Edison

In the 1960’s and 1970’s college science classrooms were clad with a map of the Biochemical Pathways. This compendium of thousands of enzymes and substrates and products was the culmination of over 5 decades of work. This included the identification of small organs within cells– organelles, with specialized functions, and the biochemistry carried out within each specialized structure. As this work product came to its natural conclusion, one organelle– the nucleus has, and is, preoccupying us. It contains the book of life– our genetic code. We have spent the last 30 years in earnest deciphering this code, and learning how stored genetic information is translated into proteins, and how these proteins interact in reproduction, health and disease. Today, we have a first pass at the human compendium of genes, and now are working feverishly to understand their function. If 1930 – 1960 produced the compendium of enzymology and biochemistry, 1960 – 2005 produced the compendium of the human genome. But we have a significant challenge ahead.

These two books, one of life (genes) and one of function (enzymology) have not been reconciled. As we now know that enzymes come from genes, we lack in its totality an integrated picture of what regulates their synthesis and biological function. While the human genome is often referred to as the book of life, more accurately it could be described as the words of life. Its plot, characters, punctuation, and prose are forthcoming, but not complete.

The energy that powers humans is derived from the sun. It is harnessed in a usable form from atmospheric carbon dioxide (CO2) by plants in a process called photosynthesis. In photosynthesis, solar, or electromagnetic energy is converted into usable chemical energy: Solar Energy + CO2 + H20 → sugars + O2. There is a symbiotic interplay between plants, animals, and microbes. Animals are not photosynthetic, and derive energy by eating plants and other animals, in turn consuming O2 derived from photosynthesis and producing CO2. This symbiotic cycle is often called the carbon cycle, and describes the ornate interplay between elements of the animate and inmate biosphere.

And as if to make matters more complex, we now have a first glimpse at the end of this book, that hints at telling us that the book of life may not be fully described in genetic words. Thus, the race is on today to assemble genetic information derived from each individual and species into their biological story. Ironically, the race has come full circle, and many genetic researchers, who thought they escaped college biochemistry, are resurrecting dusty editions of their college textbook– Lehninger Biochemistry, to figure out how these genes “work”.

The opening chapters of Lehninger’s Principles of Biochemistry, and other similar iconic textbooks, focused on basic physics and chemistry, with a special emphasis on biological energy. The early editions of these texts started with a detailed description of enzymology and energetics. The theme was catabolism and anabolism– the breakdown and engineering of food components into biochemical building blocks to assemble life forms. The nexus and integration of catabolism (breakdown) and anabolism (synthesis) was defined as metabolism, and the feedback of products of each, thought to form an autoregulatory feedback loop that kept this biological engine functioning. We now complement this first description of metabolism, with a comprehensive view of genetics, and understand that metabolism is controlled both through the substrates and products of enzymes and through complex genetic elements that dictate synthesis and regulation of a myriad of enzymes and other control elements.

If the last 80 years have been spent sorting through and casting the characters of the book of life– staring metabolism and genetics, the next decades will be spent compiling and editing this book. We are now in the era of molecular biology– understanding the molecular basis of life, the complex interplay of genetic information and biochemicals.

As with most books, the book of life appears to have plots and subplots. It has been drafted via evolution, trial and error, and we view it today as a mystery (book). One major subplot is genes- they are our hereditary material and are rich in instructional information. We can trace this information through almost all life forms, and today we understand that our genes have 80% of common elements with plants. Evolution is, if nothing, efficient. Another major subplot is energy.

How energy is derived from raw chemicals, and interconverted on the planet is central to all life forms. Some forms, like humans, have miniature combustion engines similar in operation to those found in an automobile. (Others like bacteria living at the bottom of the ocean use energy stored in raw sulfur.) We take food substances we eat, and oxygen we breath, and combine them to generate energy. This occurs in a specialized organelle called a mitochondrion. But, this is only half the story. The mitochondria more accurately resemble a hybrid automobile. They contain both an engine and a generator. The mitochondria are configured as a combustion engine to produce energy, cross-coupled with a battery to store and distribute energy. The bulk of life’s energy comes from the mitochondrial battery, and this battery goes through cycles of charge – discharge – and recharge in thousandths of a second. As with all batteries, this charge is generated by the flow of electrons.

The same chemical reactions that a fossil fuel plant employs to generate energy to power a community, are the identical chemical reactions used within the mitochondria to power every cell in the human body: fuel + O2 → energy, CO2 + H2O. At rest the average 70Kg adult burns an estimated 250mL of oxygen resulting in an oxygen consumption (VO2) of ~2.5mL O2/Kg-min. This represents a current flow of ~65 amperes, which approximates the current service to a small size residential home. Highly trained endurance athletes can increase their oxygen consumption ~20-fold to support muscle work resulting in VO2 values of ~ 75mL O2/Kg-min. This represents a current flow of over 1,250 amperes.

There are an estimated 750 enzymes that form an electrical network across the cell to distribute power. These enzymes are called oxidoreductases. They are energy transformers, with a tie-in to the mitochondrial central power generator. They form a biology energy grid of the cell. They use a trickle of energy derived from the mitochondria to power individual enzymes. We now understand through the use of genomic information that defects can occur in both the primary energy generator– the mitochondria, and the secondary energy transformers– oxidoreductases. In some instances, we can trace one-to-one how genetic defects result in a decrement in energy generation. If a human at rest generates ~ 70 amps, we have a clear concordance of single gene defects, and a decrement of energy output to 35 amps.

We are on the verge of deciphering a major subplot of the book of life– how genes and energy relate. As this picture is maturing, advances in therapies to tackle “energy disease” has lagged other therapeutic endeavors.