A Cell's Secret Machinations

The Attraction of New Materials for Data Storage

Berkeley Engineers: Changing Our World

Dean's Digest

Printer-friendly version

Dan Fletcher with a custom Atomic Force Microscope designed and built by his research group to analyze the mechanisms of cell motility. Understanding how a cell moves could someday make it possible to engineer novel devices that take inspiration from cellular mechanisms, such as advanced drug delivery systems. (David Pescovitz photo)

A cell is an engineering tour de force, perfected through four billion years of research and development. That's why many diseases are so tough to beat. Fortunately, researchers like UC Berkeley bioengineering professor Daniel Fletcher are developing new techniques to deepen our understanding of a cell's mechanical properties. Teasing out those underlying engineering principals could pay off with new drugs that throw a wrench into the works of diseased cells.

"Much of my research is aimed at developing techniques that help us understand the mechanics of cells and proteins and their role in diseases," says Fletcher, who will present his research at the 4th annual Berkeley in Silicon Valley symposium on April 24.

Currently, Fletcher is studying the cellular mechanisms underlying giardiasis, a severe diarrheal illness prevalent in many developing countries, and leukemia, a cancer originating in bone marrow that results in the uncontrolled accumulation of immature and malfunctioning white blood cells. Some types of leukemic cells have been found to clog small blood vessels, resulting in strokes and respiratory failure.

"A white blood cell that's ten microns in size needs to deform to fit through a blood vessel that's several microns smaller in diameter," says Fletcher. "But if leukemic cells aren't flexible enough, they won't make it through and can aggregate in the vessel."

Fletcher--who is affiliated with the UC San Francisco/Berkeley bioengineering graduate group and the UC Berkeley bophysics graduate group--employs the tools of nanoscience and biology to probe the abnormal cells much as an auto mechanic examines a car's engine. For example, a fluorescence microscope hits a sample with a special high-intensity light that causes it to glow, resulting in a vivid image of structural proteins in a cell that's then magnified by the instrument. Meanwhile, an atomic force microscope physically scans a sample much like a needle travels across a record. As the probe moves over the surface of a cell, a cantilever at the end of the tip bends in response to the sample's topography and mechanical properties. That deflection is captured by a laser and translated into a measurement with nanometer (one-billionth of a meter) resolution.

In the case of leukemia, Fletcher and graduate students Mike Rosenbluth and Wilbur Lam are using the instruments to measure the flexibility of various types of diseased cells. Comparing those measurements with clinical data will reveal whether the clogs are in fact related to stiffness, stickiness, or some other mechanical property of certain leukemic cells. Eventually, Fletcher says, a leukemia patient's blood sample could be analyzed to determine if the cells are in a category of stiffness that's likely to cause aggregation in the blood vessels.

"If a patient is known to be at risk, steps can be taken to treat the patient before vessels become clogged," he says.

Giardia intestinalis is a microscopic parasite that once swallowed, attaches itself to the intestinal wall. It can be found in soil, water, or food contaminated by waste from humans or animals. (courtesy the researchers )

While his Leukemia research continues, Fletcher has also launched a new project targeting Giardia intestinalis, a one-celled parasite that causes acute diarrhea. While the parasite is all-too-common in the United States, the problem is even more serious in developing nations where it contributes to malnutrition. Treatments are available, but according to Fletcher none of them attack the organisms' parasitic mechanism of attachment. That's because the way in which the organisms latch on to the intestinal wall remains a mystery.

"Surprisingly, they can grab on to a wide variety of materials, even glass, that aren't anything like the intestines," Fletcher says.

To suss out their secret mechanism of attachment, Fletcher and graduate student Wendy Hansen are poking, prodding, and shaking the parasites in various ways. They've pushed them around with the atomic force microscope and spun them loose using a centrifugal assay of their own design. After numerous experiments, the researchers now believe that the parasite's magic mechanism may not be so different from a toilet plunger.

How do you think the mechanics of cells and proteins and their role in diseases might benefit society? We want to hear from you...

"I think the cells use suction," Fletcher says. "They go through a motion when they attach that looks like they're pressing down, pulling up, and forming a nice tight seal."

Once the mechanics of the parasite are proven, the researchers hope their measurement techniques will evolve into a tool to improve treatments or aid in drug discovery. For example, a drug under study could be added to the mix in the centrifuge to determine if the compound successfully inhibits the parasite's attachment mechanism.

"Cells are mechanical objects," says Fletcher. "My work is focused on understanding how cells generate various forces and respond to them."

Fletcher Lab

Biophysics Graduate Group

Lab Notes is published online by the Public Affairs Office of the UC Berkeley College of Engineering. The Lab Notes mission is to illuminate groundbreaking research underway today at the College of Engineering that will dramatically change our lives tomorrow.

Media contact: Teresa Moore, Lab Notes editor, Director of Public Affairs
Writer, Researcher: David Pescovitz
Web Manager: Michele Foley

Subscribe or send comments to the Engineering Public Affairs Office: lab-notes@coe.berkeley.edu.

© 2004 UC Regents. Updated 3/22/04.