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A closer look at living cells

Frog cells

These images show how a single frog cell reacted over a period of 105 minutes as its temperature was gradually raised from the normal body temperature for frogs to the normal body temperature for humans.

Sometimes the best ideas arise from the combination of two seemingly different concepts. Such is the case with a combined microscope being developed by Pacific Northwest National Laboratory.

This device marries two existing technologies to create a new research capability. It provides researchers a noninvasive way to observe living cells in real time.

"Many biological techniques start with breaking up cells, which causes valuable information to be lost. This is a new way to gain information about a cell without destroying it," said Eric Ackerman, a staff scientist in Pacific Northwest's Molecular Biosciences Department.

The combined microscope represents the union of an optical microscope and magnetic resonance microscopy (MRM), which is similar to magnetic resonance imaging, or MRI, used at hospitals to create visual images of the human body. With an MRM probe at the top and an optical microscope at the bottom, a sample placed between the two can be observed for the first time using both techniques simultaneously, explained Robert Wind, a staff scientist in macromolecular structure and dynamics. "We'll be able to see things with one technique that you can't see with the other," he said.

Narrowing in on environmental health regulations

The combined microscope may help researchers gain insight into how cells react and recover when exposed to heat, chemicals or radiation because the same living cells can be studied over time. As part of Pacific Northwest's work focused on determining how the environment affects human health, researchers are studying how complex environmental stresses affect individual cells.

Building an understanding of what happens in a cell when it's exposed to contaminants can help ensure that environmental regulations and limits on worker and public exposure are safe and based on solid scientific evidence. According to Ackerman, some existing regulations may be unnecessarily conservative because current scientific data is limited. "Money spent adhering to unnecessarily restrictive regulations might be better utilized to improve public health," he said.

Exploring cancer research

Scientists studying dissected tumors with conventional instruments used in cancer research can get only a snapshot of the tumors' properties at the time they were removed. Using the combined microscope, however, the evolution of a living tumor and the effects of therapy can be studied over time. "In order to improve our understanding of cancer formation, we need to see what's happening in the whole cell, in real time, without destroying it," Ackerman said.

Researchers will be able to track which healthy cells become cancerous as the disease spreads, which could improve diagnostic methods in the future.

Cell death, or apoptosis, can be studied with this tool. Built-in instructions for an aberrant cell to stop living can protect a person from developing diseases such as cancer.

"The fact that cells have the ability to kill themselves is a dangerous but essential process," Ackerman said.

"As a control mechanism, cells must go through all kinds of locked doors before they can commit themselves to death. We hope to gain new insights into the controls on those doors."

Zooming in on cell chemistry

The combined microscope also will collect information about certain chemical compounds present in different parts of a cell or in different types of cells using nuclear magnetic resonance spectroscopy. Spectroscopy maps the chemical compounds that are found in each section of an established grid pattern that can be laid over an image to select areas of interest. grid cells

So far, researchers have used this technique only with relatively low-resolution images. With the detailed image from the optical microscope guiding this technique, however, specific chemical information can be obtained from much smaller sections.

"The whole idea is to overlay the spectral grid with high resolution optical microscopic images to get much richer information," Wind said. With this ability, researchers can compare healthy cells to stressed cells and apoptotic cells.

Starting with a diverse culture

Just as the device marries two technologies, the team developing the combined microscope represents a multidisciplinary approach. The idea originated less than two years ago with Wind and Kevin Minard, both of whom are physicists. Ackerman is a molecular biologist. Others involved are Gary Holtom, an optical expert; Paul Majors, a physical chemist; biologists and data analysis specialists. Researchers at MIT are collaborating on the development of the magnetic resonance portion.

The first results from the combined microscope are expected at the William R. Wiley Environmental Molecular Sciences Laboratory in early 2000. As a part of this U.S. Department of Energy user facility, researchers from around the world have the opportunity to use the equipment.

Real-time cellular stress tests under way


Cellular observations at Pacific Northwest National Laboratory are heating up. Using tools similar to the magnetic resonance imaging equipment found in hospitals, scientists have collected real-time images of single living frog cells as they reacted to increased temperatures.

Researchers have accepted the fact that in response to heat or other stresses, all cells—from bacterial to human—start creating "heat shock" proteins and stop creating the proteins necessary to sustain unstressed life. What remains unknown is how this process protects cells and its consequences.

"There is a very high probability that the response mechanisms in frog cells would be very similar in humans," said Eric Ackerman, a staff scientist in Molecular Biosciences.

During initial heat shock experiments, researchers observed the changes over time in single large pre-egg cells called oocytes, and even in specific parts of an oocyte. In one, major structural changes were observed after heating the frog cell to human body temperature. By applying magnetic resonance microscopy, images were recorded as the cell partially disintegrated and eventually died.

Using a technique called spectroscopy, scientists also have obtained chemical information from the nucleus of a living cell and the surrounding cytoplasm without harming the cell in the process.

A new tool that combines an optical microscope with magnetic resonance microscopy will give researchers a new way to observe cells and further this research.

"We're hoping that the combined microscope will give us new insight into how cells respond to environmental stresses," Ackerman said. "We'll understand more about recovery and learn to determine how much stress is tolerable and what actually constitutes a stress or hazard to health."

Tropical island a haven for intense climate research

A month-long stay on a tropical island may sound like a vacation, but for climate change experts gathered on the tiny Western Pacific island of Nauru in June and July, the trip represented a first-of-its-kind atmospheric research effort.


The goal of the Nauru99 campaign was to learn more about how the tropics influence weather and climate worldwide. While it is known that the Tropical Western Pacific serves as the earth's heat engine driving global weather events such as El Niño and La Niña, little is known about how this furnace works.

During the campaign, simultaneous measurements were taken from the land, sea and air to build a better understanding of the energy transfer between the ocean and the atmosphere and the effect of clouds on this transfer. The studies were also aimed at determining if land-based measurements serve as effective surrogates for measurements taken in the ocean.

The National Oceanic Atmospheric Administration and the Japan Marine Science and Technology Center each provided a research ship loaded with sophisticated instruments. Instruments on the island, more than 70 instrumentation buoys and a Cessna research aircraft provided by Australia's Flinders University also collected data.

ship -Ron Brown

The U.S. Department of Energy's Atmospheric Radiation Measurement Program (ARM) sponsored Nauru99. Pacific Northwest staff coordinate many activities of this program, which involves more than 60 organizations, including seven other DOE national laboratories. Scientists at the Laboratory also develop and integrate instruments like those used in Nauru99, as well as prepare and package the data for scientists working with the program.

Pacific Northwest hosted a workshop for Nauru99 participants in October. The researchers discussed the project and preliminary results. The final results will ultimately lead to more accurate climate change models.

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