Nanoscience is Out of the Bottle

 SUPER GOO: Nanotech and Super Heroes? It's a natural. A nanoscale adhesive, developed by University of Manchester researchers, lets this Spiderman hang with confidence. (Reprinted with permission from Nature Materials, 2:461-63, 2003) Don't look now, but the nanotech revolution is already here. It began as a collection of curiosities: nano-enabled sunscreens, tennis racquets, fishing rods, and stain-resistant pants. And more are coming. Nanotech supporters say the technology will benef

By | July 28, 2003

 SUPER GOO: Nanotech and Super Heroes? It's a natural. A nanoscale adhesive, developed by University of Manchester researchers, lets this Spiderman hang with confidence. (Reprinted with permission from Nature Materials, 2:461-63, 2003)

Don't look now, but the nanotech revolution is already here. It began as a collection of curiosities: nano-enabled sunscreens, tennis racquets, fishing rods, and stain-resistant pants. And more are coming.

Nanotech supporters say the technology will benefit every facet of society, from energy to electronics, healthcare to telecommunications. "Nanotechnology will be woven into the fabric of science and technology in a very broad way," predicts Terry Michalske, director, Center for Integrated Nanotechnologies, Sandia National Laboratories in Albuquerque, N. Mex. The National Science Foundation estimates that nanotechnology will create a $1 trillion (US) worldwide market by 2015, and governments worldwide are staking their claims. The US Congress has appropriated $2.36 billion over three years for nanotech R&D, while the European Union's Sixth Framework Programme for Research and Technological Development has earmarked ¤1.3 billion between 2002 and 2006. All told, public and private concerns will pour some $3 billion into nanotech this year, according to The Nanotech Report 2003, an investment overview compiled by the venture capital firm, Lux Capital, of New York. Some of that money will find its way into life science labs, where it will fund research in diagnostics and biosensing, tissue repair and regeneration, and therapeutics.

But make no mistake: The brass ring that is nanotech success still lies out of reach. A substantial amount of R&D fills the future, and the specter of governmental oversight looms; naysayers contend that too little attention has been paid to possible negatives. Vicki L. Colvin, director of Rice University's Center for Biological and Environmental Nanotechnology (CBEN), Houston, writes in an essay that of the $700 million in nanotech R&D funding in fiscal year 2003, less than $500,000 was devoted to environmental impact.1

CBEN is one of six Nanoscale Science and Engineering Centers funded by the National Science Foundation, where researchers study the environmental impact of new nanomaterials. "We have an opportunity, for the first time in history, to consider environmental and health consequences well before the industry has developed," says Colvin in an interview. Yet even if a research moratorium is issued in the United States or in Europe, progress would continue somewhere, says Jack Uldrich, author of The Next Big Thing is Really Small. "The science is out of the bottle."

WHAT IS NANO? Unlike such fields as immunology and electronics, nanoscience deals not with a specific area of research so much as a length scale: 0.1 to 100 nanometers. (A nanometer is 10-9 meter, about as wide as 10 hydrogen atoms; by comparison, a white blood cell is about 10,000 nm in diameter.)

Simply put, nanoscience seeks to understand matter at the nanoscale level, and nanotechnology seeks to manipulate and control it. The US National Nanotechnology Initiative says: "Nanotechnology is concerned with materials and systems whose structures and components exhibit novel and significantly improved physical, chemical, and biological properties, phenomena, and processes due to their nanoscale size. The goal is to exploit these properties by gaining control of structures and devices at atomic, molecular, and supramolecular levels and to learn to efficiently manufacture and use these devices."2

Nanotech futurists such as K. Eric Drexler, president of the Foresight Institute, expect to see self-replicating, nanoscale robots able to patrol bodies and repair everything from cancers to tooth decay. Most nanotechnologists dismiss these notions as science fiction, or at least extremely remote. "It's not something I can foresee any time soon," says nanotech entrepreneur and venture capitalist Larry Bock.

Many serious scientists do, however, envision a time when nanotech and biotech will coalesce, producing nanoscale devices that employ biological principles. "Many of these natural processes and machinery of life are constructed on the nanometer scale--the chemical pathways, the molecular machinery," says Michalske. "As we begin to develop our expertise in manipulating synthetic nanostructures on that same scale, the opportunity for direct interaction coupling between biological and synthetic systems becomes really enormous." Recently, for instance, researchers at the University of Manchester, UK, synthesized a nanoscale adhesive akin to gecko footpads.3

So far though, progress can be measured only in nanosteps. Research has created growing islands of knowledge, but commercialization is in its infancy, focusing on passive nanostructures, said Mike Roco, the NSF's senior advisor on nanotechnology, at a recent conference. Says Michalske: "The emphasis right now is really on what goes on at the nanoscale."

