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Nanotech Dreams

Increased federal spending, new technologies, and savvy researchers combine to harness the power of thinking small


©1999 Vik Olliver

Future or Fantasy: Three iridescent respirocytes float through a small artery in the company of numerous red blood cells. The respirocyte is a bloodborne 1-µm-diameter, spherical nanomedical device that acts as an artificial mechanical red blood cell, conceived by Robert A. Freitas Jr. (www.foresight.org/Nanomedicine).

Nanotechnology hit the big time in July 1995, when it debuted on the television show, The Outer Limits. In an episode entitled "The New Breed," a scientist develops nanorobots capable of repairing damaged cells and correcting physical defects. But, like any good morality play, the experiment goes horribly wrong, turning a panacea into a nightmare. Clearly, nanotechnology makes for good science fiction, but scientists have been working to make it an interesting reality, too.

Nanotechnology refers to the science of building, visualizing, and manipulating at the nanometer scale. The prefix nano means one billionth of something; thus, a nanometer (nm) is one billionth of a meter. An atom is about one-third of a nanometer wide, and a human hair is 200,000 nm in diameter.1

Richard P. Feynman, 1965 Physics Nobel laureate, first discussed nanotech in a lecture entitled "There's Plenty of Room at the Bottom," at the American Physical Society's 1959 annual meeting.2 The ensuing 40 years have seen tremendous progress in the field, and much that seemed fantastical in 1959 seems possible today. In fact, 2001 was a banner year for nanotechnology, culminating in Science magazine's naming nanoelectronics as its 2001 Breakthrough of the Year.3

Some scientists approach nanotechnology the same way they would approach Mount Everest—it's worth doing simply because it's there. But most nanotech supporters envision advances in materials and manufacturing, electronics, medicine, energy, biotechnology, pharmaceuticals, information technology, and more. "It's an unusual field," says Chad A. Mirkin, George B. Rathmann professor of chemistry and director, Institute for Nanotechnology at Northwestern University. "It's a field that focuses on a scale rather than on a material. So it affects everything."

To spur these developments, former President Bill Clinton announced the formation of a multi-disciplinary National Nanotechnology Initiative (NNI) in January 2000. The NNI's funding has increased along with public awareness: The proposed fiscal year 2002 budget of $519 million (US) represents a 23% increase over FY2001's $422 million.4 The Federal agencies requesting NNI funding in FY2002 reflect the breadth of nanotech's possibilities, ranging from $174 million for the National Science Foundation to $1.4 million for the Department of Justice, for forensics research.

Yet rarely has one field produced so much confusion. K. Eric Drexler, chairman of the Foresight Institute, and author of Engines of Creation (Anchor Press/Doubleday, New York, 1986), imagines a nanoscopic world in which molecular-scale "assemblers" can construct anything, including replicates of themselves, from individual atoms.5 One the other hand, Richard E. Smalley, the Gene and Norman Hackerman professor of chemistry and physics at Rice University and 1996 Chemistry Nobel Prize recipient, states flatly that such devices "will never become more than a futurist's daydream."6 Robert A. Freitas Jr., research scientist, Zyvex Corp., and author of Nanomedicine (Landes Bioscience, Georgetown, Texas, 1999), straddles these worlds. "My vision of nanomedicine ranges from the near-term to the far-term," he says. "I look at the things that can't be done for 20 years as a vision, as the ultimate goal, as a wonderful thing, way out there, that we can grasp for. And in the meantime, we have to do all the things that are necessary to get up to that point, and there's an awful lot of work to be done, and lots of work for everybody."

Near-Term Prospects

Though uncontrolled nanorobots remain science fiction fantasy, products based on nanotechnology do exist, and more are coming. In fact, nanotech can be found in the most unlikely of places, such as in sunscreen. The nanoparticulate zinc oxide is used in sunscreens produced by Romeoville, Ill.-based Nanophase Technology Corp.

In general, though, most nanotechnology is more aptly called nanoscience, as little true technology exists. "Nanotechnology really, in my opinion, is not yet a technology per se, where there are products that are out there that are selling to every household or to every drug company, in any vast quantity," says Max Lagally, E.W. Mueller professor of materials science and engineering at the University of Wisconsin, Madison.

Rashid Bashir, associate professor, electrical, computer, and biomedical engineering at Purdue University, shares that assessment. "We use the word 'nanotechnology,' but the fact is we have to keep working at trying to actually extract the technology from it." Diagnostics and therapeutics are now primed to do this in the next few years.

Diagnostics Advances

One diagnostic tool poised to benefit from nanotechnology is the biochip. Typical microarrays contain indexed arrays of oligonucleotides on a solid support, such as glass. To determine which genes a given sample expresses, researchers prepare fluorescently labeled cDNA from the sample, hybridize it to the array, and detect the expression pattern by observing the tag's fluorescence.

Unfortunately, this approach limits the maximum achievable array density, because it is not possible to distinguish two spots separated by less than half the wavelength of the observed light. If scientists observed hybridization events using an atomic force microscope (AFM),7 however, they could place an entire array in the AFM's field-of-view—a 100 x 100 micron area—and fill the area that a standard array normally consumes with 1,000 such arrays, Mirkin says.

