Why Carbon Nanotubes Spell Trouble For Cells

It's been long known that asbestos spells trouble for human cells. Scientists have seen cells stabbed with spiky, long asbestos fibers, and the image is gory: Part of the fiber is protruding from the cell, like a quivering arrow that's found its mark.

But scientists had been unable to understand why cells would be interested in asbestos fibers and other materials at the nanoscale that are too long to be fully ingested. Now a group of researchers at Brown University explains what happens. Through molecular simulations and experiments, the team reports in Nature Nanotechnology that certain nanomaterials, such as carbon nanotubes, enter cells tip-first and almost always at a 90-degree angle. The orientation ends up fooling the cell; by taking in the rounded tip first, the cell mistakes the particle for a sphere, rather than a long cylinder. By the time the cell realizes the material is too long to be fully ingested, it's too late.

"It's as if we would eat a lollipop that's longer than us," said Huajian Gao, professor of engineering at Brown and the paper's corresponding author. "It would get stuck."

The research is important because nanomaterials like carbon nanotubes have promise in medicine, such as acting as vehicles to transport drugs to specific cells or to specific locations in the human body. If scientists can fully understand how nanomaterials interact with cells, then they can conceivably design products that help cells rather than harm them.

"If we can fully understand (nanomaterial-cell dynamics), we can make other tubes that can control how cells interact with nanomaterials and not be toxic," Gao said. "We ultimately want to stop the attraction between the nanotip and the cell."

Like asbestos fibers, commercially available carbon nanotubes and gold nanowires have rounded tips that often range from 10 to 100 nanometers in diameter. Size is important here; the diameter fits well within the cell's parameters for what it can handle. Brushing up against the nanotube, special proteins called receptors on the cell spring into action, clustering and bending the membrane wall to wrap the cell around the nanotube tip in a sequence that the authors call "tip recognition." As this occurs, the nanotube is tipped to a 90-degree angle, which reduces the amount of energy needed for the cell to engulf the particle.

Once the engulfing - endocytosis - begins, there is no turning back. Within minutes, the cell senses it can't fully engulf the nanostructure and essentially dials 911. "At this stage, it's too late," Gao said. "It's in trouble and calls for help, triggering an immune response that can cause repeated inflammation."

The team hypothesized the interaction using coarse-grained molecular dynamic simulations and capped multiwalled carbon nanotubes. In experiments involving nanotubes and gold nanowires and mouse liver cells and human mesothelial cells, the nanomaterials entered the cells tip-first and at a 90-degree angle about 90 percent of the time, the researchers report.

"We thought the tube was going to lie on the cell membrane to obtain more binding sites. However, our simulations revealed the tube steadily rotating to a high-entry degree, with its tip being fully wrapped," said Xinghua Shi, first author on the paper who earned his doctorate at Brown and is at the Chinese Academy of Sciences in Beijing. "It is counter-intuitive and is mainly due to the bending energy release as the membrane is wrapping the tube."

The team would like to study whether nanotubes without rounded tips - or less rigid nanomaterials such as nanoribbons - pose the same dilemma for cells.

"Interestingly, if the rounded tip of a carbon nanotube is cut off (meaning the tube is open and hollow), the tube lies on the cell membrane, instead of entering the cell at a high-degree-angle," Shi said.

Agnes Kane, professor of pathology and laboratory medicine at Brown, is a corresponding author on the paper. Other authors include Annette von dem Bussche from the Department of Pathology and Laboratory Medicine at Brown and Robert Hurt from the Institute for Molecular and Nanoscale Innovation at Brown.

The National Science Foundation, the U.S. Department of Commerce National Institute of Standards and Technology, the National Institute of Environmental Health Sciences Superfund Research Program, and the American Recovery and Reinvestment Act funded the research.

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How Asbestos Fibers Trigger Cancer In Human Cells

ScienceDaily (Dec. 18, 2008) — Ohio State University scientists believe they are the first in the world to study the molecular underpinnings of cancer by probing individual bonds between an asbestos fiber and human cells.

See Also:Health & MedicineMesotheliomaLung CancerCancerLymphomaDiseases and ConditionsOvarian CancerReferenceAsbestosMesotheliomaIndoor air qualityCarcinogen

Though any clinical application is years away, the researchers hope their findings could aid in drug development efforts targeting illnesses caused by excessive exposure to asbestos, including the deadly cancer called mesothelioma.

The researchers use atomic force microscopy to observe how a single asbestos fiber binds with a specific receptor protein on cell surfaces. They suspect that at least one of the more lethal forms of asbestos triggers a cascade of events inside cells that eventually lead to illness, sometimes decades later.

The conditions most commonly associated with long-term exposure to airborne asbestos are lung cancer; asbestosis, a chronic respiratory disease; and mesothelioma, a cancer that forms in the membrane lining most internal organs of the body, including the lungs.

Eric Taylor, a doctoral candidate in earth sciences at Ohio State and a coauthor of the study, describes atomic force microscopy as “Braille on a molecular level,” meaning it allows scientists to feel and observe what’s happening on molecular surfaces.

“We’re looking at what molecules are involved in the chain of events when the fiber touches the cell. Does the binding occur over minutes, or hours? And what processes are triggered?” said Taylor, who presented the research at the American Geophysical Union meeting in San Francisco.

Asbestos comprises six different minerals that naturally occur in both fragment and fibrous forms. Because of its high durability and heat resistance, the fibrous form has been used in many manufacturing products since the late 1800s. Though its use is now highly regulated, asbestos is still present in many materials. The U.S. Department of Labor estimates that 1.3 million employees face significant asbestos exposure on the job. Environmental exposure is also possible because asbestos is a naturally occurring mineral in soils and exposed bedrock.   

Crocidolite, or blue asbestos, is part of the amphibole group of asbestos minerals, which were banned in most of the Western world by the mid-1980s. Before that, they were used in such products as ceiling tiles and thermal insulation.

Ohio State researchers have focused so far on the crocidolite form of asbestos, but eventually hope to study how all six forms of asbestos interact with certain proteins on cell surfaces. Some forms of asbestos can dissolve in the lungs if they are inhaled, but others are believed to essentially “stick” to cells, especially at high concentrations, and eventually cause lung diseases.

“For the first time, this will give us data on biological activity that should help policymakers determine which forms of asbestos are the most dangerous,” said Steven Lower, associate professor of earth sciences at Ohio State and a coauthor on the study.

“The hypothesis we’re testing is that binding of cell surface receptors to asbestos fibers triggers a signal event, which initiates the cancer,” said Lower, also a faculty member in the School of Environment and Natural Resources. “There seems to be something intrinsic about certain types of asbestos, blue asbestos in particular, that elicits a unique signal, and it triggers inflammation, the formation of pre-malignant cells and, ultimately, cancer.”

The first protein to be studied is epidermal growth factor receptor, which is present on the surface of every human cell. Understanding the intricacies of the binding process between the mineral and one or more proteins will provide an index of the biological activity of a particular type of asbestos, and might lead the researchers to figure out how to prevent or undo that interaction, Lower said.

Taylor said the driving motivation behind the research is the potential to find a way to intervene and prevent illness even after someone is exposed to asbestos. Mesothelioma symptoms don’t typically appear until 30 to 50 years after exposure. After diagnosis, however, the cancer is difficult to control, and there is no cure.

This work is supported by the National Science Foundation.

Taylor and Lower conducted the research with Ann Wylie of the University of Maryland and Brooke Mossman of the University of Vermont.

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