Beyond the Parts List

 

Even the most inveterate tinkerer must occasionally consult the instruction manual. Unfortunately, for some important machines we rely on every day - the assortment of microscopic machinery that makes up our body's cells - no such manual exists. While the parts list - genes, proteins and biological molecules - grows longer by the day, scientists are just beginning to understand how these components all work together to make up the complex machinery of cells, and how breakdowns in this equipment, the cause of many diseases, might be fixed.

A new international research project aims to improve this situation by setting out to write a "Cell Operations Manual" and a "Cell Repair Manual." This project is part of an ambitious initiative of the National Institutes of Health (NIH) in the U.S. called the "Roadmap for Medical Research." The brainchild of NIH director Elias Zerhouni, the Roadmap was set up to fund innovative biomedical research in a number of areas, with no less a goal than that of transforming medical science. In the futuristic area of nanomedicine, four groups were awarded grants totaling $43 million over five years. Prof. Benjamin Geiger, Dean of Biology and researcher in the Molecular Cell Biology Department at the Weizmann Institute of Science, is a member of one of these four groups, the NanoMedicine Center for Mechanical Biology. Each member of the group, which includes biologists, materials scientists, physicists and theoreticians from the U.S., Israel and Switzerland, will bring his or her own research experience to bear on fundamental questions concerning the mechanics of life on the incredibly tiny scales of cells and molecules.

Scale, in fact, is one of the more tangled puzzles the scientists plan to address. How do cells, around 40 microns across (a micron is a millionth of a meter), self-organize to become organisms that are meters in size? At the other end of the scale, single molecules, the information-bearing units of the cell, are in the nanometer range - just thousandths of the cell's size. If cells were the size of people, their sense organs would be little bigger than grains of sand. How does communication between a cell and its parts take place across this range?

Communication is another subject the scientists will tackle. Cells are continually subjected to mechanical forces, whether the pumping force of blood or the structural force of bones, tissues and neighboring cells. Endowed with sophisticated means of sensing these forces, they are able to convert their "readout" on the nature of the force into biochemical signals that then inform the cell's actions. But how exactly does this happen? Many diseases - including metastasis, in which cancer cells stop clinging to their neighbors and move away - might be tied to the cells' failure to properly sense and interpret forces. In addition, bioengineers attempting to grow tissues from various stem cells have found that cells need the proper mechanical cues in their environment to know how to develop into specific cell types.

From nanomaterials and nanoelectronics to molecular biology, the world of the ultra-small has its own physical laws, which very often differ from those of the everyday world. By incorporating knowledge from varied fields, the research group intends to develop new approaches to understanding the mechanics of the cell. As their work progresses, the scientists hope to gain insight into many of the major health issues facing us today: wound healing, hypertension and cardiovascular diseases, osteoporosis, nerve regeneration,immune responses and cancer. The "instruction manuals" they're planning will then become works-in-progress that can be applied to maintaining the machinery of life in good working order.

 

For a number of years Prof. Geiger, a molecular cell biologist, and Prof. Joachim Spatz of the University of Heidelberg, a materials scientist, have been working together to try to figure out how the cell "reads" and responds to the information in its environment. Spatz and his group in Heidelberg create materials with surfaces that mimic collagen, one of the body's support materials. They simulate different conditions by controlling various properties of these materials, such as their surface topography or relative hardness, and they also produce nanopatterned surfaces with minuscule areas of differing properties. Onto this carefully designed surface they anchor assorted molecules using gold nanoparticles.

These molecules are positioned so as to create tiny islands on which only one receptor (a cellular "antenna" through which cells connect to the world outside their walls) can gain a foothold at a time. "With these materials, we see exactly which molecules the receptors recognize and interact with," says Geiger. In recent studies, the scientists have discovered that the placement of the binding molecules affects the ability of the cell receptors to work together either to keep the cell stuck to the surface or to help it move. The method has the added advantage of providing a relatively large surface - a centimeter or so square (several football fields to a cell) - to work with.