Bioimaging: Exploring Life in the Fourth Dimension

CAMBRIDGE, Mass. — When Anton Van Leeuwenhoek first transformed a small glass ball into a magnifying lens, he opened a new window into the world of scientific discovery. Four centuries and millions of magnifications later, researchers are able to see the inner workings of the cell and use their observations to unravel many mysteries of life.

Using a synthesis of biology, bioengineering, and physics, Whitehead scientist Paul Matsudaira is exploring territory that Leeuwenhoek and his predecessors could only dream of. With the ability to peer into what scientists call the fourth dimension—three dimensions across time—Matsudaira and his colleagues are transcending the limits of traditional microscopy.

“The next phase in biology, fueled in part by advances in genomics, will be to understand how a cell does what it does,” says Matsudaira. “Advanced biological imaging allows us to actually watch a cell work, in three-dimensions and in real time. This enables us to bring together information about systems within cells and to tease out how the cell changes over time.”

Building a Core Facility

Matsudaira is part of a joint effort between Whitehead and the School of Engineering at the Massachusetts Institute of Technology (MIT) to launch a new bioimaging center, which will refine bioimaging technologies and tackle a host of complex biological questions. This type of effort will require researchers from diverse backgrounds with unique expertise to work together.

The center, seeded by a grant from the W.M. Keck Foundation, will be organized around a core facility that will house some of the best bioimaging tools available. The centerpiece of the facility is a custom-built, remote controlled cryroelectron microscope—the first of its kind—and a super computer called “Kahuna.”

“The bioimaging center will be devoted to promoting the development of imaging technologies and their application in biomedicine and bioengineering,” says Matsudaira. “By bringing together the best equipment, the best software, and the best people, we can begin to apply and modify new bioimaging technology to get answers to biological questions that no one else can get.”

The center will also focus on developing the computational tools necessary to create, process, and store high-resolution images. “Imaging generates data that is fundamentally different from other data. We need to understand how to recognize and extract it,” says Matsudaira. “As a result, developing strong computational core services will be critical to the center’s success.”

Life in the Fourth Dimension

The Matsudaira lab is using advanced bioimaging techniques to study how cells move throughout the body, a process known as cell motility. Since motility is an important function for many normal cells, understanding this process can provide valuable information about what goes wrong in disease.

As their first model system, the lab is studying how immune cells called macrophages quickly rove the body in search of foreign invaders. Researchers now know that this process is dependent upon the activity of cell structures called podosomes. Until recently, how these button-like adhesions form and function to move the cell forward was a mystery. But, four-dimensional microscopy has provided a global perspective on the mechanics of cell motility and a better understanding of how podosomes work, says Matsudaira.

James Evans, a postdoc in the Matsudaira lab, is using a combination of biochemical and microscopy-based techniques to investigate how podosomes, comprised of more than 100 different proteins, form, assemble and disassemble to initiate cell movement. “To understand how podosomes function, we need to visualize how they change over time and interact with other cell structures,” says Evans. “You can’t see this in a test tube and you can’t see it in two dimensions.”

To observe this process over time, Evans uses a confocal or deconvolution microscope to take a series of pictures. Evans feeds this series of three-dimensional snapshots into a powerful computer. Aided by a sophisticated software package, the individual images are assembled into a fluid rendition of podosomes in motion.

To crawl forward, the leading edge of the cell must create traction. Podosomes rapidly create sticky adhesions at the front of the cell, enabling the cell to move forward. As the rear part of the cell is also pulled forward, the podosomes at the leading edge are disassembled so that new and “refreshed” podosomes can move to the front of the cell, create new structures, and continue the cycle.

“In two dimensional images you can have objects that are on top of each other, so when you compress the image, it looks like the objects are occupying the same space. In four dimensions, we not only see objects more fully, we begin to understand how they interact as part of a system.”

In addition to their work with podosomes, the Matsudaira lab is also looking at models of how cells store energy to induce movement. Using high resolution imaging, researchers are studying a unique cellular engine that works by storing energy like a spring, instead of burning fuel like a car engine does.

“By studying such specialized systems, we might be able to recognize other occasions in which a cell stores energy in a particular way to produce an effect,” says Matsudaira. “In ten years, we may know that this is a common mechanism, but until now, we just couldn’t see it.” And in biology, as in life, seeing in believing.