Molecular Biology of the Cell Vol. 25, No. 22 Perspectives Free Access
The quantified cell
Avi Flamholz, Rob Phillips, and Ron Milo
Doug Kellogg, Monitoring Editor Jennifer Lippincott-Schwartz, Guest Editor
Published Online:13 Oct 2017 https://doi.org/10.1091/mbc.e14-09-1347
FIGURE 1: Which is larger, mRNA or the protein for which it codes? When we ask, most peoples' instinct is to say that proteins are larger. As seen in this figure, the opposite is overwhelmingly the case. The mRNA for actin is more massive and has a larger geometric size than the actin monomers for which it codes because the mass of a codon of mRNA is an order of magnitude greater than that of the average amino acid.
Abstract
The microscopic world of a cell can be as alien to our human-centered intuition as the confinement of quarks within protons or the event horizon of a black hole. We are prone to thinking by analogy—Golgi cisternae stack like pancakes, red blood cells look like donuts—but very little in our human experience is truly comparable to the immensely crowded, membrane-subdivided interior of a eukaryotic cell or the intricately layered structures of a mammalian tissue. So in our daily efforts to understand how cells work, we are faced with a challenge: how do we develop intuition that works at the microscopic scale?
I have deeply regretted that I did not proceed far enough at least to understand something of the great leading principles of mathematics, for men thus endowed seem to have an extra sense.
—Charles Darwin, Autobiography
In aiming to build better intuition for the alien world of cells, it is useful to first imagine how we would introduce our modern human society to curious aliens. If and when we meet an alien, we plan to come prepared with copies of the most recent census—chock full of numbers, charts, and summary statistics. Numbers will tell our alien friend when we will likely marry, how many children we will have, and what will most likely cause our deaths. They will also report how many hours we spend commuting to work and watching TV and what we eat when we do those things. Just as quantitative data clearly describe the behavior of human populations, numbers offer a clear path to understanding the alien world of cells. Yet there is still so much to be learned—our current cellular census is woefully incomplete. We biologists should improve the cellular census and document the budgets of cells so that we can leverage the incredible capacity of numbers to describe biological systems and generate testable predictions about them.
Applying this quantitative approach to biology is inherently difficult because life is dynamic and diverse. For example, when we ask our fellow biologists how many copies of their favorite protein are found in a particular cell line, they often answer that “it depends.” And indeed it does depend—on the carbon source, the presence of different signaling molecules, and the temperature in the lab that day. Sometimes, after a long day in lab, it may seem like “it depends” also on the whims of mercurial and vengeful gods. But we want to make the case that it is nonetheless important to supply a number. To see why, let's examine how intuitively we process dynamic ranges of values in a more familiar scenario.
How much does a car cost? You would certainly be right to say that the price depends on the make, the model, and the dealer. But that answer conveys no information. You might also tell us that the Honda Civic you want costs $12,895 at the dealership downtown. But that is only that one Honda—the answer is too precise to be informative about other cars. Finally, you might tell us that a car costs about $10,000. This number is not so accurate—a cheap car might be $8000 and a more expensive one $40,000—but it is a very useful estimate. We would probably have a similar discussion about the cost of a TV, only scaled down by an order of magnitude. Like a car, the cost of a TV also depends. If all we knew was that “it depends,” without a rough estimate of the price, it would be difficult for us to choose a free car over a free TV as a game show contestant. But everyone knows you should choose the car because a car costs ≈$10,000 and a TV costs ≈$1000. Luckily, we carry with us such intuition-building order-of-magnitude estimates as we forage through the modern jungle.
Moving to the world of cell biology, we can test our intuition by asking, Which is heavier, a protein or the mRNA that codes for it? Even after years of studying and manipulating DNA, RNA, and protein in our labs, we may not be prepared for this question. Equipped with a few numbers, however, we can answer the question easily and begin to renovate our intuition. Natural amino acids vary somewhat in their molecular mass, but their average mass is ≈100 Da or about threefold less than a nucleotide (weighing ≈300 Da; for full reference to the primary literature Google “BNID 104886,” the BioNumbers ID for this particular quantity). Because the genetic code uses three nucleotides to encode each amino acid, we quickly conclude that an mRNA has a mass about ninefold greater than the protein it encodes (without even accounting for the mass of untranslated regions of mRNA). In contrast to the usual cartoon representations of the central dogma, which can obscure the relative sizes of molecular components, Figure 1 is drawn to scale. If more of our models and textbook figures respected quantitative properties like size and concentration, we might have developed a better intuitive grasp of these properties (for an example of a situation in which paying attention to the relative sizes of proteins was vital see Davis and van der Merwe, 2006; James and Vale, 2012).
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