The Way of the Cell: Molecules, Organisms and the Order of Life – A Review (Read This Book if any of the Life Sciences are of even remote interest to you)

I’m an integrator, a contextual learner and a big picture kind of guy. I am willing to ‘slog’ through the details, the analyses of experts, to understand what is going on, when the details help me understand, in this case, the operation or ‘life’ of the whole organism. What are the processes, how do they influence one another and how does that result in the condition we recognize as the dynamic, animated phenomenon of living. Franklin Harold, a professor emeritus in biochemistry at Colorado State University when he wrote, “The Way of the Cell: Molecules, Organisms and the Order of Life”, in 2003, has produced the ‘best’, and most comprehensible, review I’ve found of the life in the cell, to date. This book does not require an advanced degree to follow. It requires an interest in biology. A botanist, horticulturist or even avid gardener pursuing a more thorough understanding of what life is and what is occurring within the plants and animals around will find much that is accessible to them here. This book is not a slog. It is readable and readily comprehensible, though for those with less of a science background, a little more challenging, but hey, nothing ventured, nothing gained. The jargon he uses I would say is necessary. Science can be very precise in how it views its subject, necessarily so, because meaning becomes lost when the precision of language is too generalized. I’m adding it to my own library. I include some extensive quotes here to give you a sense of his style and philosophy. I also gleaned much from these particular passages. In school I endured too many professors and lecturers who seemed more interested in impressing their students with their own brilliance, and our inferiority, and came to relish those who were true teachers, who were able to impart to their students, there own love and fascination with their topic. Harold is one of these. He set out to write a book that would reach out to the reader making his topic more accessible, more comprehensible and thus widen the circle of understanding…and he has succeeded.

The cell, scientists would agree, is the smallest fully functional unit of an organism, any organism. It is the basic structural unit that has been joined together to create larger, more complex organisms. If you attempt to reduce it any further, divide it into its component parts, which science typically does in its process of reduction to understand it in its parts, it loses functionality and dies. Single celled organisms, bacteria, archae, and the larger single celled eukaryotic organisms, like amoebas, comprise the majority of living species on earth, by both number of species and by sheer mass. They are as complete as any single organism, like ourselves, a Redwood or Blue Whale, can be. Whether a single celled organism or a massive multi celled organism made up of several billions of many thousand ‘types’ of different specialized cells, almost all cells are capable of all of their essential functions, as long as they are supplied with proper nutrients and flows of energy. Cells, as Harold describes them, are highly coordinated ‘societies’ comprised of many millions of individual proteins, enzymes, lipids and ions, with various forms of RNA, bound within a protective, limiting and self-regulating membrane, often with other internal membranes, which protect and allow other more specialized functions within the cell…and DNA, or in the cases of some bacteria, RNA, which contain the ‘code’ which prescribes the organism. It is within the cell membrane where the particular mixes of their constituent parts are held in dynamic flux, where the ‘work’ of living occurs. Within what was once described as a ‘soup’ of chemicals, suspended within a virtual sea of water, the cell conducts the ‘business’ of life. Today we understand that within a single cell water molecules far out number any other substance. Cells possess a complex internal structure, a cytoskeleton, grown from proteins, that is integral to the transport of metabolites, the regulation of its thousands of internal processes, the structure of the cell itself and essential to its ability to respond and move. The actions within the cell are largely self-regulating, influenced, certainly, by outside, and internal energy gradients. The various reactions influence the rate of other reactions in a complex system of feedback loops, with a ‘logic’ often compared to that utilized by a computer. Processes are chemical, electrical and ‘mechanical’ as one reaction induces a conformational change, a change in ‘shape’, of a particular protein or enzyme, which directly influences what it can do. These changes in ‘shape’ act as effective ‘switches’ within the cell, switches operating amongst thousands of other such switches, creating an intricate system of feedback loops which regulate just what the next step will be. Only functions tend not to be linear. They can be extremely complex, with a redundancy that also allows the cell to vary internally widely, while maintaining itself, overall, in a relatively stable state. Its internal complexity then accounts for its responsiveness and adaptability. It imparts a degree of flexibility, of adaptability to a system within the cell. All of this going on at a molecular level that plays out, with powerful effect, at the organismic level.

