22 Sep 2018
Ever wondered how groups of cells managed to build your tissues and organs while you were just an embryo?
Using state-of-the-art techniques he developed, UC Santa Barbara researcher Otger Campàs and his group have cracked this longstanding mystery, revealing the astonishing inner-workings of how embryos are physically constructed.
Not only does it bring a century-old hypothesis into the modern age, the study and its techniques provide the researchers a foundation to study other questions key to human health, such as how cancers form and spread or how to engineer organs.
“In a nutshell, we discovered a fundamental physical mechanism that cells use to mold embryonic tissues into their functional 3D shapes,” said Campàs, a professor of mechanical engineering in UCSB’s College of Engineering who holds the Duncan & Suzanne Mellichamp Chair in Systems Biology. His group investigates how living systems self organize to build the remarkable structures and shapes found in nature.
Cells coordinate by exchanging biochemical signals, but they also hold to and push on each other to build the body structures we need to live, such as the eyes, lungs and heart. And, as it turns out, sculpting the embryo is not far from glass molding or 3D printing. In their new work,”A fluid-to-solid jamming transition underlies vertebrate body axis elongation,” published in the journal Nature, Campàs and colleagues reveal that cell collectives switch from fluid to solid states in a controlled manner to build the vertebrate embryo, in a way similar to how we mold glass into vases or 3D print our favorite items. Or, if you like, we 3D print ourselves, from the inside.
Most objects begin as fluids. From metallic structures to gelatin desserts, their shape is made by pouring the molten original materials into molds, then cooling them to get the solid objects we use.
A fluid-to-solid jamming transition underlies vertebrate body axis elongation
As in a Chihuly glass sculpture, made by carefully melting portions of glass to slowly reshape it into life, cells in certain regions of the embryo are more active and ‘melt’ the tissue into a fluid state that can be restructured. Once done, cells ‘cool down’ to settle the tissue shape, Campàs explained.
“The transition from fluid to solid tissue states that we observed is known in physics as ‘jamming’,” Campàs said. “Jamming transitions are a very general phenomena that happens when particles in disordered systems, such as foams, emulsions or glasses, are forced together or cooled down.”
This discovery was enabled by techniques previously developed by Campàs and his group to measure the forces between cells inside embryos, and also to exert miniscule forces on the cells as they build tissues and organs. Using zebrafish embryos, favored for their optical transparency but developing much like their human counterparts, the researchers placed tiny droplets of a specially engineered ferromagnetic fluid between the cells of the growing tissue.
The spherical droplets deform as the cells around them push and pull, allowing researchers to see the forces that cells apply on each other. And, by making these droplets magnetic, they also could exert tiny stresses on surrounding cells to see how the tissue would respond.
“We were able to measure physical quantities that couldn’t be measured before, due to the challenge of inserting miniaturized probes in tiny developing embryos,” said postdoctoral fellow Alessandro Mongera, who is the lead author of the paper.
“Zebrafish, like other vertebrates, start off from a largely shapeless bunch of cells and need to transform the body into an elongated shape, with the head at one end and tail at the other,” Campàs said.
The physical reorganization of the cells behind this process had always been something of a mystery. Surprisingly, researchers found that the cell collectives making the tissue were physically like a foam (yes, as in beer froth) that jammed during development to ‘freeze’ the tissue architecture and set its shape.
These observations confirm a remarkable intuition made by Victorian-era Scottish mathematician D’Arcy Thompson 100 years ago in his seminal work “On Growth and Form.”
Read About: D’Arcy Wentworth Thompson
“He was convinced that some of the physical mechanisms that give shapes to inert materials were also at play to shape living organisms. Remarkably, he compared groups of cells to foams and even the shaping of cells and tissues to glassblowing,” Campàs said. A century ago, there were no instruments that could directly test the ideas Thompson proposed, Campàs added, though Thompson’s work continues to be cited to this day.
