nano-canary in the nanotoxicology coalmine

New nano-canary in the nanotoxicology coalmine: The body itself

With an eye on disembodied cells and virtual organs, researchers attempt to track biological changes as they occur

There is growing consensus among scientists, regulators, politicians, industry and the public that we need to know more about the possible harmful or adverse effects of nanoparticles on human health.

Likewise, most agree that these incredibly small materials can behave quite differently from conventional materials. Nonetheless, neighborhood stores feature products that promise benefits from these near-atomic level materials, from paints and cosmetics to toothpaste and sunscreens. But, could we be putting human health at risk by exposing consumers to potentially toxic materials?

To investigate the damage potential of sub-micron sized particles, S.K. Sundaram and Thomas J. Weber, scientists at the Department of Energy's Pacific Northwest National Laboratory in Richland, Wash., have harnessed living cells to monitor responses to a variety of biologically active test agents. They presented their findings Friday at the American Association for the Advancement of Science annual meeting.

"Our process requires that live cells be grown on an infrared transparent substrate giving us an opportunity to closely examine the biological effects in living cells," said Sundaram. Live cell Fourier transform infrared, FTIR, spectroscopy offers several attractive features for these investigations. These include the potential to detect biologically active nanoparticles without any prior knowledge of cell signaling pathways affected by them or need of a contrast agent to detect the biological response. Thus, live cell FTIR spectroscopy is expected to be a sentinel of exposure to help identify the physico-chemico properties of nanoparticles that mediate biological activity, without bias of what that biological activity represents.

The PNNL scientists are also developing infrared transparent chemistries that are expected to improve FTIR measurements in live cell experiments. "We believe this report outlines the first use of FTIR spectroscopy to examine the biological response of living cells to nanoparticles, and expect this technology will enable us to identify chemical changes associated with the biological response," said Weber. FTIR spectroscopy measures a broad spectrum of chemical bonds and will provide information that is complementary to genomic and proteomic approaches.

FTIR spectra are captured in minutes in live cell studies, offering a tool to rapidly detect whether nanoparticles are biologically active. This information can be used to prioritize nanoparticles for further study to ascertain the nature of the biological activity in terms of toxicity.

A broader approach underway at PNNL for discovering what environmental nanomaterials can do once they enter the body – and how they enter and where they go – is part of a large collaborative effort funded by NIH, DOE and private industry. This research is aimed at developing predictive respiratory system models for laboratory animals and humans. A key component of this multi-institution collaborative effort is a $10 million, 5-year Bioengineering Research Partnership, BRP, funded by the National Heart Lung and Blood Institute that is designed to devise 3-D imaging and computational models that provide unsurpassed detail of respiratory systems in humans and other mammals.

Advancements in medical imaging, data analysis and computation have increased "the speed and accuracy of developing detailed models of the complete respiratory system," reported Richard Corley, PNNL staff scientist and director of the multi-institutional BRP. "New imaging techniques also show promise for validating particle deposition models. Atlases of airway geometries and functional characteristics are also being constructed to facilitate analyses of variability, reduce uncertainties in animal to human extrapolations and contribute to a more quantitative representation of environment-disease interactions." ###

Pacific Northwest National Laboratory (pnl.gov/) is a DOE Office of Science laboratory that solves complex problems in energy, national security, the environment and life sciences by advancing the understanding of physics, chemistry, biology and computation. PNNL employs 4,100 staff, has an annual budget of more than $700 million annual budget, and has been managed by Ohio-based Battelle since the lab's inception in 1965.

The capability of measuring and modeling subcellular responses to toxicants represents significant progress toward an important capability within PNNL's Environmental Biomarkers Initiative (biomarkers.pnl.gov/). The EBI applies system science and pattern recognition to the discovery of biomolecular signatures. PNNL believes biomarkers provide the next generation of risk assessment tools, replacing whole-organism measures of response with directly measured sub-cellular responses from first exposure through terminal disease state.

Contact: Geoffrey Harvey geoffrey.harvey@pnl.gov 509-372-6083 DOE/Pacific Northwest National Laboratory

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There's something fishy about human brain evolution

There's something fishy about human brain evolution

Forget the textbook story about tool use and language sparking the dramatic evolutionary growth of the human brain. Instead, imagine ancient hominid children chasing frogs. Not for fun, but for food.