NANO MEDICINES That said, there is some progress. In private and public labs worldwide, research is advancing on several fronts. According to Gary Liversidge, senior director of operations at NanoSystems in suburban Philadelphia, many drug candidates, perhaps as many as 60%, exhibit poor water solubility, which limits their usefulness. But when those same compounds are milled into nanoscale particles and coated to prevent reaggregation, the result is a stable and generally soluble formulation, owing to the structure's extremely high surface area-to-volume ratio. NanoSystem's parent pharma company, Dublin-based Elan, currently has no nano-particulate products on the market, though some are in the pipeline, says Liversidge. But American Home Products and Merck & Co. do: They have released formulations of Rapamycin (Rapamune) and aprepitant (Emend), respectively, based on NanoSystems' NanoCrystal® technology.

Courtesy of Flavio Robles/Protein Data Bank
 PROTEIN DIVING BOARD? Not all biosensors require nanowires and nanocircuitry. In this device, three cantilevers are coated with antibodies to prostate-specific antigen (PSA). The left cantilever bends as the protein PSA binds to the antibody. The other cantilevers, exposed to human plasminogen and human serum albumin, do not bend because the anti-PSA antibodies do not recognize these molecules.

Researchers at Nanospectra Biosciences in Houston, meanwhile, are developing a novel therapeutic approach to cancer based on the interplay of light and metal. Consider a shiny car on a sunny day: As the sunlight strikes the car, some light is reflected, and some is absorbed, heating the surface. Nanospectra's severely downsized version of this involves a laser and nanoscale silicon particles bearing an ultrathin coating of gold, like an M&M's candy.

The properties of these so-called nanoshells are tunable, based on the silicon core's size and the coating's thickness. The company typically adjusts its particles to respond to light in the near-infrared range, which is a part of the spectrum where tissues are minimally absorptive, says president and CEO J. Donald Payne. Like that shiny car, these particles can either scatter light, or absorb it, in which case they generate heat. In the former case, says Payne, the spheres can function as image contrast agents; in the latter, they literally can cook nearby cells to death. And there's no reason the two options cannot be merged. Payne notes that the US Department of Defense is funding a study into "the seamless diagnosis and treatment of breast cancer."

In a preliminary study using mice, Nanospectra demonstrated that it could ablate tumors through the animals' skin, leaving them tumor-free within two days. The researchers observed no toxicity, says Payne, who anticipates starting human trials within a year. Rice University researchers Jennifer West and Naomi Halas, who founded Nanospectra, have been enhancing the technology for use as a drug-delivery platform. By coating the shells with a heat-labile, drug-infused polymer, it could be possible to deliver medicine on demand with a zap from a laser.

Another company, C Sixty in Toronto, is developing a series of drugs based on buckyballs. Formally called buckminsterfullerene, buckyballs are hollow shells containing 60 carbon atoms arranged like the stitching on a soccer ball. These nanosized molecules possess a number of useful chemical properties, says company president Uri Sagman. They are efficient free-radical scavengers; they can hold another atom within their core; and their surfaces can be functionalized. The company is devising a series of drugs to exploit these properties. It is, for instance, investigating the fullerene's efficacy as an antioxidant against neurodegenerative disorders such as Parkinson and Alzheimer diseases; designing caged gadolinium fullerenes for use as a contrast agent in magnetic resonance imaging; and studying functionalized fullerenes for use as a scaffold to develop novel antiviral agents.

Researchers at Starpharma in Victoria, Australia, are developing novel drugs based on yet another nanomaterial: dendritic polymers, or dendrimers. These three-dimensional branching structures, which grow from the inside out, layer by layer, like a growing pearl, can be designed as a "smart device," says author Uldrich. These structures would have one branch identifying a cancerous cell, a second branch containing an imaging agent, and a third bearing a toxin to kill the cell. Starpharma announced June 30 that it has filed an investigational new drug application with the Food and Drug Administration (FDA) to initiate Phase I clinical trials for a dendrimer-based vaginal microbicide called VivaGel.