The new Nature paper also provides a jumping-off point from which the Campàs Group researchers can begin to address other processes of embryonic development and related fields, such as how tumors physically invade surrounding tissues and how to engineer organs with specific 3D shapes.
“One of the hallmarks of cancer is the transition between two different tissue architectures. This transition can in principle be explained as an anomalous switch from a solid-like to a fluid-like tissue state,” Mongera explained. “The present study can help elucidate the mechanisms underlying this switch and highlight some of the potential druggable targets to hinder it.”
Alessandro Mongera, Payam Rowghanian, Hannah J. Gustafson, Elijah Shelton, David A. Kealhofer, Emmet K. Carn, Friedhelm Serwane, Adam A. Lucio, James Giammona & Otger Campàs
30 Apr 2015
The group works with the precious metal to create nanoscale silver clusters with unique fluorescent properties. These properties are important for a variety of sensing applications including biomedical imaging.
The team’s latest research is published in a featured article in this month’s issue of ACS Nano, a journal of the American Chemical Society. The scientists positioned silver clusters at programmed sites on a nanoscale breadboard, a construction base for prototyping of photonics and electronics. “Our ‘breadboard’ is a DNA nanotube with spaces programmed 7 nanometers apart,” said lead author Stacy Copp, a graduate student in UCSB’s Department of Physics.
“Due to the strong interactions between DNA and metal atoms, it’s quite challenging to design DNA breadboards that keep their desired structure when these new interactions are introduced,” said Gwinn, a professor in UCSB’s Department of Physics. “Stacy’s work has shown that not only can the breadboard keep its shape when silver clusters are present, it can also position arrays of many hundreds of clusters containing identical numbers of silver atoms — a remarkable degree of control that is promising for realizing new types of nanoscale photonics.”
The results of this novel form of DNA nanotechnology address the difficulty of achieving uniform particle sizes and shapes. “In order to make photonic arrays using a self-assembly process, you have to be able to program the positions of the clusters you are putting on the array,” Copp explained. “This paper is the first demonstration of this for silver clusters.”
The colors of the clusters are largely determined by the DNA sequence that wraps around them and controls their size. To create a positionable silver cluster with DNA-programmed color, the researchers engineered a piece of DNA with two parts: one that wraps around the cluster and the other that attaches to the DNA nanotube. “Sticking out of the nanotube are short DNA strands that act as docking stations for the silver clusters’ host strands,” Copp explained.
The research group’s team of graduate and undergraduate researchers is able to tune the silver clusters to fluoresce in a wide range of colors, from blue-green all the way to the infrared — an important achievement because tissues have windows of high transparency in the infrared. According to Copp, biologists are always looking for better dye molecules or other infrared-emitting objects to use for imaging through a tissue.
“People are already using similar silver cluster technologies to sense mercury ions, small pieces of DNA that are important for human diseases, and a number of other biochemical molecules,” Copp said. “But there’s a lot more you can learn by putting the silver clusters on a breadboard instead of doing experiments in a test tube. You get more information if you can see an array of different molecules all at the same time.”
The modular design presented in this research means that its step-by-step process can be easily generalized to silver clusters of different sizes and to many types of DNA scaffolds. The paper walks readers through the process of creating the DNA that stabilizes silver clusters. This newly outlined protocol offers investigators a new degree of control and flexibility in the rapidly expanding field of nanophotonics.
The overarching theme of Copp’s research is to understand how DNA controls the size and shape of the silver clusters themselves and then figure out how to use the fact that these silver clusters are stabilized by DNA in order to build nanoscale arrays.
“It’s challenging because we don’t really understand the interactions between silver and DNA just by itself,” Copp said. “So part of what I’ve been doing is using big datasets to create a bank of working sequences that we’ve published so other scientists can use them. We want to give researchers tools to design these types of structures intelligently instead of just having to guess.”
The paper’s acknowledgements include a dedication to “those students who lost their lives in the Isla Vista tragedy and to the courage of the first responders, whose selfless actions saved many lives.”