LIFE'S RATCHET (Through Chapter 2)

Hoffmann, Peter M.  Life’s Ratchet: How Molecular Machines Extract Order from Chaos.  New York, New York: Basic Books, 2012.

This book is 288 pages in length (paperback version published by Basic Books).  It describes how physics, chemistry, and biology intersect to define what life is in terms of what turns seemingly inert molecules collectively into a self-propelling molecular machine driving what we know as life.  At the molecular level, the author notes that the “secret of life’s activity is found at the scale of a nanometer”.  Peter Hoffmann is a physicist  whose conversion to biology began when, as a doctoral student, he used an atomic force microscopy to view deposits of DNA molecules.  Years later, after inheriting a collaboration as a Wayne State University professor with a molecular biologist measuring the “motions of particular molecular machines implicated in the spread of cancer”, he changed course, reinforced his biology knowledge, and started a new research direction on the science of molecular machines (from the Introduction section of the book).

INTRODUCTION: WHAT IS LIFE?

In the introduction to the book, the author gives a preview of what the book aims to accomplish for the reader. The goal of this book is to answer the question to which the book title alludes to:  What controls this collection of molecules into a life-giving machine?  The author’s short and cryptic answer is the “force that drives life is chaos”.  The author will relate the many discoveries by philosophers early in the debate and the scientists to explain “what it takes to turn a molecule into a machine and many molecular machines into a living cell”/

CHAPTER 1 – THE LIFE FORCE

This chapter traces very early ideas arising from debates about what gives life to living organisms.  Starting from the creation of the universe, the author notes that “All life started as a circle dance of molecules billions of years ago.”  It then goes on to give a summary of how the discourse on what constitutes life has evolved over the ages beginning from ideas put forth by Greek philosophers. For hundreds of years, the debate about what constitutes “life” has centered on the concepts of “purpose and mechanism”.  The author states that the three most prominently held explanations for life, starting from the Greek philosophers to the early-19^th century biologists are embodied in the philosophies of the following believe systems: animism, vitalism, and mechanism/atomism.  The practice of medicine gave the first empirical insinuations in this debate that contributed to an increasingly scientific and quantitative knowledge of the workings of the human body and offered some concrete evidence related to the debate of what constitutes life.     For example, William Harvey was noted as being one of the first to infuse a more quantitative method of understanding of the workings of the human body questioning how the heart could possibly be the source of blood and where it eventually by measuring blood volume and pump rates.  Studies and analyses which were mainly proponents of the mechanical view helped user in the scientific revolution of which Galileo Galilei (1564 – 1642) and Isaac Newton (1642 – 1726) were the major players.  Both of these men were atomists and used experiment and reason to investigate nature.  This more mechanical and atomistic view emerging during the scientific revolution helped propel the pursuit of instruments (with help from improvements in the understanding of optics) to study the living world, i.e. the microscope being one of the most important.  The microscope gave the first glimpse of the fundamental unit of life, the cell, unbeknownst to these scientists who first observed their presence.  In his most popular work, L’homme machine, de la Mettrie concluded that organisms function as a result of their physical and mechanical make-up based on observations of how bodily and mental functions were altered by injury and the observation that muscle tissue even without being attached to a living body.  Animal heat was also big on the mind of those studying the basis of life.  Before Harvey’s time, Galen had correctly suggested a relationship between food and heat and respiration.  Further experiments by Boyle, Mayow, and Lavoisier contributed some solid observation supporting this relationship.  The birth of modern biology in the 19^th century ushered in new methods and new ideas for investigating the “self-sustaining, self-organizing activity” basic attribute of life.  In the field of embryology, the thinkers were divided along the lines of preformationists and the epigenesists but this era also gave birth to the teleomechanistic philosophy and ideas supporting vitalist views.  The teleomechanistic views of Kant and Blumenbach led to the development of the cell theory, the idea that all living organisms are composed of fundamental units called cells. In de la Mettrie’s view, however, irritability is evidence of the purely mechanistic basis for life.  The study of irritability gained traction using new methods of applying electricity to animal parts. These experiments and observations suggested that electricity could be the vital force propounded by many believers.  The mid-19^th century saw the revival of the mechanistic view driven by the work of Charles Darwin (1809 – 1882) who “destroyed teleology” and Hermann von Helmholtz (1821 – 1894) who “vanquished the vital force”. Helmholtz’s dismissed any utility of the vital force theory instead suggesting that energy must be conserved.  His experiments showed that “all the hallmarks of being alive, from animal heat to irritability – had to occur within the energy budget prescribed by the physicochemical world”.   By the end of the 19^th century, the success of these mechanistic studies brought to light the fact that biology, physics, and chemistry must intersect to explain what gives life to organisms but did not answer the fundamental question issue of “purpose”.  Charles Darwin and Alfred Russell Wallace provided an answer when they developed the theory of evolution based on natural selection.  In his Origin of the Species published in 1859, Darwin presented his observations and his arguments for natural selection as the driving force of evolution: variations within individuals of a given species that favor reproductive success lead to progeny, thus survival and propagation.  Mendel’s work on genetics and inheritance answered the follow-up question of how those traits leading to survival and propagation are transferred to the offspring:  “traits are inherited whole, and that traits from each parent can be combined in various ways in the offspring”.  The fact that some of these individual traits from parents can be conserved, and not always blended, was crucial to Darwin’s theory for only through the complete conservation and transfer of a specific trait that favor reproduction and not its dilution can lead to the trait’s propagation within the species.  In the next chapter, the author will answer the question of what gives rise to these variations.