Harold goes into some detail here, not nearly as much as the science could take us, to begin to explain why there is such a need today for a more wholistic approach. DNA he argues, is not responsible for either the function of the cell/organism, nor its precise structure. It simply cannot be. There are far to many variables to be accounted for by DNA. It codes for an organism’s many proteins. What they do and how they do it, how they result in the life of a particular individual or species, is not coded. Instead he argues that these particular proteins, these massive macromolecules, have inherent ‘behaviors’, properties, which increase the likelihood that they will form very precise structures, under particular conditions, structures which have very specific chemical and mechanical properties themselves. He presents the idea that these molecules, in the presence of others and the appropriate levels of available other nutrients, ions and energy, ‘self-assemble’, organize themselves, forming particular more complex structures. These structures, with appropriate energy flows, prepare the way for an even more complex hierarchy of structures and processes, which overlap in complex networks, preparing the way for successive more complex structures/tissues/organisms. Each such structure leads to the next. At any one level, not all things are possible. The pieces ‘fitting’ together in limited, precise ways. He speaks of this process of self-organization, autopoiesis (from Greek αὐτo- (auto-) ‘self’, and ποίησις (poiesis) ‘creation, production’) referring to a system capable of producing and maintaining itself by creating its own parts..
From physics, and its study of thermodynamics, we know that energy carries the capacity to influence matter and that a flow of energy can support a ‘higher’, less stable state, a more complexly ordered structure which is dependent upon a continuous throughput of energy. I’ve gone into this, the thermodynamics of the organism, much more elsewhere and won’t again here. Suffice it to say that science has demonstrated a remarkable ability to ‘understand’ the details of the organism’s structure and, increasingly, of its operation and reproduction, by ‘breaking it’ into ever smaller parts. By doing so they have also laid bare the fact that there is much more going on here than a reductionist approach can ever fully explain. That, Harold sees, as the next big and essential challenge, if we are to ever develop a more complete understanding of just what an organisms is and what being alive means.

He explains in a logical outline kind of form, laying out the problem and then expanding upon each of his ‘subheadings’ presented in chapters, using enough detail to make his point, without burying the reader in detail, but giving enough for the reader to fully respect the complexity of his topic. He utilizes footnotes and indicates which other sources a reader might pursue to more fully understand how the details fit. This book, like any good book on a technical subject, can be read successfully by readers of diverse and nonspecialized backgrounds…though there is a clear message for those more expert here.

Again, this is the best book on this problem I’ve found yet. Science keeps describing in increasing detail all the particular proteins as well as the intricate pathways of its many internal processes, the complex and often redundant steps to those, which can give the reader/student a greater appreciation for the complexity of life, while laying bare the ever more essential ‘absence’ at the core of this science which it cannot touch, limited as it is with its self-imposed reductionist approach. Like so many things, living organisms will always be far more than the sum of their parts. Change one protein molecule and you will effect everything that follows, but how and by what degree, we do not know, because we do not fully understand the nested relationships they participate in. We know that the vast majority of possible forms of protein, never occur, that particular patterns/structures, persist. The processes of cell sensing, signaling and regulation are not simple switches, we cannot know what the outcome will be with certainty. Life, at every level, is a very complex process and it is so because it provides the organism with an essential adaptability necessary not only to survive and reproduce, but to thrive.

Harold at times waxes philosophical as he delves closer and closer to the question, ‘What is life?’ He discusses various theories of life’s origin, a question that will likely remain ‘unanswerable’ as its origin lies so far in the past, with few traces of it remaining. This is a problems of time and evolution which works in a way ‘erasing’ or at least blurring organisms of the past, those extinct species and theoretical ‘proto-cells’ which left no record of their existence. At life’s most basic level today, an organism is incredibly complex and all we can do, so far, is speculate, in an informed manner as to its nature, why this limited set of 20 amino acids and relatively few proteins; did RNA evolve later into the more complex and stable form of DNA; when and how did the enzymes which make cell division possible arrive; did chemistry drive the process from the beginning; if DNA/RNA is essential to reproduction how to did it come about? how were the evolving functions of the earliest proton-cells brought together? How were these earliest proto-cells able to reproduce and make possible evolution? If these earliest proto-cells were not able to reproduce with great fidelity, how were these pattern ‘tested’ and proven? Evolution cannot occur with randomly mutating individual organisms, they are generated from existing ‘patterns’ then ‘selected’. Harold is an excellent guide through this journey he expertly lays out for the reader.

