Theoretical biology

Theoretical biology applies reason toward the goal of explaining the biological world, and aspects of it, through ideas and theories. It thereby distinguishes itself from observational and experimental biology, though without the latter disciplines of biology, theoretical biologists would have no information with which to produce theories, or evaluate them.

Professor Richard Gordon, President of the Canadian Society for Theoretical Biology, writes:

The theoretical biologist delves deeply into all the data available, comes up with unexpected relationships, tries to quantify them using all the tools of reason (math, logic, computers, etc.), and makes specific predictions about the outcome of future experiments and observations. Sometimes a critical experiment would never have been done without the inspiration of your theory in the first place.

Biophysicist and mathematical biologist Marc Mangel, in his 2006 book The Theoretical Biologist’s Toolbox, elaborates on Professor Gordon's brief description of theoretical biology:

Theoretical biology begins with the natural world, which we want to understand. By thinking about observations of the world, we begin to conceive an idea about how it works. This is theory, and may already lead to predictions, which can then flow back into our observations ot the world. The idea about how the world works can also be formalized using mathematical models that describe appropriate variables and processes. The analysis of such models then provides another level of predictions which we can take back to the world (from which new observations may flow). In some cases, analysis may be insufficient and we choose to implement our models using computers through programming (software engineering). These programs then provide another level of prediction, which can also flow back to the models or to the natural world.

In describing their research program, the Biospheric Theory and Modeling group of the Max-Planck-Institut für Biogeochemie highlight many of the main approaches and advantages of theoretical biology:

Our research aims to identify the general organizing principles of the biosphere in order to better understand and predict its interactions with biogeochemical cycles and the climate system….Our view of biospheric theory….is that the development of theory goes hand in hand with observations, which serve as a reality check for the theory, as well as inspiration for more precise research questions. The precise research questions in return can be used to streamline the experiments and measurement campaigns to allow new insights. As the theory develops, models become helpful for understanding the implications of the theory and for rejecting unrealistic assumptions or formulating new research questions. Conceptual models are particularly helpful for determining similarities or incompatibilities between different theories. Emergence-based models are useful for linking small-scale processes with large-scale effects, while Optimality-based models are useful for making reproducible predictions directly at the scale of interest.... Theoretical concepts help us to formulate hypotheses how the biosphere should function and respond to change. We work on several concepts, such as optimality, multiple steady states, and pattern formation.

In summary, observational checks of theory, inspiring more precise questions, leading to better experiments, with modeling to test assumptions, leading to new questions and revised theories: a systems biology approach. Most biologists will recognize themselves as theoretical biologists on some level and at some times.

In their 2003 book on the organization of organismal form, Gerd B. Müller and Stuart A. Newman stress the breadth of the field and its applicability beyond mathematical biology:

Theoretical biology is firmly rooted in the experimental biology movement of early twentieth-century Vienna. Paul Weiss and Ludwig von Bertalanffy were among the first to use the term theoretical biology in a modern scientific context. In their understanding the subject was not limited to mathematical formalization, as is often the case today, but extended to the general theoretical foundations of biology. Their synthetic endeavors aimed at connecting the laws underlying the organization, metabolism, development, and evolution of organisms….A successful integrative theoretical biology must encompass not only genetic, developmental, and evolutionary components, the major connective concepts in modem biology, but also relevant aspects of computational biology, semiotics, and cognition, and should have continuities with a modern philosophy of the sciences of natural systems.

In describing the aims of the Dutch journal of theoretical biology, Acta Biotheoretica, Thomas A. C. Reydon and Lia Hemerik illustrate the Dutch perspective on theoretical biology:

In this understanding, theoretical biology is seen as encompassing the entire spectrum of theoretical investigation of the living world, ranging from philosophy of biology to mathematical biology. Consequently, the process of biological theory formation in the journal is allowed to range from purely verbal argumentation to the mathematical analysis of biological theory.

One can appreciate to some extent the broad range of topic categories published by theoretical biologists in Acta Biotheoretica from the Table of Contents shown in the cited reference to the Current Themes book by Reydon and Hemerik.. As theoretical biology transcends national boundaries, those topic categories qualify as representative of the field.

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The Journal of Theoretical Biology

The diversity of biological disciplines represented in the Journal of Theoretical Biology indicates the diversity of biologists engaged in theoretical biology. The editors of the journal emphasize the role of theory in giving insight to biological processes:

The Journal of Theoretical Biology is the leading forum for theoretical papers that give insight into biological processes. It covers a very wide range of topics and is of interest to biologists in many areas of research. Many of the papers make use of mathematics, and an effort is made to make the papers intelligible to biologists as a whole. Experimental material bearing on theory is acceptable…. Research Areas Include: Cell Biology and Development; Developmental Biology; Ecology; Evolution; Immunology; Infectious Diseases; Mathematical Modeling, Statistics, and Data Bases; Medical Sciences and Plant Pathology; Microbiology; Molecular Biology and Biochemistry; Physiology.

