The building blocks of living cells are subjected to wear and tear. They need to be continuously repaired or replaced. Even constant upkeep may not suffice. Most cells possess a limited lifespan. Primordial cells must continue proliferation to make up for the losses.

To satisfy these needs, cells rely on two essential tools. One tool is a repository of construction plans for the cellular components. The DNA in the cellular nucleus encodes these plans. The other tool is the machinery that reads the plans, can duplicate them and use the instructions to synthesize the proteins needed to build the cells' components and even entirely new cells. It is existential to protect the plans and keep the machinery functional in order to prevent the manufacture of faulty, useless, and even harmful products.

Free radicals, e.g. highly reactive forms of oxygen, constitute a major group of agents that may modify the construction plans and interfere with proper protein synthesis. Aromatic products of the incomplete combustion contained in barbecue and cigarette smoke, e.g. benzo[a]pyrene, are another group.

Cells possess quality control and repair mechanisms to contain the damage such agents cause, entering into a ceaseless contest between destruction and restoration. If vital functions cannot be repaired, either because of the magnitude of the damage or because the repair comes to a halt, the cells die.

In addition, cells may contain programs that are specifically in place to enact their death (apoptosis) and are used in regular development. For example, skin fuses our fingers together early in embryonic development. Eventually, programmed cell death separates the digits. When the programs for cell death are disabled and programs for cell proliferation are falsely engaged, the tissue may grow out of control, a condition known as cancer.

In the battle for renewal, the brain holds a special place among our organs. Nerve cells proliferate only in a few places in the mature brain, e.g. the olfactory bulbs and the hippocampus. Replacement is a scarce option. Much of the maintenance and repair is left to different cells called glia. The picture shows an early rendering of these cells in the work of Auguste Forel. He called them spider cells.

To date, the precise role of glia remains little understood. Early scientists believed that they constitute the glue that holds the brain together. We know now that one major type, astrocytes, plays an important role in keeping the environment viable for the nerve cells. They remove salts and molecules from the fluid in the extracellular space, preventing levels that would trigger cell death. In contrast to nerve cells, astrocytes multiply after brain injury inflicted by stroke and trauma, producing a gliosis. Astrocytes are also known to enter proliferation erronously. The most deleterious brain cancer, glioblastoma multiforme, is of astrocytic origin.

Microglia are the other major type of glia in the brain.  Their role is more mysterious than that of astrocytes. The difficulty mainly arises from the fact that these cells change considerably in appearance as part of their reaction to brain injury. In the absence of direct observation, it is hard to ascertain whether and how the various cell forms are related that scientists identify as microglia. Hence, it remains difficult to pinpoint their origin. A scientist I worked with had evidence to believe that the microglia accumulating at the site of injury are derived from cell populations resident in the brain. Others believe that they consist mainly of bone marrow-derived white blood cells that infiltrate the brain from the blood stream through a blood-brain-barrier rendered leaky by the injury. Recent findings support both contentions.

Irrespective of their provenance, microglia are supposed to provide the immune response of the brain. They are known to incorporate the debris left behind by dying nerve cells. They attain a plum shape in the process and some remain unchanged on location for many years, even decades, after the insult. We do not yet understand, why they reside there and what purpose they still serve. Regardless, I take it that they are good soldiers in our cosmic fight against entropy and see to it that we do not reach Fahrenheit -459.67 too quickly.

I omitted to mention a formidable tool of living cells to stem entropy: enzymes. Enzymes are catalyzing proteins. That is, they facilitate chemical reactions that may happen only at random otherwise by bringing the components of the reaction together, accelerating the biochemical processes important to vital functions of living cells. Compartmentalization of enzymes, that is confining enzymes in distinct parts of the cell, helps organize the reactions into orderly sequences of separate processes, enabling meaningful signal transduction and the regulation of enzymic activity involved in cell anabolism and catabolism as well as in protein synthesis, replication and proliferation. The eminent biochemist Jaques Monod argued in his famed book "Chance and Necessity: An Essay on the Natural Philosophy of Modern Biology" that the first biochemical process of life in its simplest form might have been an enzyme synthesizing nucleic acids containing the information needed to synthesize this enzyme, hence empowering the protein to replicate itself. Alas, enzymic reactions are profoundly temperature dependent and come to a halt far above zero degrees Kelvin.


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