Guest post – What Protoplasm can tell us about systems biology

Jagesh Shah writes: In a recent perspective piece, Rick Welch and James Clegg re-visit the timeline of modern theories of cellular function.  Their central thesis is that the theory of the protoplasm (e.g. as proposed by Edward Curtis), which was displaced nearly one hundred years ago by the cell theory (e.g. as laid out by Schwann), is the antecedent to modern-day holistic cellular systems biology approaches.  The piece highlights a remarkable struggle between a view of the basis of life that focuses on cellular forms and constituents, versus a focus on the dynamical behaviour of cells in their environment.  Modern systems biology is undergoing a similar struggle.

The conception of the protoplasm was an attempt to describe the living dynamical nature of the cellular constituents.  It derived from observations of cellular behavior that were shared between the smallest unicellular organisms and the cells of much larger multi-cellular creatures.  Competing with this view was that of the cell.  This view again aimed to describe the commonality between living organisms, that they were all composed of cells (a la van Leeuwenhoek), but it emphasized structure and composition over cellular behavior.  In both views we see the tension between the long-standing epistemological distinction between form and function.

Long attributed to Aristotle, the idea of objects — both animate and inanimate — having both matter and essence is at the heart of all scientific questions.  Understanding how a car works requires both an understanding of kinematics and combustion and a plan of the mechanical layout and list of parts. But these two aspects of living systems were not initially integrated:  the form was emphasized by the cell theorists and the function by the protoplasmists.  Can the two really be separated?  The answer is certainly no, but if we consider that era in science, when physicists were identifying the building blocks of all matter, it is easy to imagine that the success of the atomic theory may have had a significant influence on the cytologists of the time and encouraged a focus on identifying basic elements.

While the cell theory did emerge as the dominant view, starting with the cataloging of parts and layout, and continued in this vein as molecular biology, this approach is also largely responsible for what we now know about cellular function.  Although we no longer talk about the protoplasm, and may bemoan molecular myopia for the absence of a holistic view of cellular function, the bottom-up approach identified modules of biological function in which function-seeking scientists could hope to link molecules to mechanism.

As we consider the systems view of biology and how it may differ from the past, I propose to you that Welch and Clegg have unknowingly revealed an old division in our new field.  Systems biology will always struggle with the question of what is the appropriate description of a “system”. Is it an accounting of the parts and their layout?  To describe a car, is it enough to know where and what everything is? This would be analogous to -omics methods, which provide detailed measurements of constituents and their interactions. But to understand how your car functions, and how to fix what’s wrong with it, you’d better understand the dynamics of the four stroke cycle and the principle of a slip differential so that the car can turn. I submit that this is an equally, perhaps more, important aspect of systems biology, the effort to study functional modules in detail, abstract key principles of operation, and gain a holistic view of how all the parts contribute to the function of the module.  This functional view is not often discussed in articles attempting to define ‘what is systems biology?’ (although it can be found in commentaries from Marc Kirschner, Chuck Stevens and Art Lander), but in the end it may lead to a new view of biological systems, as well as a new appreciation of old ideas about the protoplasm.

These two views of systems biology are often cast as -omics vs. dynamics (or statistics vs. differential equations).  Both have provided key insights into biological questions.  Consider the diauxic shift measured by transcript profiling or the elucidation of robustness in bacterial chemotaxis demonstrated by mathematics – both are examples of what I hope most would consider systems biology.  Yet these approaches still remain poorly integrated.  As systems biologists we should take a lesson from the century-old cell vs. protoplasm debate, that an understanding of both form and function will be required in the multi-millennial quest for the nature of living material.  When we make routine the connections between the parts of our car and the functions that those parts perform — integrating the -omics and dynamical views — well, then we’ll be ready to put the pedal to the metal.