  —Journal's ten most downloaded articles in agricultural and biological sciences, April-June 2008

A listing of the ten most downloaded articles from the journal (in agricultural and biological sciences, April-June 2008) give an indication of the kinds of theoretical and conceptual approaches and topics that interest theoretical biologists:

• Thermodynamics of natural selection I: Energy flow and the limits on organization

• From the Abstract: This is the first of three papers analyzing the representation of information in the biosphere, and the energetic constraints limiting the imposition or maintenance of that information. Biological information is inherently a chemical property, but is equally an aspect of control flow and a result of processes equivalent to computation. The current paper develops the constraints on a theory of biological information capable of incorporating these three characterizations and their quantitative consequences….The main result of the paper is that the limits on the minimal energetic cost of information flow will be tractable and universal whereas the assembly of more literal process models into a system-level description often is not.

• Biofilms in the large bowel suggest an apparent function of the human vermiform appendix

• From the Abstract: The function of the human appendix has long been a matter of debate, with the structure often considered to be a vestige of evolutionary development despite evidence to the contrary based on comparative primate anatomy. Based (a) on a recently acquired understanding of immune-mediated biofilm formation by commensal bacteria in the mammalian gut, (b) on biofilm distribution in the large bowel, (c) the association of lymphoid tissue with the appendix, (d) the potential for biofilms to protect and support colonization by commensal [living together, with some benefitting, none detrimenting] bacteria, and (e) on the architecture of the human bowel, we propose that the human appendix is well suited as a “safe house” for commensal bacteria, providing support for bacterial growth and potentially facilitating re-inoculation of the colon in the event that the contents of the intestinal tract are purged following exposure to a pathogen.

• Modeling the segmentation clock as a network of coupled oscillations in the Notch, Wnt and FGF signaling pathways

• From the Abstract: The formation of somites [body segments containing the same internal structures] in the course of vertebrate segmentation is governed by an oscillator known as the segmentation clock, which is characterized by a period ranging from 30 min to a few hours depending on the organism. This oscillator permits the synchronized activation of segmentation genes in successive cohorts of cells in the presomitic mesoderm in response to a periodic signal emitted by the segmentation clock, thereby defining the future segments….A complex oscillating network of [three] signaling genes underlies the mouse segmentation clock….By means of computational modeling, we investigate the conditions in which sustained oscillations occur in these three signaling pathways. The model provides a framework for analyzing the dynamics of the segmentation clock in terms of a network of oscillating modules involving the….signaling pathways.

• Thermodynamics of natural selection II: Chemical Carnot cycles
• A protein interaction network associated with asthma
• Self-organization at the origin of life
• The timing of TNF and IFN-γ signaling affects macrophage activation strategies during Mycobacterium tuberculosis infection
• Thermodynamics of natural selection III: Landauer's principle in computation and chemistry
• Prevention of avian influenza epidemic: What policy should we choose?
• Evolutionary stability on graphs

  —Journal's ten most downloaded articles in biochemistry, genetics, and molecular biology, April-June 2008

The corresponding top ten downloads in the areas of biochemistry, genetics and molecular biology:

• The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells
• Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors
• Direct Reprogramming of Terminally Differentiated Mature B Lymphocytes to Pluripotency
• Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors
• SnapShot: Hematopoiesis
• Nuclear Receptor-Enhanced Transcription Requires Motor- and LSD1-Dependent Gene Networking in Interchromatin Granules
• The Hallmarks of Cancer
• TGF-β Primes Breast Tumors for Lung Metastasis Seeding through Angiopoietin-like 4
• Acetylation Is Indispensable for p53 Activation
• An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells

It appears from the titles alone that currently theoretical biology covers a widely diverse types of subject matter, not all qualifying as mathematical or philosophical biology.

The National Academies' National Research Council report on theoretical biology

A committee of the National Research Council of the National Academies reported in 2008 on "The Role of Theory in Advancing 21st-Century Biology: Catalyzing Transformative Research". In the summary of their report they discuss the nature of theoretical biology:

The committee was charged with examining the role of concepts and theories in biology, including how that role might differ across various subdisciplines. One facet of that examination was to consider the role of the concepts and theories in driving scientific advances and to make recommendations about the best way to encourage creative, dynamic, and innovative research in biology....The committee concluded that a more explicit focus on theory and a concerted attempt to look for cross-cutting issues would likely help stimulate future advances in biology. To illustrate this point, the committee chose seven questions to examine in detail. The list of questions is not comprehensive but rather illustrative. The questions, as shown below, were chosen to show that a focus on theory could play a role in helping to address many different types of interesting and important questions at many different levels.

