Morphogenesis in biology always fascinated me. As a developmental neurobiologist at the bench, I studied how homeobox genes patterned the neural epithelium, the retina in particular, to understand the events that turn a flat sheet of epithelium into a three-dimensional hemisphere, the optic cup.
Since I came of age scientifically during the “genetic revolution” era, I was mesmerized by the ability of that technology to alter the mouse genome and allow me to watch powerful genes operating in vivo. However, I also had at the back of my mind an idea for a different if complementary approach to genetics. I envisioned a new kind of theoretical modeling that could take into account the physical forces acting on single cells while shaping a developing tissue. In particular, when imagining the retina’s formation, I always thought of the role of mechanical forces on cells, bending the epithelium sheet into an optic cup, and how this must be achieved with the lowest possible energy consumption.
Recently, a fabulous paper that appeared in Cell1 revived my interests and my dreams, although this time, the action was at a subcellular level. The paper by Mark Terasaki and colleagues at the University of Connecticut Health Center in Farmington takes a deep dive into the membranes of the endoplasmic reticulum (ER). The researchers emerge with experimental data and a simple theoretical model that unravels how stacked ER membranes form a continuous membrane system interconnected into a structure that corresponds to the minimum elastic energy needed to connect all sheets.
When we took Biology 101, we learned that all eukaryotic cells need an ER, which is an organized labyrinth of tubules and membrane sheets all interconnected. Textbooks then went on to say that this complex membrane system has a central function in lipid and protein biosynthesis and so on and so forth. After the July 18 paper by Terasaki and colleagues, the textbooks will need a refresher, containing an extra paragraph describing how the ER sheets are stacked together. In fact, this was unknown until last week. Scientists used stunning new electron microscopy techniques with improved membrane staining protocols to collect large numbers of serial ultrathin sections, which allowed 3D reconstruction of the ER membrane stacks in mouse cortical neurons and in the parotid salivary gland.
This recent paper caught my attention because it is a great example of how core cell biological questions can be addressed through genetic-driven principles, imaging techniques, and mathematical modeling. It is known that proteins shape the curvature of both ER tubules and sheets, helping stabilize curvatures of the edges. But this paper also examines mathematical modeling to reveal how a mathematical object called the helicoid exactly models how membranes in the ER are stacked. It uses the lowest energy state possible while allowing the packing together the maximum density of membranes, which is what is needed, especially in professional secretory cells like the salivary gland.
These results show that ER sheets are all interconnected with twisted membranes in a fashion that resembles the helicoids ramps connecting the different floors of a parking garage. And surprise, surprise, mathematical modeling shows that this structure corresponds to the minimal elastic energy of sheet edges and surfaces, while generating the optimal arrangement for a large number of membranes in the ridiculously crowded space of a cell, as Susan Lindquist defined the cellular environment at the December 2012 ASCB meeting.
Along with the Terasaki paper in Cell, I recommend that the readers of the Activation Energy blog also peruse the Leading Edge paper preview by Wallace Marshall2, which perfectly captures the relevance of this scientific contribution. Wallace will be the ASCB 2014 Annual Meeting Program Chair, so we are expecting some of this wonderful science to be featured in Philadelphia! This juncture of core cell biology, biophysics, imaging, and computational biology is a particularly exciting area, which is receiving increasing attention at ASCB.
Alas, as blown away as I am by the multi-disciplinary approach taken by the authors of the Cell paper, I can’t resist a final digression into science policy. Once again, I am struck by how little we know about living systems. We have made incredible progress but I am firmly convinced that we only know about 5% of the biology of living systems. And here in the folding of the ER is another clear example. I realize that asking policy makers in Congress ponder the folding of the ER membrane requires an almost unimaginable suspension of probability but the sequestration that Congress has let crash into research science since March 1 has already hurt progress toward understanding fundamental aspects of human biology. The worst thing is that we don’t know—and will never know—what would have been discovered during the sequestration. We will only know later on how long it took to reach levels of understanding that might have been in reach years before. This is the science that the locusts will eat.
How do we expect to deliver more effective drugs and cures to suffering patients if we don’t know (or didn’t until last week), the structure of the main organelle that synthesizes proteins? As Genentech VP James Sabry told Congress last month, industry needs to be able to count on NIH to make fundamental discoveries because industry itself cannot invest in such research. Cures begin with hard won discoveries of great principles in very small places like the ER.
1 Terasaki, M. et al. Stacked endoplasmic reticulum sheets are connected by helicoidal membrane motifs. Cell 154, 285-296, doi:10.1016/j.cell.2013.06.031 (2013).
2 Marshall, W. F. Differential geometry meets the cell. Cell 154, 265-266, doi:10.1016/j.cell.2013.06.032 (2013).