To produce arrays on this scale, researchers use dip-pen nanolithography (DPN), which Mirkin and his team developed in 1999.8 The idea, Mirkin says, is to miniaturize 4,000-year-old quill-pen technology, except that in DPN the AFM tip is the pen, and the ink is whatever chemical reagent is to be patterned. The advantage of this approach, says Mirkin, is that these arrays are much smaller, and have the potential to be much more sensitive than conventional microarrays. Also, the spot size is so small that intermolecular interactions change the feature's physical characteristics, opening up new detection possibilities.

Mirkin's team recently published a proof-of-concept test, producing a protein nanoarray with 100-nm diameter features.9 But the group is also developing a process to array spots 15-nm wide, allowing scientists to place millions of features in the area normally occupied by a single microarray point. Mirkin founded venture capital-financed NanoInk of Chicago to commercialize DPN applications.

Courtesy of Chad Mirkin

Incredible Shrinking Arrays: Miniaturization offers the prospect of ultra-high-throughput arrays. As shown here, reducing a biochip feature's diameter from 170 µm to 15 nm, increases throughput 100 million times.

Nanotechnology also offers the possibility of diagnostic systems based on cantilever deflection. These cantilevers, akin to those found in AFMs, are coated with a specific antibody or DNA sequence. Binding the appropriate protein or DNA induces sufficient stress to bend the cantilever so that a laser can detect it. A recent publication demonstrated the ability of an anti-prostate-specific antigen (PSA) antibody-coated cantilever to detect PSA in complex solutions.10 Arrays of such devices could function as rapid and specific diagnostic tools, akin to standard DNA or protein-detection arrays.

Some nanotechnologists are working to improve diagnostic labels. Fluorescent dyes, the backbone of the diagnostics industry, are stimulated at one wavelength and detected at another. Each dye has distinct excitation/emission properties, but sometimes these wavelengths overlap, diminishing the experimental signal. Also, extended excitation times can lead to photobleaching.

Quantum dots are one alternative to fluorescent dyes that overcome these two problems. Offered by such companies as Quantum Dot Corp. of Hayward, Calif., and Evident Technologies Inc. of Albany, NY, quantum dots are nanometer-scale particles—nanoparticles—whose fluorescent properties are based on the particle's size. Because each quantum dot has the same excitation wavelength regardless of size, but an emission wavelength that is size-dependent, these dots eliminate the need for multiple laser sources in microscopy setups. Also, unlike standard fluorescent dyes, quantum dot fluorescence decays slowly, and, because of its tunable nature, offers the possibility for virtually limitless multiplexing.

Nanosphere of Northbrook, Ill., is developing another alternative to fluorescent labels. The company's gold- and silver-based nanoparticle probes offer significantly improved sensitivity and selectivity compared to fluorophores, and simple, cheaper readers, says Mirkin, who founded the company along with Bob Letsinger. Mirkin adds that this type of technology could eliminate the need for PCR as a diagnostic tool. "If you have a system so sensitive that you don't need to amplify [the target], then you can get rid of PCR," he says.

Therapeutic Advances

The most likely near-term therapeutic nanotechnology applications are in drug delivery. Bashir says that a number of researchers are working with nanoparticles that could eventually be targeted to specific cells or a tumor to deliver their cargo, possibly following internalization. These vehicles could even be externally induced to release their payload, or to destroy specific cells by heating. Targeting medicine directly to the cells that need it would both increase drug efficacy and decrease side effects.

Kenneth J. Klabunde, Kansas State University chemistry professor, is developing nanoparticulate bacteriocides. These particles function in both dry and wet states, he says. "We've shown that you can spray nanoparticles into the air, and they will find the airborne bacteria and glom onto them and kill them." These dried particles could disinfect airspace, or work surfaces that cannot be exposed to water.

Klabunde explains that particles display unexpected properties when they are reduced to the nanoscale. In a normal particle, such as a grain of salt, less than 1% of the atoms are exposed and available for surface chemistry. But on a nanoparticle, that number jumps to around 30%. So while a standard particle squanders most of its potential, says Klabunde, the nanoparticles' surface-to-volume ratio makes them highly efficient absorptive substrates.

Also, as nanoparticles form, their shape changes, translating into increasing chemical reactivity as the crystal begins to expose more edges and corners. In other words, explains Klabunde, nanoparticulate materials have more surface area on which to perform chemical reactions, and enhanced reactivity per unit surface area. Thus, nanoparticles could potentially advance applications, such as filtration, that depend on surface chemistry.

The National Aeronautical and Space Agency (NASA) recently awarded Sanford, Fla.-based Argonide Corp. an SBIR grant to study the use of the company's NanoCeram™ fibers for on-board water sterilization. According to company president Fred Tepper, these particles, measuring only 2 nm in diameter, can filter bacteria and viruses as small as 30 nm from water, achieving purity levels up to 99.99999% with a faster flow rate than standard filtration membranes allow.

