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EDITORIAL

The Art to Science of Cell and Developmental Biology in EBM

And it is becoming increasingly clear that to understand living systems in any deep sense, we must come to see them not materialistically, as machines, but as (stable) complex, dynamic organization. Twenty-first century biology will concern itself with the great "nonreductionist" 19th century biological problems that molecular biology left untouched. All of these problems are different aspects of one of the great problems in all of science, namely, the nature of (complex) organization.

—Carl R. Woese (1)

With its recent restructuring, Experimental Biology and Medicine (EBM) acknowledges the promise of understanding how the individual components of cells and organisms interact to effect life and the impact this will have on the future of medicine. One’s ability to define the principles of biological organization, in quantitative terms, is advancing at a historic pace. The canvas of biological design is becoming digitized. Lord Kelvin recognized long ago that ‘when you can measure what you are speaking about and express it in numbers you know something about it; but when you cannot measure it, when you cannot express it in numbers, your knowledge is of a meager and unsatisfactory kind’. The founding artist of computer programming Donald Knuth expressed a similar sentiment: ‘Science is what we understand well enough to explain to a computer. Art is everything else we do’. Indeed, profound advances in scientific instrumentation are quickly blurring the boundaries of reductive disciplines; with ever increasing expansion of fully sequenced genomes of first species and now individuals, protein–protein interaction maps being drawn with suborganellar precision, and the ability to scrutinize spatial and temporal scales of the metabolome becoming routine, the networks of life are being viewed for the first time.

Although it is not clear at present if the nonlinear nature of life and the stochastic processes of evolution will preclude the derivation of biological laws, it does seem that the temporal and spatial scales of a sufficiently variable number of complex biological networks will soon be defined in sufficiently quantitative terms to determine if mathematical laws of life indeed exist. The suggestion has been made that "biology is mathematics’ next physics" and that entirely new realms of mathematics will be needed to cope with the high diversity of life and its many scales of spatial and temporal organization (2). At the least it appears clear that we are moving away from the purely reductionist mechanical views of life offered by molecular biology and beginning to "see" the emergent properties of living systems.

Consistent with the historical focus of the Society for Experimental Biology and Medicine (SEBM), we at Experimental Biology and Medicine strive to become again a principal recorder of the new knowledge that is enabling an understanding of the self-organizing complexity underlying the mechanics of life. Although Cell and Developmental Biology debuted as a "category" only with the recent reorganization of existing multidisciplinary categories and emergence of new interdisciplinary categories introduced by our new Editor-in-Chief Steven R. Goodman, EBM and its former iteration Proceedings of the Society for Experimental Biology and Medicine have published highly cited papers focusing in one manner or another on cell and developmental topics since its inception in 1903. As a matter of fact, of the 50 most-frequently cited articles in EBM, the top five fall into this category (3). For many decades, Proceedings of the Society for Experimental Biology and Medicine was recognized as a (the) leading journal of the multidisciplinary life sciences. A great deal of new knowledge from disciplines that generally consider biological systems as whole entities such as anatomy, physiology, and metabolism were published in its pages, enabling insight into interactions among these components.

Fundamental cross-disciplinary collaboration between biologists and computer scientists will be required to understand interactions among components that lie beneath the cell being the fundamental unit of biological organization. Recognizing this, the Computer Science and Telecommunications Board of the National Research Council convened recently a Committee on Frontiers at the Interface of Computing and Biology, who identified ‘Some (relevant) Questions for Cell Biology in the 21st Century’ (4):¹

• What is the proteome of any given cell? How do these individual protein molecules organize themselves into functional subnetworks—and how do these subnetworks then organize themselves into higher- and higher-level networks? What are the functional design principles of these systems? And how, precisely, do the products of the genome react back on the genome to control their own creation?
  
• To what extent are active elements (such as RNA) present in the noncoding portions of the genome? What is the inventory of epigenetic mechanisms (e.g., RNA silencing, DNA methylation, histone hypoacetylation, chromatin modifications, imprinting) that cells use to control gene expression? These mechanisms play important roles in controlling an organism’s development and, in some lower organisms, are defense responses against viruses and transposable elements. However, epigenetic phenomena have also been implicated in several human diseases, particularly cancer development due to the repression of tumor suppressor genes. What activates these mechanisms?
  
• How do these dynamically self-organizing networks vary over the course of the cell cycle (even though most cells in an organism are not proliferating and have exited from the cell cycle)? How do they change as the cell responds to its surroundings? How do they encode and process information? Also, what accounts for life’s robustness—the ability of these networks to adapt, maintain themselves, and recover from a wide variety of environmental insults?
  
• How do cells develop spatial structure? The cytoplasm is far from a uniform mixture of all of the biomolecules that exist in a cell; proteins and other macromolecules are often bound to membranes or isolated inside various cellular compartments (especially eukaryotes). A full account of the regulatory networks has to take this compartmentalization into account, along with such spatial factors as diffusion and the transport of various species through the cytoplasm and across membranes.
  
• How do the networks organize and reorganize themselves over the course of embryonic development, as each cell decides whether its progeny are going to become skin, muscle, brain, or whatever? Then, once the cells are through differentiating, how do the networks actually vary from one cell type to the next? What constitutes the difference, and what happens to the networks as cells age or are damaged? How do flaws in the networks manifest themselves as maladies such as cancer?
  
• How do the networks vary between individuals? How do those variations account for differences in morphology and behavior? Also—especially in humans—how do those variations account for individual differences in the response to drugs and other therapies?
  
• How do multicellular organisms operate? A full account of multicellular organisms will have to include an account of signaling (in all its varieties, including cell–cell; cell–substratum; autocrine, paracrine, and exocrine signaling), cellular differentiation, cell motility, tissue architecture, and many other "community" issues.
  
• How do the networks vary between species? To put it another way, how have they changed over the course of evolution? Since the "blueprint" genes for proteins and RNA seem to be quite highly conserved from one species to the next, is it possible that most of evolution is the result of rearrangements in the genetic regulatory system?
  

Turning the art of cell and developmental biology into science requires answers to such questions. We seek to publish these contributions not only to archive astounding advancements, but as emphasized often by Samuel James Meltzer, MD (1851–1920), the founder of SEBM, to also ‘understand the fundamental to develop the practical’. Integrating Science and Medicine is the motto of SEBM. We are especially encouraged that knowledge of the interplay between biological pathways within and between cells offers significant promise for novel means of detecting and treating the chronic and complex diseases that remain recalcitrant, and hence the advancement of medicine.

Footnotes

This editorial contains material reprinted with permission from the National Academies Press, Copyright [2005], by the National Academy of Sciences.

¹ Reprinted with permission from the National Academies Press, Copyright [2005], National Academy of Sciences.

References

1. Woese CR. A new biology for a new century. Microbiol Mol Biol Rev 68:173–186, 2004.[Abstract/Free Full Text]
2. Cohen JE. Mathematics is biology’s next microscope, only better; biology is mathematics next physics, only better. PLoS Biology 2:e439, 2004.[CrossRef][Medline]
3. The 50 Most-Frequently Cited Articles in Experimental Biology and Medicine as of August 1, 2007. http://www.ebmonline.org/reports/mfc1.dtl.
4. Committee on Computing Frontiers: Prospects from Biology, National Research Council. 21st Century Biology. In: Wooley JC, Lin HS, Eds. Catalyzing Inquiry at the Interface of Computing and Biology. Washington, D.C.: The National Academies Press, pp28–29, 2005.

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