According to Dr. Stephen Cunnane it was a rich and secure shore-based diet that fuelled and provided the essential nutrients to make our brains what they are today. Controversially, according to Dr. Cunnane our initial brain boost didn't happen by adaptation, but by exaptation, or chance.

"Anthropologists and evolutionary biologists usually point to things like the rise of language and tool making to explain the massive expansion of early hominid brains. But this is a Catch-22. Something had to start the process of brain expansion and I think it was early humans eating clams, frogs, bird eggs and fish from shoreline environments. This is what created the necessary physiological conditions for explosive brain growth," says Dr. Cunnane, a metabolic physiologist at the University of Sherbrooke in Sherbrooke, Quebec.

The evolutionary growth in hominid brain size remains a mystery and a major point of contention among anthropologists. Our brains weigh roughly twice as much as our similarly sized earliest human relative, Homo habilis two million years ago. The big question is which came first – the bigger brain or the social, linguistic and tool-making skills we associate with it?

But, Dr. Cunnane argues that most anthropologists are ignorant or dismissive of the key missing link to help answer this question: the metabolic constraints that are critical for healthy human brain development today, and for its evolution.

Human brains aren't just comparatively big, they're hungry. The average newborn's brain consumes an amazing 75-per cent of an infant's daily energy needs. According to Dr. Cunnane, to fuel this neural demand, human babies are born with a built-in energy reservoir – that cute baby fat. Human infants are the only primate babies born with excess fat. It accounts for about 14 per cent of their birth weight, similar to that of their brains.

It's this baby fat, says Dr. Cunnane, that provided the physiological winning conditions for hominids' evolutionary brain expansion. And how were hominid babies able to pack on the extra pounds? According to Cunnane their moms were dining on shoreline delicacies like clams and catfish.

"The shores gave us food security and higher nutrient density. My hypothesis is that to permit the brain to start to increase in size, the fittest early humans were those with the fattest infants," says Dr. Cunnane, author of the book Survival of the Fattest, published in 2005.

Unlike the prehistoric savannahs or forests, argues Dr. Cunnane, ancient shoreline environments provided a year-round, accessible and rich food supply. Such an environment was found in the wetlands and river and lake shorelines that dominated east Africa's prehistoric Rift Valley in which early humans evolved.

Dr. Cunnane points to the table scrap fossil evidence collected by his symposium co-organizer Dr. Kathy Stewart from the Canadian Museum of Nature, in Ottawa. Her study of fossil material excavated from numerous Homo habilis sites in eastern Africa revealed a bevy of chewed fish bones, particularly catfish.

More than just filling the larder, shorelines provided essential brain boosting nutrients and minerals that launched Homo sapiens brains past their primate peers, says Dr. Cunnane, the Canada Research Chair in Brain Metabolism and Aging.

Brain development and function requires ample supplies of a particular polyunsaturated fatty acid: docosahexaenoic acid (DHA). DHA is critical to proper neuron function. Human baby fat provides both an energy source for the rapidly growing infant grey matter, and also, says Dr. Cunnane, a greater concentration of DHA per pound than at any other time in life.

Aquatic foods are also rich in iodine, a key brain nutrient. Iodine is present in much lower amounts from terrestrial food sources such as mammals and plants.

It was this combination of abundant shoreline food and the "brain selective nutrients" that sparked the growth of the human brain, he says.

"Initially there wasn't selection for a larger brain," argues Dr. Cunnane. "The genetic possibility was there, but it remained silent until it was catalyzed by this shore-based diet."

Dr. Cunnane acknowledges that for the past 20 years he's been swimming upstream when it comes to convincing anthropologists of his position, especially that initial hominid brain expansion happened by chance rather than adaptation.

But, he says, the evidence of the importance of key shoreline nutrients to brain development is still with us – painfully so. Iodine deficiency is the world's leading nutrient deficiency. It affects more than a 1.5 billion people, mostly in inland areas, and causes sub-optimal brain function. Iodine is legally required to be added to salt in more than 100 countries.

Says Dr. Cunnane: "We've created an artificial shore-based food supply in our salt." ###

Contact: Stephen Cunnane stephen.cunnane@usherbrooke.ca 819-821-1170 Natural Sciences and Engineering Research Council

Arnet Sheppard, NSERC Public Affairs, (613) 859-1269

Dr. Cunnane's AAAS Presentation, Expatiation, Metabolic constraints and Human Brain Evolution, Saturday, February 18, 2006, 8:00 a.m. - 9:30 a.m. Central Time

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