Harold writes in the closing section, ‘And Therefore, What?’, of his fifth chapter, ‘A (almost) Comprehensible Cell’:

“A cell is an orderly society whose molecular citizens weave interactive patterns on many planes—spatial, temporal, functional, historical. Biochemistry is a science of molecules. Physiology deals in collectives. To put this more formally, a cell is a complex system. It’s numerous and interdependent parts engage in accordance with fixed internal constraints, and in consequence the characteristics of the whole are invariant by comparison with the fluctuations of its constituents. [Life creates a calm point where it tends to stay, despite the seeming chaotic nature of all that occurs within it, not unlike the center point of a spinning mass, continuously returning to center, the gyroscopic forces making it so. My comment.] Nature presents us with many kinds of systems, some simpler than cells and others vastly more complicated, but none that are more highly ordered. The question here is how order (regularity) and organization (purpose, adaptation) come about in the molecular society that we designate a cell.

“Several keys to understanding lie near at hand. A cell is made up of standard parts, arranged in a hierarchical manner, that interact in ways governed by their molecular specificities. The cell is also a dynamic system formed by the confluence of several streams, flows of matter, energy and information. It is specially organized not merely in the sense of having an external boundary, but in relying upon molecular processes that have location and direction. And it is endowed with a genetic program that ensures the accurate reproduction of all the working parts and is functionally tied into all cellular operations. The genome is also the seat of variations, whose systemic consequences are the substrate upon which natural selection acts. These system properties constrain evolution’s freedom to experiment with novelty since only mutations compatible with the existing pattern can pass the filter of natural selection. In this manner the phenotype [visible structure] feeds back upon the genotype, imposing a measure of stability and even direction upon change; tinkering is possible, radical redesign is not. Evolution is thus directed into channels whose course can be traced in the homology [similarities due to shared ancestry] of macromolecules long after their functions have been transformed.

“…. Biological patterns do change over time as the geologist measure it, but not quickly.

“The genetic program has rightly been the focus of intense scientific scrutiny and of public celebration, but adulation has gotten out of hand. The fallacy is the tacit assumption, taken as an article of faith, that all the levels of biological order are spelled out in the genome. That is obviously not true for E. coli, and a fortiori not for more elaborate cells and organisms without qualifying carefully just what is a meant by such throwaway phrases as “cellular functions are programmed by a genetic network”. First, it is clear that the cell (of which the genome is apart) provides the context for the expression of that genetic network, mediates it’s interaction with the environment and constrains its implementation in space and time. Second, many facets of a cells complex and adaptive behavior arise from the interplay of its molecular components without the intervention of a central directing agency, just as the economy of the city operates quite smoothly in the absence of a plan or direction.”

In his sixth chapter, ‘It Takes a Cell to Make a Cell’, he finishes with:

“What we seek to understand emerges from the sociology of molecules, not the chemistry, and carries us into a different layer of reality. Indeed, how could it be otherwise? A growing cell is not a self assembling set of puzzle pieces, but the product of generative processes mediated by multiple molecules, physiological pathways deployed in space.

“The reactions that shape the cell have, of course, a chemical dimension, but unlike their fellows in the test tube, many of them display direction, location and timing. So biology is about chemical and physical events that take place here, rather than their, transport matter from here to there, not now, but later, when called for. Once your eyes have been open to these upper levels of order (you see that a cell) practices biochemistry with an attitude.

“So cellular organization is chemical and molecular, bred in the genes; but a cell reaches much farther, flaunting capacities that are rooted in the operation of the larger unit. If you think of the genome as software, then cellular organization correspond to the interpretation of the program by its own unique reader. This way of thinking gives one a more realistic appreciation of the peculiarly biological kind of self-assembly commonly known as ‘growth’…(Growth obeys) both the digital dictates of a stretch of DNA and the subtler promptings of the epigenetic landscape. (That term, the epigenetic landscape) remains an indispensable metaphor for those of us who strive to identify and make intelligible the levels of order that intervene between molecules and cells.

When discussing what controls these processes, Harold writes:

“ A rather more plausible candidate is the plasma membrane which defines the cell. The membrane creates the enclosed and controlled space, within which, societal behavior emerges from the interactions among individual molecules.”