Tejal A. Desai, associate professor of biomedical engineering at Boston University, is developing yet another therapeutic application. Desai's lab is working with sheets of nanoporous silicon whose 7-nm pores are large enough for ions and small proteins to pass through, yet small enough to exclude antibodies. By sandwiching cells between silicon sheets, the lab can implant foreign cells into a host and avoid immune rejection. The technology may be used to implant insulin-producing cells into diabetics. Columbus, Ohio-based iMEDD Inc. licensed this technology to develop its commercial applications.

Long-Term Prospects

Probably the most contentious issue among nanotechnologists is nanorobotics. Some researchers envision devices capable of navigating throughout the body, seeking out and repairing injuries, destroying tumors, and repairing genes, but others believe that the technical hurdles are simply too great to overcome. Northwestern's Mirkin bluntly surmises, "I think it's baloney."

Indeed, nanorobotics faces substantial technical obstacles. An independent robot must have on-board intelligence, motion control, sensing, energy, and the ability to do something. All of these functions must be packaged in a device small enough to move throughout the body, limiting its size to that of a human cell.

University of Pennsylvania neuroscience professor Phil Haydon has developed a nanoscale sensing device that uses a combination of confocal and near-field scanning optical microscopy to image ion channels on individual cells. Such a device, if miniaturized and placed on a nanorobot, could help the machine find specific cells, for example, cells secreting large amounts of a given protein. But though this device opens a window to the nanoscale world, it is not a nanoscale device; rather, the microscope is massive, Haydon says.

Other researchers are studying the use of biological motors for mechanical purposes. For example, Carlo Montomagno studies modified ATPases,11 which he mounts on nickel pedestals and to which he attaches propellers, creating a nanoscale motor. "Granted," says Freitas, "it piggybacks off of biotechnology, and it uses what nature has to offer, but there are people who are looking at these sorts of things and trying to fiddle with the innards of the motor and make them do different things."

Scientists have also made strides in nanofabrication. Sandia National Laboratories recently announced the assembly of a microscale chain motor whose links could fit on a human hair. This motor is too large to be considered a nanodevice, but Bashir explains that many microscale devices actually use nanoscale features. He adds that instruments that function in the nanoscale world must have a real-world interface, which often causes them to exceed the nanoscale. By analogy, a functioning computer requires considerably more hardware than the small silicon wafer that is a computer's CPU, to be useful.

Nanotech opens up many other research avenues as well. Scientists can now study the behavior of individual molecules in a population instead of that of the aggregate group. Stephen Kowalczykowski, professor of microbiology, molecular, and cell biology, University of California, Davis, says this is like comparing what one learns by interviewing each person in a group to getting a consensus view. "If you ask the group, you'll get the average response, and you will not know that there are people who have strong opinions to one extreme or another, or behaviors that are far from the norm," he says. "Oftentimes, it's these more outrageous opinions that are the most controversial or interesting."

By the time the credits roll on The Outer Limits, the nanorobots have cured their host's cancer and improved his virility. They've also given him gills so he can swim and put eyes in the back of his head before they move to his girlfriend. It is a cautionary tale that warns against the hubris of trying to act like God. Fortunately, most nanotechnologists see a future ripe with possibility without resorting to such futuristic fantasies.

Whether nanorobotics or any other nanotechnology will live up to its hype is unknown. But Bashir compares nanotech today with computer science in 1947, when the transistor was invented. Back then, he says, it was probably hard for people to predict the computational power available today.

And as they did in 1947, scientists must now come to understand the power—and the limits—of this new technology. "I think a lot of people, including scientists, try to say, 'This is pie-in-the-sky. A lot of it is really far out. It's going to have a big impact, but it's not going to be realized for 25 to 50 years,'" says Mirkin. "That's wrong, and it's also wrong to say it's going to revolutionize everything in the next couple of years. Something in the middle is correct."

Jeffrey M. Perkel can be contacted at jperkel@the-scientist.com.

1. "Nanotech executive summary," Technology Review, www.technologyreview.com/articles/nanotech101.asp.

2. www.zyvex.com/nanotech/feynman.html.

3. R.F. Service, "Molecules get wired," Science, 294:2442-3, Dec. 21, 2001.

4. M.C. Roco, "Research and Development FY 2002," www.nano.gov/2002budget.html.

5. K.E. Drexler, "Machine-phase nanotechnology," Scientific American, 285:74-5, September 2001.

6. R.E. Smalley, "Of chemistry, love and nanobots," Scientific American, 285:76-7, September 2001.

7. C. Wright-Smith, C.M. Smith, Atomic force microscopy, The Scientist, 15[2]:23, Jan. 22, 2001.

8. R.D. Piner et al., "'Dip-pen' nanolithography," Science, 283:661-3, Jan. 29, 1999.

9. K.-B. Lee et al., "Protein nanoarrays generated by dip-pen nanolithography," Science Express, published on http://www.sciencexpress.org/, Feb. 7, 2002, 10.1126/science.1067172.

10. J.M. Perkel, "Quantifying intermolecular interactions," The Scientist, 15[19]:30, Oct. 1, 2001.

11. R.K. Soong et al., "Powering an inorganic nanodevice with a biomolecular motor," Science, 290:1555-8, Nov. 24, 2000.


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