In the Table of Contents of the committee's report, they center their report around these questions:

• Are There Still New Life Forms to Be Discovered? The Diversity of Life - Why It Exists and Why It's Important (38-66)
• What Role Does Life Play in the Metabolism of Planet Earth? (67-80)
• How Do Cells Really Work? (81-89)
• What Are the Engineering Principles of Life? (90-109)
• What Is the Information That Defines and Sustains Life? (110-129)
• What Determines How Organisms Behave in Their Worlds? (130-144)
• How Much Can We Tell About the Past - and Predict About the Future - by Studying Life on Earth Today? (145-156)

Achieving answers to those kinds of questions would seem to require interdisciplinary collaboration among many different biological and non-biological scientific disciples, which brings a diversity of concepts, hypotheses, and theories.

The NRC committee emphasized the integral role of theory in biology, in chapter so titled, and selected for the chapter's epigraph a quote from Leonardo da Vinci: He who loves practice without theory is like the sailor who boards ship without a rudder and compass and never knows where he may cast. The first chapter, broken to bullet sentences, serves to summarize their conclusion:

• This chapter:

• describes several different ideas about scientific theories,
• emphasizes the diversity of theoretical activities throughout biology, and
• discusses ways in which theory is integral to each specific kind of scientific activity, including
• experimentation,
• observation,
• exploration,
• description, and
• technology development as well as
• hypothesis testing.

• Biologists use a theoretical and conceptual framework to inform the entire scientific process, and they frequently advance theory even when their work is not explicitly recognized as theoretical.

• Explicit recognition of the many entry points of theory into the scientific enterprise may provide greater opportunity for developing

• new concepts, principles, theories, and perspectives in biology that would

• not only enhance current scientific practices
• but also facilitate the exploration of cross-cutting questions that are difficult to address by traditional means.

The committee makes a specific recommendation:

Theory, as an important but under appreciated component of biology, should be given a measure of attention commensurate with that given other components of biological research (such as observation and experiment). Theoretical approaches to biological problems should be explicitly recognized as an important and integral component of funding agencies’ research portfolios. Increased attention to the theoretical and conceptual components of basic biology research has the potential to leverage the results of basic biology research and should be considered as a balance to programs that focus on mission-oriented research.

Common topic categories

With the following introductory remarks, in their 1993 book, Thinking About Biology: An Invitation to Current Theoretical Biology, Wilfred D. Stein and Francisco J. Varela offer a sample of then current and still topical areas of work in theoretical biology:

One the of main purposes of this book is to offer a sample of thinking about biology….one that avoids both the extremes of empiricist myopia and of theoretical aloofness. We offer this sample not as a survey of the "entire field” of theoretical biology….we see the process of thought as being an integral part of asking questions that make science both productive and more fun….Thinking about biology is done in various ways. One of the most useful approaches to this variety, we have found, is expressed in the notion of levels of theory. We distinguish between macro-, meso-, and micro-theories…..Macotheories are the large, imaginative canvases that constitute the conceptual scaffolding of a large portion of biology, and that appear only rarely in history. One ideal example is due to Darwin….Macrotheories are usually not that interesting to most practicing biologists. As students, they absorb the major dominant macrotheories, which became second nature in their minds, and they leave it at that. The large issues, such as what is life and its origins, how can a brain secrete a mind, or can evolution be sustained on a planetary scale, are left for occasional reading at best….Mesotheories, on the other hand, are more numerous…. they attempt to cover only a selected domain of biology. A good example of classical mesotheory is the introduction of the notion of a morphogenetic gradient to account for various developmental phenomena….Microtheories are phenomenon-specific. Their purpose is to account in some conceptually clean or analytically astute manner for a given set of observations. For instance, a very famous microtheory was Hodgkin's and Huxley's equations for the action potential in nerve conduction.

They offer the following samples:

• Table of Contents::

• Thinking About Biology: An Introductory Essay

• Section I: The Emergence of Life

• Defining the Transition to Life: Self-Replicating Bounded Structures and Chemical Autopoiesis

• "[Pier Luigi] Luisi emphasizes the fundamental operation of the life process, rather than the chemical structures that make up the living cell, but he also considers various actual model systems that point to possible paths along the road to life's origins."

• The Organism as a Dynamical System

• "['Peter T.] Saunders introduces us gently to some solutions of systems of differential equations and shows us that systems of nonlinear, but not of linear, differential equations haw sufficient complexity to be good models for embryological, and even for evolutionary, development. We learn about the "attractor," that stable set of values of the parameters of a system to which the system evolves and to which it will return if perturbed."

• Designing Bacteria
• Structural Patterns in Macromolecules

• Section II: Development and the Individual: Processes of Identity

• Development as a Robust Natural Process
• Generation of Morphological Patterns: Mechanical Ways to Create Regular Structures in Embryonic ::*Development
• Gastrulation and the Evolution of Development
• Biological Organization, Coherence, and Light Emission from Living Organisms
• What is the Immune Network For?
• Randomness and Pattern Scale in the Immune Network: A Cellular Automata Approach

• Section III: Species and Societies: Communication Among Multiple Agents

• Self-Organized Criticality and Gaia
• Requirements for Evolvability in Complex Systems: Orderly Dynamics and Frozen Components
• Modeling the Behavior of Ant Colonies as an Emergent Property of a System of Ant-Ant Interactions