Harold sees not only that life propagates from life, from the cell, but that structure and order does as well, as of his writing, 2003, that particular molecules, under supportive conditions, result in particular, more complex structures, up to the cell and organism itself, that the structures and processes of life, ‘inform’ what follows. As in physics, this path of development is not deterministic, not ‘knowable’, but one that is less certain, probable. He sees no reason to invoke the concept of ‘coherent excitation’, a still argued phenomenon of quantum physics, as bio-physicist Mae-Wan Ho has done. This is the idea that similar particles are coherently linked despite being physically separated. The idea is that changes induced in a particle can be exhibited by separate like particles. It is a tad more complicated than this! I appreciate Ho’s thinking on this point….How exactly it may come in to play, I don’t know. Harold, in this discussion, is limiting himself to a single E. coli cell, magnitudes of scale less than organisms comprised of one or more far more complex and large eukaryotic cells and multi-celled organisms. Einstein once dismissed this idea, quantum coherence, ‘as spooky action from a distance’. Biology, as it continues to move forward, demonstrates time and again that there is no one-size-fits-all answer.

“Physicists use the term self-organization to describe what happens in a system whose constituents convert from individual, random motions to a state of global cooperativity….If we are prepared to tolerate some creative ambiguity, self-organization will also serve to underscore the distinctive feature of the biological systems: spatial and temporal order emerges spontaneously, in the absence of a central directing agency, in a complex molecular system kept away from equilibrium by a flux of energy. Self-organization is not a mechanism; it is the label for a pigeonhole that will hold relevant forces and rules of engagement.”

At the end of his chapter, “It Takes a Cell to Make a Cell”, Harold opens the door to morphogenesis, the development of the cell/organism into its particular form and function from its constituent parts and the possibility of morphogenetic fields, fields being those effective forces which are characteristic of, part of, the ‘fabric’ of space/time itself and directly influence, in this case, the form and function of organisms. He sees the physical cell itself as the ‘model’, the templet, upon which each cell is built, in a systematic process of growth and division, not a process strictly delineated by the organism’s genome. In later chapters he moves on to evolution and natural selection, descent with modification, always beginning with the how this plays out at the cellular level, the essential seat of all life. Through all of his book he is a thoughtful and questioning guide, never balking to mention that which we don’t know and requires an explanation that we don’t yet have.…

Biologist have never been persuaded that purely physical and chemical processes can explain, in its entirety, what goes on in an amoeba or an embryo. They are generally firmly wedded to the genetic program as the mechanism which informs living organisms, absent from nonliving structures. But dynamic patterns generated by physical and biological systems do have something in common that hinges on the concept of a field.
“Like other metaphors imported from every day life, the field is an elastic idea who’s content depends on the speaker. I shall employ the term with very general sense to designate a territory that displays coordinated activity, controlled by the differential distribution of some property or agent. The virtue of this abstract notion is that it lends itself to mathematical formulations and incorporates such features as continuity of field values, at every point in space, smooth transitions and directional change.
“Fields have a holistic quality that given a global mathematical expression and a few local numerical values, it is often possible to reconstruct the field in it’s entirety. Furthermore, since the essence of a field resides in its mathematical description, one can examine the properties of the field without knowing anything about its physical nature. That is a great advantage, for the agents and properties, whose distribution determines field behavior, come in many forms. Fields of force, electrical, magnetic or gravitational, are familiar, but fields of biological interest can also be sustained by concentration gradients or by a pattern of mechanical stress and strain.
“The fields most pertinent to morphogenesis and patterning, are those generated by dynamic, rather than static systems, the flame like character of living things is more than a poetic simile.
“Dynamic systems are characteristically maintained in a state remote from equilibrium, by a continuous flow of energy. Given the right parameters, physical systems of this kind commonly under go spatial self organization with concurrent enhancement of the energy through put. Such patterns were designated ‘dissipative structures’ by Ilya Prigogine who regards them as one of the chief sources of order in the universe.
“Note that like a living organism dissipative structures coordinate the random motions of innumerable particles, over an extended territory, and persist indefinitely, so long as the supply of matter and energy lasts. The behavior of dynamic systems is typically non-linear. Over a certain range, an incremental input of energy or matter, produces in incremental output, but at a particular threshold there is an abrupt change in behavior. Non-linearity is commonly a consequence of feedback interactions among coupled processes, their mathematical description calls for a sequence of couple differential equations. To be sure designating a growing hypha or a regenerating ciliate, as a dynamic field, does not in itself explain anything. But the label helps to focus the mind on the features that call for explanation and it highlights parallels with a physical world that could be described with a common formalism. The fact that, in a growing number of instances, the field formalism rationalizes or predicts biological behavior and sometimes allows one to compute the shape an organism ought to display, engenders confidence that there is more to this than formalism alone.” pp. 149-150.