Modifying these technologies--with antibodies, peptides, or carbohydrates, for instance--enables their use in targeting specific cells or tissues. "That combination creates a 'smart bomb'," explains Robert Paull, coauthor of The Nanotech Report 2003, "that can be programmed to a specific type of cancer cell." By encapsulating and directing these drugs only to the tissues that need them, drug concentrations can be decreased, diminishing toxicity and increasing efficacy.

INCREASING COMPLEXITY Some nanotechnology companies are developing more complex nanotech devices, such as biosensors and implants. "With all of the interest in homeland security and chemical and biological detection, [biosensing] is white hot right now," observes Paull. Some researchers favor circuitry composed of carbon nanotubes, the relatives of buckyballs that can function as either electrical conductors or semiconductors, while others, such as Nanosys in Palo Alto, Calif., prefer inorganic nanowires. Nanosys' CEO Bock explains that these wires can be functionalized with capture reagents such as antibodies or nucleic acids. When they bind to their targets, the electrical resistance across the device changes, enabling sensitive detection. Bock anticipates such devices will come online within two to three years.

For those who can't wait, Chicago-based NanoInk recently released the Nscriptor, based on one of nanotech's most fundamental tools: the atomic force microscope. An AFM can act as both the hands and eyes of nanotech researchers, as its ultra-fine probe can either push individual atoms around like checkers on a game board, or sense their presence like fingers moving across a page of braille type.

NanoInk founder Chad Mirkin developed another approach, whereby the AFM is used as a pen to directly deposit materials on a surface. The technique, called Dip Pen Nanolithography™, can deposit multiple nanoscale materials in perfect registration and in close proximity on almost any surface. "You can put down a receptor molecule--say, an antibody--and also connect that antibody with the outside world by laying down your nanocircuitry," says NanoInk's Linette Demers.

Eric Henderson, chief science officer of BioForce Nanosciences, an instrumentation developer in Ames, Iowa, says such devices could be used to generate simple point-of-care diagnostics akin to a home pregnancy test: The clinician spots a drop of blood onto a dipstick, waits five minutes, and inserts it into the array reader to get the results. "It's just limited by money and resources," he says. "It's not limited by anything else. No new technology needs to be invented."

SMALL SCIENCE, BIG FEARS The road to nano-nirvana is long. For starters, the NSF predicts that approximately two million workers worldwide must be trained in nanotech and nanoscience then there are the nano-naysayers, who worry that science is progressing so fast that proper steps to ensure safety are not being taken. They worry that the same properties that make nanomaterials so beneficial to medicine, that is, the ability to enter cells and cross the blood-brain barrier, for instance, opens the door to negative health and environmental consequences. Another fear raised: sentient nanorobots running amok (as they do in Michael Crichton's Prey).

Courtesy of Daniel T. Colbert
 NANO-TUBULAR: Four peptide rings surround a single-wall carbon nanotube. Nanotubes, relatives of buckyballs, are lighter and stronger than steel. More importantly, they can function both as electrical wires and semiconductors, and can be functionalized with receptor molecules. These properties are driving scientists to look for ways to incorporate them into biosensors.

Rice's Colvin points out that "in a field with more than 12,000 citations a year, we were stunned to discover no prior research in developing nanomaterials risk-assessment models, and no toxicology studies devoted to synthetic nanomaterials."1 In an interview, Colvin cites two reasons to be concerned about nanomaterials. Because of their small size, they may access areas of the body larger materials cannot, like healthy cells. In addition, properties are very different at the nanometer scale. Researchers do not know, she says, how nanomaterials are cleared from the body, whether they are degraded, and whether they accumulate in the environment.

Says NSF's Roco: "All the studies that we've done so far show that unexpected consequences have a much smaller effect than the positive outcomes of the technology." Roco is also chair of the National Science and Technology Council's Subcommittee on Nanoscale Science, Engineering, and Technology.

Studies have not possessed a universal theme, however. In a nonpeer-reviewed study presented at the recent American Chemical Society meeting, two teams of toxicologists found that inhalation of carbon nanotubes produces granulomas, which are typically characteristic of tuberculosis and inhalation of beryllium dust. But, every material is different, says Colvin. "The only thing I know after 18 months is that it's not going to be an easy answer, and it's not going to be a single answer for all materials."