CHAPTER 2 – CHANCE AND NECESSITY

In the minds of many scientists and philosophers pondering what life is, randomness was not entertained at all as a viable player in the discussion until the end of the 19^th century.  This chapter starts off with a brief history of the development of statistics and the calculation of probabilities.  The author used Pascal’s triangle as an early example of calculating the number of times one can choose a certain number of items (k items) out of n available items.  This number can also be calculated using the binomial coefficient expression: n!/(n-k)!k!  “Statistics has been called the theory of ignorance” but it “provides the clues to understanding the underlying regularities or the emergence of new phenomena arising from the interaction of many parts.”  The real story started when biologists themselves began to apply statistics in their own studies of organisms with Galton and Quetelet being the pioneers of these extensive studies. Charles Darwin’s cousin, the mathematician Francis Galton, applied Quetelet’s ideas (“how the error law, the normal distribution, and the central limit theorem governed almost everything”) to a wide range of biological phenomena: heights, masses of organs, and circumferences of limbs and found that they all follow a normal distribution.  It is these statistics that Mendel used to develop his laws of heredity. In the section “Randomness and Life: Three Views”, the author described the beliefs of the main players in the role of randomness in understanding life:  the how and why of the many phenomena of life and life itself can be understood given enough understanding of the complexities involved (Thompson); life events happen due to a higher purpose reconciling science and religion (Chardin); and the beginning of life is an improbable event but once it happened, evolution and the game of chance took over (Monod). These beliefs can summarized into two dichotomies: dichotomy of mechanics (“mere physics”) versus higher forces (life forces, the soul) and the dichotomy of chance and necessity. The physicists found themselves at the intersection of mechanics (physical forces) and necessity. With the development of the kinetic theory which evolved and broadened into the Laws of Thermodynamics and mathematically sharpened into Statistical Mechanics, they finally found a way to incorporate and tame randomness into their efforts to explain (and predict) the properties of matter based on the existence of atoms: with well-defined probability distributions developed by averaging over large numbers the random motions of atoms. Quantum mechanics came into the picture in the early 19^th century replacing the “iron-clad model of necessity, classical physics” with a “fundamentally statistical picture of nature”.  Meanwhile, developments have been occurring in biology. Chromosomes (bundles of DNA) and their duplication during cell division were known by 1882 but it was not until 1900 that a connection was made between chromosomes and Mendel’s hereditary traits. By 1909, genetic experiments were being conducted on fruit fly drosophila by Thomas Hunt Morgan (1866 – 1945).  Morgan discovered that traits are not independent as Mendel thought but are linked suggesting that “traits were contained in some kind of linear arrangement on chromosomes with nearby traits more likely to be inherited together.  The mixing of traits was assigned to a crossing-over of linear molecules.”  By 1920, it was clear that hereditary information was contained in the linear arrangement of the chromosomes. In 1926, Joseph Muller discovered after years of experimentation and using a controlled dose of x-ray that radiation increased the probability of new genetic traits being created due to mutations. This correlation was later refined with the help of Max Delbruck and they subsequently showed that the mutation rates depend on temperature and x-ray dose.  In the words of the author, this sequence of events during the first half of the 20^th century illustrates how “previously mysterious biological processes, such as heredity and variation, became connected to measurable physical (molecular) entities”.  Erwin Schrodinger got a hold of these ideas and expounded on them, not correctly all the time.  Based on Delbruck and others’ data, he surmised that this genetic entity must be a molecule of about a thousand atoms with very stable bonds that can withstand the elevated thermal motions with the cell.  To contain a large complex amount of information, they have to be aperiodic or non-repetitive.  We now know of course that the genetic material is an “aperiodic” polymer called DNA).  Towards the end of the chapte, the author offers the following statement to reconcile the interplay between necessity, laws of nature, and randomness: “Life can best be understood as a game of chance – played on the chessboard of space and time with rules supplied by physics and mathematics.”  These games begin at the level of the atoms