“I take the position argued compellingly and in detail, by Goodwin and others, that an especially extended dynamic field generated by the cell as a whole isn’t an obligatory intermediate between genes and form. It’s function is to organize gene action in space. The morphogenetic field is the agency that defines the pathways of molecular transport in positioning and ultimately localizes the forces in compliances that shape the cell. Fields remain hypothetical in their physical nature a subject for speculation and research, but it seems to be self evident that a morphogenetic field must revolve around the organization of the cytoskeleton. A particular field, or more likely fields, that guide morphogenesis, need not be the same in all organisms, but organisms related by descent will surely Sherrfield dynamics justice this year gene sequences in molecular architecture. with each generation a more for genetic field is re-created a fresh. The reason that forms are nevertheless faithfully transmitted is that each cell carries two kinds of heritable information the linear sort written in nucleotide sequences in the three-dimensional sore embodied in the special architecture of the cell as a whole. Jean specify macromolecular functions and collectively determine the kinetic and thermodynamic parameters of the morphogenetic field. pp-156-157.

Harold‘s book is an intelligent and insightful guide to our understanding of life today. Over his 50 years of study he has come to recognize the essential role played by genetics in life as well as those in which it falls someone short. Here he champions those who are now choosing the complementary pass of holism. There is an increasing movement of those who have found that while genetics is absolutely necessary to life and our understanding of it, it will be forever in complete. Organisms are indeed greater than the sum of their parts.

That while there is indeed still more to learn at the genetic and molecular levels of the organism, there is perhaps today an even greater need for us to consider what we are missing. There are indeed higher, more complex and unexpected functions that arise from the more complex, whole structures of individuals, communities and systems. Reduced as it is, our conventional perspective delivers a necessarily reduced understanding of the whole.

When discussing the early evolution of the cell Harold tells us of Woese, a notable microbiologist whose study focused on ribosomes, their genetics and how these could be used to date and link all organisms. He argued that all prokaryotes evolved from a population of proto-cells that were still in the ‘progenote’ stage, a life form lost to us, unlike any still in existence.

“Molecular science, for all it’s no nonsense airs, asks one to swallow some real Humdingers, and none bigger than the assertion that all extant organisms have descended from a unique population of cells in the distant past (in principle from a single ancestral cell). This hypothetical organism is referred to as the last common ancestor (more technically, the cenancestor)….” Later in reference to these ancient ancestors Woese writes of them: “Their genetic machinery would have been far less accurate than that of any contemporary organism hampered by rudimentary mechanisms of translation and replication and beset with frequent errors. The metabolism and architecture of these early forms of life would be lacking structures common today. “Woese now envisages the cenancestor, not as an organism, but as a miscellaneous community of proto-cells that frequently exchanged primal genes and evolved as a unit. Genetic complements were not fixed but subject to continuous remodeling by mutation rearrangement and unregulated traffic and genes. Overtime functional systems would’ve crystallized into successful configurations and therefore become less receptive to the import of novelty the first modules to emerge were, probably those concerned with the processing of genetic information. In consequence the fluid population differentiated into a small number of stable types among which were the progenitors of the three domains [recognized today]. Woese’s argument is rich in implications for the very nature of early evolution….”

Harold takes the reader on a trip through our modern understanding of life, noting the major ‘markers’ along the way, those greatest theories and ideas put forth, investigated and tested, and more than a few of which are still contested, which once understood, influence and shape that understanding itself. This is the nature of all science in it endeavor to more fully understand the world around us. It does not move from solid known to solid known, but requires the freedom to speculate and theorize as our current theories, under critical examination, begin to show their limits. Biology, like the other sciences, has evolved with us, with many corrections along the way, new doors opened, allowing us to see the world through a new ‘lens’ previously unavailable to us…such is the way of all science.
This is to illustrate just what is inside of a single E. coli cell which measures just a few microns in length. A micron is equivalent to one millionth of a meter. With some 40 billion water molecules inside, there are relatively few, 2.4 million, 1,850 different types, of the ‘massive’ protein molecules, which make up about .6% of this cell by number; the RNA’s are responsible for the production and replacement of proteins, Ribosomes are the places where proteins are created; Lipids comprise much of the cell membranes and the singular Peptidoglycan, is knitted into a single structure that forms the surrounding cell wall. E. coli is a relatively small and simple cell when compared to the much larger and complex eukaryotic cells that make up all higher and multi celled organisms.


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