So, stop the research, some say. In January, and again in April, a Canadian watchdog group that calls itself ETC, a veteran of the genetically modified (GM) food fight, called on governments to "declare an immediate moratorium on commercial production of new nanomaterials and launch a transparent global process for evaluating the socioeconomic, health, and environmental implications of the technology."4

Such a moratorium is a bad idea, countered the Center for Responsible Nanotechnology in a press release. The "ETC's report went too far in calling for a complete moratorium. An attempted global shutdown of molecular nanotech development would not assure anyone's safety or security. Rather, it would drive research underground and could result in a dangerous and unstable black market."5

So far, the requested moratorium hasn't materialized, and governments seem content to let current regulatory guidelines stand. Across the Atlantic, where, according to Ottilia Saxl, CEO of the Institute of Nanotechnology, a UK-based advocacy group, fears about GM foods have spilled over into the nanotech arena, the UK government recently asked the Royal Society and the Royal Academy of Engineering to consider whether new regulations are necessary to control nanotechnology. Trying to preempt a public backlash akin to the GM debate, many nanotech researchers in Europe are "bending over backwards to provide information to demonstrate that there's nothing to hide, there's no dark secrets," says Saxl. The NSF, too, is reaching out to the public, says Roco, noting, "Our role is to inform."

BOTTLENECKS These nascent technologies are far from FDA consideration, but when they do get there, a bottleneck could be waiting, says F. Mark Modzelewski, executive director of the NanoBusiness Alliance in New York. "I think the FDA is going to probably be the biggest slowdown, much more so than innovation." With a ponderous drug approval process, some companies, including Nanospectra, are spinning their inventions not as drugs, but as devices, a strategy Modzelewski says provides an easier path to FDA acceptance. Others are focusing on cancer and HIV, because the FDA offers fast-track consideration for these indications.

Author Uldrich says he's seen many smart, viable technologies. But it takes more than clever science and a stamp of approval to be successful. Factors such as marketing saavy, cost, and the public's trust count, too. "Dendrimers floating through the body might be the most effective way to control cancer," he says, "but if people are uneasy about the notion of devices floating free in their blood systems, it might not take off, even if it's been proven safe and effective." In other words, nano's best might not be good, or big, enough.

Jeffrey M. Perkel can be contacted at

1. V.L. Colvin, "Responsible nanotechnology: Looking beyond the good news," available online at

2. National Nanotechnology Initiative's implementation plan, available online at:

3. A.K. Geim et al., "Microfabricated adhesive mimicking gecko foot-hair," Nat Materials, 2:461-3, July 2003.

4. ETC Group, "From genomes to atoms: The Big Down. Atomtech: Technologies converging at the nano-scale," available online at

5. Center for Responsible Nanotechnology press release, available online at

Courtesy of BioForce NanoSciences
As the probe tip in an atomic force microscope (AFM) scans across a sample, it bends with the height of the material beneath it. BioForce Nanosciences has exploited this capability in its NanoReader, a customized AFM optimized for reading NanoArray chips. Such arrays have several advantages over traditional microarrays: they require no fluorescence, radioactivity, or enzyme-linked detection; use less sample; and are more sensitive.

According to The Nanotech Report 2003, more than 2,800 nanotech patents have been filed since 1996. But with most of that intellectual property untested in the courts, just how strong those patents are remains to be seen.

Steve Maebius, partner and head of the nanotech practice group at Foley & Lardner in Washington, DC, says that nanotechnology presents several new intellectual property challenges. First, the technology cuts across so many industry lines that it makes it difficult to fully protect an invention's every possible application. Another reason, says Maebius, is that "the Patent Office is not fully up to speed with nanotech," which slows patent consideration.

"Clearly nanotech is patentable subject matter," Maebius says, but the real question is, how broadly. "Every patent is to some extent prophetic," and tries to extrapolate beyond the immediate result to other possible applications. In the early days of the biotech revolution, the patent office issued a number of exceedingly broad patents, which the courts later trimmed back, producing a tightening of biotech intellectual property. Maebius anticipates a similar cycle will play out in nanotech. "We are today where we were with biotech in the late '80s to early '90s."

His conclusion: "I think we in the patent bar have to accept that there's going to be some difficulty in prosecuting nanotech patents, as the Patent Office faces a growing backlog." But, he adds, "One thing that is clear is that in nanotech right now, there are opportunities to patent very broadly ... because there's not as much prior art."
--Jeffrey M. Perkel


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