By Geoffrey Lovely | October 15th 2009 07:05 PM | Print | E-mail
SIMPLE BIOLOGY VS. DYNAMIC BIOLOGY
An astonishing feature of this planet is the existence of life. We have acknowledged this fact by creating biology, a field for its study, but this discipline has yet to present life with a fair assessment. The biology courses taught today take life, this feature of planet Earth that is solely dependent on our unique position in the universe, and reduce it to simple monomeric units that when coalesced yield a biochemical pathway or a cell. This message is conveyed to thousands of students each year, and continues the output of biologists who fail to understand the dynamics of life ( I was one of them). The evident reality which was most aptly disclosed in Schrodinger's "What is Life?" is that life is dynamic and is made up of various components that interact . A conceptual understand of this interactome embedded in all biotic factors is not sufficient to elucidate its mechanics. This truism champions a quantitative understanding of biology, Max Delbruck called it Physical Biology.
Furthermore, to prevent the risk of readers assuming that biology was analyzed conceptually since its inception, I must provide this disclaimer; the study of biology from experiment to publication has a rich history of being quantitative. Gregor Mendel, the father of Classical Genetics established the allelic principle of inheritance, a quantitative assessment of heredity. Even the double helix, a beautiful structural motif owes its discovery to a tool of physical biology, X-ray Crystallography. Therefore in practice, biology remains to be quantitative as a result of the techniques we use to investigate it.
In contemporary times it is most expedient to study the dynamics of biological systems because of advances in optical resolution. Optics have made major contribution to physical biology for centuries, Robert Hooke initiated the study of organic matter via microscopy, once he gazed through a lens, reducing his wide view to myopia, resulting in him coining the term a "cell". Optimization in this field has yielded nanometer resolution of complex biological processes occurring at different time scales. Therefore, the teaching of biology is not fully responsible for the apparent lack of resolved processes; the arrival of these new discoveries on the dynamics of biology are proportional to the invention of the tools to assay them.
A major discovery which has arisen from biophysics that most biologists can appreciate is a revision of the Alberts Model for DNA replication. Antoine Van Oijen and colleagues, showed that the DNA replication fork could occupy more then two DNA polymerase molecules . This rendered the Alberts model of DNA replication inaccurate, not as a result of intrinsic error, but due to the development of single molecule techniques that allowed for Van Oijen to revisit this fundamental question. DNA Replication is one of many processes that has been revised by physical biology, and a potential product of these revisions includes an appreciation for calculation by biologists.
WHAT IS NATURE MADE OF?
The utility of order of magnitude calculation is truly indispensable, but unfortunately its not harnessed by most biologists. These calculations yield estimates that can give rise to a more intuitive understanding of the components making up complexity. The estimations are rooted in stoichiometry, a tool we all learned in freshmen chemistry. During this course it was imperative that we kept track of our units and if we produced an incorrect answer, it could be sited via intuition. But what are we actually doing once we carry out these calculations? We are literally taking an amalgamated solution or process, and calculating some intrinsic property that is smaller then the sum of the solution or the duration of the process. We can exploit this unique feature of stoichiometry to gain a feel for biological complexity by calculating the magnitude of its parts. For instance, a fundamental model organism in biology is Escherichia coli, and from its exterior its fairly difficult to determine what its made of, but by exploiting centrifugation and gene expression data on the components making up E.coli, we can calculate the amount of a particular molecule in a single cell.
For example, RNA Polymerase (RNAP) is a molecule that mediates Transcription, and the magnitude of its expression in the E. coli genome affects the fidelity of its global activity, which in turn makes this molecule a great candidate to quantify. Now lets undertake this calculation; an E.coli cell has a dry weight of ~1pg, and macromolecules make up 30% of the dry weight. Proteins make up 1/2 of the total macromolecules in the cell, giving it a mass of .15pg, since RNAP makes up .5% of total protein and the average molecular mass of a protein is 300kD the number of RNAP molecules equals 1.5 X 103.
This simple calculation allowed us to plunge ourselves deeper and deeper into E.coli's molecular infrastructure, a tangible value to bolster our intuition.
NOW LETS GET PHYSICAL
Rob Phillips of Caltech said "One of the key tenets of physical biology is that quantitative data demands quantitative models." A tool used to model biological dynamics is statistical mechanics. One approach we can use is to exploit entropic maximization to determine the allowed microstates of an object or process. You can think of microstates like a cartoon flip book, each piece of paper contributes to the overall macrostate you observe. Now if you know all the microstates (pieces of paper) associated with charlie brown eating dinner, and he is eating peas, rice, and roast beef, you can determine the probability of charlie brown eating peas. If there are 30 pages in the flip book and 10 of them have him eating peas then he eats peas 1/3 of the time. Macromolecules also exhibit these microstates as well.
To keep with the theme of transcription, Phillips developed a beautiful statistical mechanical model of promoter occupancy. He took experimental data which suggested that although RNAP has a binding site (promoter) it spends most of its time not free in solution but bound to chromatin and 1D diffusing to its binding site. The idea is DNA has more non-specific binding sites than specific binding sites (promoters). Therefore, we can predict the probability of a RNAP binding to its promoter by dividing the microstates associated with RNAP bound specifically by the sum of the microstates of nonspecific binding and specific binding . This example is no different then charlie brown eating dinner. Moreover, model building can help us learn more about biological complexity, we just have to get quantitative.
THE FUTURE OF PHYSICAL BIOLOGY
The physical biology grand challenge will be to provide a quantitative assessment of biology, and to allow the researchers of tomorrow to continue this goal by implementing and acknowledging the following:
1). Change the Discourse in Biology Education by revealing the dynamic nature of biological processes and placing these findings in modern text books
2). Encouraging undergraduates to take more math and physics
3). Harness order of magnitude calculations to bolster one’s intuition about size and scale
4). Improve the resolution of the tools used to observe biological phenomena
5). Continue to model these systems as we obtain physical outputs of catalytic activity
6). Most importantly create physical pictorial representations of every biological process discovered to date.
If we can accomplish these goals we will be one step closer to understanding our intrinsic complexity, one step closer to understanding the beauty of nature surrounding us, and one step closer to answering the question proposed by Schrodinger, What is life?>
. Schrodinger E. (1944). What is Life. Cambridge University Press
. Hamdan SM et al. (2007). Dynamic DNA helicase-DNA polymerase interactions assure processive replication fork movement. Mol. Cell.
. Phillips R et al. (2008) Physical Biology of the Cell. Garland Science