The real cycle(s) of life

 kw: book reviews, nonfiction, biochemistry, krebs cycle, citric acid cycle

Sorry, Lion King, the circle of life is actually something hidden from most of us. There are powerful wheels that turn inside every cell in our bodies (and in all bodies, from bacteria right on up). The most important of these has a name that strikes fear in students of biochemistry: the Krebs cycle. Hans Krebs received (with Fritz Lipmann) the Nobel Prize in 1953 for his elucidation of the citric acid cycle, which is usually called by his name.

This illustration, from Transformer: The Deep Chemistry of Life and Death by biochemist Nick Lane, shows how the cycle produces ATP, the energy carrier used by all living beings (on Earth at least). The steps after ATP is produced (lower left) regenerate molecules used for the next go-round. Citric acid (in the form of citrate when in solution) is the master of ceremonies.

For those interested in the structural chemistry shown here, the black balls represent carbon, the small gray balls are hydrogen, and other atoms such as oxygen or sulfur are represented by open circles with a letter inside. The dashed lines with a - sign attached to all the COO groups indicate that the electronegativity is not localized to either of the oxygens.

This book is a loving biography of the Krebs cycle and related biochemistry. Dr. Lane does his best to explain the reactions within it, and in the reverse cycle, and the environment in which this chemistry is active: on both sides of the membranes of mitochondria. These cycles are the machinery that runs our cells.

A common understanding of the Krebs cycles has what we call the forward cycle transforming energy into a form we can use (ATP), and the reverse cycle gathering energy from the environment, such as the electrons pumped by photosynthesis, to make energetic molecules, mainly sugars. But there is a whole lot more to it than that.

Other crucial parts of these metabolic cycles include "red protein" or ferredoxin, which catalyzes reactions that run too slowly otherwise, forcing electrons onto many of those COO- groups seen in the diagram, or onto intermediate chemicals that pass them onward to COO-. Another is shown as CoA here; it is "coenzyme A", a somewhat larger chain of atoms and small rings, including some phosphate groups and amino (nitrogen-hydrogen) groups. The body makes CoA from vitamin B5 (pantothenic acid). Every cell on Earth needs it to function.

It may surprise those who haven't studied biochemistry that so very many of the chemicals of life are acids. In popular culture, "acids" are powerfully corrosive chemicals such as sulfuric acid (battery acid) and hydrochloric acid (muriatic acid or swimming-pool acid). We may know that the sour taste of vinegar is due to acetic acid, and that lemons are sour because of citric acid. So not all acids are that fierce! Surprisingly, every cell in your body is powered by a cycle that begins and ends with citric acid. It's about a whole lot more than oranges and lemons! The COO- group in an organic molecule is called "carboxylate", and when the minus sign is satisfied by an attached hydrogen, the COOH group makes the molecule a carboxylic acid. These are not corrosive. Rather, they are necessary for metabolism to function. Also, a protein is a long chain of amino acids, and all amino acids contain the compound group NH2-COOH. We are built of acids!

How are these molecules built? Their building blocks are produced by tools created in the Krebs cycle. This cycle has so many uses, it has to be regulated so as to avoid conflict between producing ATP for energy and producing molecules for body construction. Dr. Lane likens a cell to a city, with lots of activity going on. At the core of all the processes to run the city are motors, and the motors all have the same brand name: Krebs. A motor is a good metaphor, for as energy flows through a motor, the motor spins. In one quote from biophysicist Harold Morowitz, "Energy flows, matter cycles."

Once the opening few chapters have described the Krebs cycle in sufficient detail, and provided examples of how the "motor" runs, later chapters delve into the question, "Which came first, genetics or metabolism?" A fundamental fact about all the reactions in the cycle are that they are reversible. We learn in early Chemistry classes that when you have a reversible reaction, it can be driven either way by changing the concentration of other chemicals in its environment (typically by adding one of the products or reactants to a solution in a beaker).

Recent experiments—usually meaning in the last 5-10 years—have shown that these reactions can proceed most of the way around the cycle with very little "driving". Having a metallic or metal-oxide substrate for the acids to temporarily attach to also seems to facilitate matters. Even more recent experiments have shown that pressure and heat—here meaning pressures of several tens of atmospheres to several hundred atmospheres and heat around boiling or not much above boiling—facilitate these reactions chains, and if certain products are removed, they are like conveyor belts or assembly lines to produce the kinds of molecules that are necessary for life. This has led to the hypothesis that life began at hydrothermal vents in the ocean deeps.

It occurred to me as I read this that hydrothermal vents should have been much more active a few billion years ago than they are today. When I was taking geochemistry, I remarked to the professor one day that radiogenic heating (heating caused by elements such as uranium breaking down) must have been six times greater than now, four billion years ago. This would lead to much faster plate tectonics (He was surprised; he had never thought of that). At that time the deep sea "black smokers" and other hydrothermal features had not yet been discovered. Eons ago submarine vents would have been correspondingly greater in extent and activity. It seems the immediate post-Hadean era could have been ideal for biologic life to begin.

Nearer the end the book turns from life and life's origins to disease and death. It is no surprise that, if our mitochondria age and wear out, the cycling of metabolism is affected. I have been wondering for a long time, if our mitochondria age, and their DNA accumulates SNP's even faster than the DNA of our cells (nuclear DNA), how do babies get born with brand-new mitochondria? Is there a corrective mechanism? There is! And it is not quite described, but briefly outlined on pages 140-141. The author calls it a "clean-up operation in the female germline" to prepare the half-million of mitochondria that fill each oocyte (egg cell).

Also, mitochondria, and the metabolic cycling that spins endlessly around their membranes, are implicated in cancer. This metabolic cancer origin hypothesis is not yet well known, and is controversial where it is known. But it makes more sense than the chain of oncogene disruptions posited by the earlier hypothesis (and it is no more than a hypothesis, not a theory).

Further, dying and death are metabolic in origin. I can't say I grasped the entirety of Dr. Lane's description, but it made sense as I read it. We really are a lot like "The Wonderful One-Hoss Shay" of Holmes's poem, that was constructed to have no weakest part. If nothing external goes wrong, we may live to great age, and then rather abruptly suffer general organ failure, when everything seems to go wrong at once: "He died in his sleep." My great uncle, having outlived his wife by a few years, at the age of 102 was working a field on his farm. He stopped the tractor and walked to one of the hired hands to say, "I feel a little tired. I'll take a little nap." Inside, he lay down and passed away peacefully. I can't think of a better way to go.

The epilogue is titled "Self". It reconsiders the question, "Which is primary, genetics or metabolism?" The conclusion (stated at the outset and then supported by evidence): "Genes never supplanted the deep chemistry of cells. They conserved it, and they built on it." The primary difference between the Krebs cycle of four billion years ago, and now, is the cluster of enzymes (built by genes) that catalyze the reactions, facilitating energy flows hundreds of times more rapid. Otherwise animal life would not be possible, and plant life couldn't have produced bamboo that is able to grow a few feet per day.

The book made me wistful. I started college as a chemistry major because I wanted to become a biochemist. Three changes of major later, I graduated as a geologist. I had a great career, but I miss chemistry. This book has become my new favorite for the year.