Why Congress Should Be Worried About the Endoplasmic Reticulum

ER-EM1-sm Electron micrograph of rough endoplasmic reticulum.
From The Cell by Don W. Fawcett M.D
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 interest 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 of 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 helicoid 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 multidisciplinary 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 to 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 Vice President 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. (2013). Stacked endoplasmic reticulum sheets are connected by helicoidal membrane motifs. Cell 154, 285-296, doi:10.1016
  2. Marshall, W. F. (2013). Differential geometry meets the cell. Cell 154, 265-266, doi:10.1016
Stefano Bertuzzi

Dr. Stefano Bertuzzi is the Executive Director of the American Society for Cell Biology. In this position he is responsible, with the ASCB Board, for strategic planning and all operations at the Society to serve the needs of its ~9,000 members and to promote the field of cellular biology and basic science.

Email This email address is being protected from spambots. You need JavaScript enabled to view it.

Most Recent Articles *

To read the full article, click on the READ MORE button below.

  • 1
  • 2
  • 3
  • 4
Prev Next
ASCB Kaluza Prize Reflects ASCB’s Concern that Young Scientists Are Now a Vulnerable Population

ASCB Kaluza Prize Reflects ASCB’s Concern that Young Scientists Are Now a Vulnerable Population

The ASCB Kaluza Prize recognizes significant research achievement by early career scientists who still pursue excellence amidst economic uncertainties and political shortsightedness. ASCB Photo.In the...

11-20-2013

Read more
Round Trip from Stockholm to ASCB

Round Trip from Stockholm to ASCB

With Stockholm still in the future, Randy Schekman (third from left) with fellow 2013 Nobel winner, Jim Rothman (far right), shared the ASCB's highest scientific honor, the E. B. Wilson Medal, with St...

11-06-2013

Read more
Colliding Worlds—A Rare Visit to the CERN Collider Gives a Biologist New Hope

Colliding Worlds—A Rare Visit to the CERN Collider Gives a Biologist New Hope

Nearly 170 meters beneath CERN, ASCB Executive Director Stefano Bertuzzi gets a rare look at the Large Hadron Collider. Here he stands in front of the detector. Photo Credit: ASCBLast week, I was invi...

10-23-2013

Read more
Watching Train Wrecks

Watching Train Wrecks

It’s full steam ahead for disaster or will the brakes stop the runaway fiscal crisis train in time? Photo by John FleischmanAlong with the future of U.S. research science, the train wreck metaphor has...

10-16-2013

Read more
UPDATED-NIH Furloughs to Widen—From Slowdown to Shutdown, U.S. Science Takes a Hit

UPDATED-NIH Furloughs to Widen—From Slowdown to Shutdown, U.S. Science Takes a Hit

The USDA is closed and no U.S. orders for international fruit flies can be processed until the government is back in business.Photo Credit: André KarwathUUPDATED—The "Activation Energy" blog has learn...

10-09-2013

Read more
Shutting Down Basic Science—Some Thoughts at Midnight (no, this is not a fairy tale)

Shutting Down Basic Science—Some Thoughts at Midnight (no, this is not a fairy tale)

Last night at midnight, the government ran out of money and shut down its main operations. Sadly, it left me wondering if perhaps our democracy ran out of steam as well. I've tried to explain what is ...

10-01-2013

Read more
New Partners and New Ventures for ASCB in Science Education Reform

New Partners and New Ventures for ASCB in Science Education Reform

In a 2012 Science editorial, Bruce Alberts, a former ASCB president who was then the journal's editor, urged professional societies to team up in leading innovation in science education. ASC...

09-25-2013

Read more
The Scholarly Paper That No One Will Want to Read Is Being Written in Congress

The Scholarly Paper That No One Will Want to Read Is Being Written in Congress

Spelling It Out: Spending on basic research has increased our longevity and the quality of that longer life. Photo Credit: John FleischmanThis week, a paper in the American Journal of Public Health, a...

09-18-2013

Read more
A Scientist-Senator with a Seat — and a Vote — for Life

A Scientist-Senator with a Seat — and a Vote — for Life

I recently spent some time on a family vacation in Italy. We have a tradition in our family; at the dinner table, each of us has to say the best and the worst thing that happened to him or her during ...

09-10-2013

Read more
Showing the Faces of Science

Showing the Faces of Science

In 2011, the Nobel Foundation awarded its prize of prizes to cell biologist, immunologist, and longtime ASCB member Ralph Steinman. When the foundation tried calling to deliver the good news, no one p...

09-05-2013

Read more
Lessons from a Society of Societies

Lessons from a Society of Societies

This week, ASCB went to ASAE, or rather five ASCB staffers and yours truly attended a meeting of the ASAE in Atlanta. ASCB, I trust you know, stands for the American Society for Cell Biology. The ASAE...

08-07-2013

Read more
The Perils of Reviewing Peer Review

The Perils of Reviewing Peer Review

As a recovering federal employee, I recognize that one of the biggest challenges the government faces in funding science is that of being truly Darwinian in a rapidly evolving scientific environment. ...

07-24-2013

Read more