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Nanobiotechnology December 2011/January 2012 Viewpoints

Technology Analyst: Edward J. Hollingsworth

2011: The Year in Review

Despite the intense research into diagnostic and therapeutic nanotechnology across the scientific community in 2011, few projects have reached commercialization. This lack is not surprising, considering the regulatory and safety legislation in health care. Nevertheless, much exists to report, and advocates of nanotechnology should be relieved that no major new safety concerns appeared in the past year. One area that stands out in nanobiotechnology is whole-genome sequencing, whose impact on health care will be huge and whose dependence on nanotechnology will only increase as devices become more sophisticated and miniaturized.

DNA-Sequencing Technology

DNA sequencing is one of the few areas of nanobiotechnology that is already commercial. Until the mid-2000s, first-generation sequencing—or Sanger sequencing—was the predominant DNA-sequencing method. Although expensive, time consuming, and laborious, high-throughput sequencing in parallel across many research institutes enabled the completion of large projects such as the Human Genome Project (HGP) in 2003 by brute force. By about 2005, the introduction of second-generation sequencing technologies enabled the completion of huge projects like the HGP in a small fraction of the time and cost. Second-generation sequencing equipment has now supplanted Sanger sequencing in all but the smallest laboratories. But now, a new generation of technology is upon us, and a pipeline of further technologies, including nanopore sequencing, is currently under research and development.

Nevertheless, two next-generation sequencing companies are struggling: Pacific Biosciences (Menlo Park, California) and Complete Genomics (Mountain View, California). This struggle is in part because of the poor economic climate (where the companies' main customers—research institutions—are seeing their funding shrink) but also because the technology is seen by investors and buyers as interim and incapable of sequencing the human genome cheaply enough. Ion Torrent (Guilford, Connecticut) is faring better and, with Life Technologies' (Carlsbad, California) backing, could make significant inroads into the whole-genome-sequencing market. Ion Torrent believes its technology will be the first to provide a $1000 genome by the end of 2012. According to the Wall Street Journal, "the current cheapest sequencing costs about $3000 and takes a week." The price of an MRI (magnetic-resonance-imaging) scan is approximately $1000, which could imply that whole-genome sequencing is close to becoming a routine procedure. Furthermore, Ion Torrent's machines are much cheaper than the competition—at about $150 000 for one of the company's higher-end devices. However, John Timmer, writing in the Ars Technica website article "Fierce competition on the road to the $1,000 genome," believes that Life Technologies' main competitor in genomic sequencing—Illumina (San Diego, California)—will the first to provide a $1000 genome, because its technology can provide huge throughputs.

However, Daniel MacArthur also lacks confidence in Ion Torrent and is critical of the company's recent scientific paper in his Wired article, "How accurate is the new Ion Torrent genome, really?" He believes the paper overstates the technology's genome-sequencing accuracy (the number of errors in the published human-genome test sequence) and its high cost for such a poor-quality genome. MacArthur concedes that the data may be from a year before the paper's publication, so Ion Torrent's technology should have improved since then. Nevertheless, Illumina's commercial sequencing technology is expensive—costing about $500 000 per machine and requiring biochemical reagents and scientists to prepare samples, both of which are expensive. To reduce costs, both consumables and labor need to be minimal. In this respect, Ion Torrent's technology is superior to Illumina's current technology because of its use of mass-producible semiconductor chips. Ion Torrent's cheaper equipment also means that it may find better infiltration into laboratories and health centers.

The quest for cheap whole-genome sequencing is far from over. Many other technologies, including nanopore sequencing, with backing from multinationals such as IBM are waiting in the wings and will no doubt surpass current technology in cost by at least an order of magnitude. Indeed, many multinationals must be chomping at the bit in anticipation of the market for genomic sequencing and the data it will produce. Presumably this market is IBM's interest in the field. We may see, therefore, big players acquiring and nurturing new technologies in much the same way that Illumina (acquiring Solexa), Roche (454 Life Sciences), and Life Technologies (Ion Torrent) have done but on a larger scale. Because sequencing technology is adopting semiconductor-manufacturing technology, companies such as Samsung and Toshiba may well enter the fray and, with their capital and manufacturing expertise, may decrease costs even further, and innovation may accelerate. Furthermore, this development may enable other companies to provide enhanced diagnosis and therapy services on the back of this new technology.

Nanotechnology and Antibiotics

For the past 80 years in the developed world, antibiotics have relegated most bacterial diseases to mere annoyances rather than life-threatening conditions. However, the emergence of antibiotic-resistant pathogens—many of which are resistant to multiple antibiotics—has thrust bacterial diseases back into the limelight. Although conventional antibiotics are still in development, their mode of action, which is usually quite specific, means that in time antibiotic-resistant genes will spread among bacterial species and render the antibiotics useless. To this end, scientists are looking at other strategies to combat bacterial infections, some of which involve nanotechnology.

Scientists from IBM and the Institute of Bioengineering and Nanotechnology (Singapore, Singapore) have developed polymers that detect and destroy antibiotic-resistant bacteria. IBM is using its expertise in semiconductor manufacturing to produce nanostructures that are attracted to infected cells, enabling them to kill pathogenic bacteria without harming healthy cells within the body. Moreover, because the nanoparticles' mode of action is different from that of current antibiotics (the nanoparticles penetrate the bacterial cell wall and membrane, a process that does not involve a particular genetic pathway), antibiotic-resistance development is avoidable. According to IBM's press release, the polymers—on contact with water or body fluids—self-assemble and target bacteria membranes using electrostatic interaction. Differences in electric charges between healthy cells and those infected by bacteria enable the nanoparticle to target diseased areas selectively. Experiments show that healthy red-blood cells are not damaged by these polymer nanoparticles. Another benefit of these nanoparticles as antibiotic agents is their biodegradability, which is not often the case with many proposed nanoparticle therapeutics. Although many nanoparticles—for example, those comprising metals—are eventually cleared from the body, their biodegradability is preferable and reduces the chance of complications or side effects of nanoparticle therapies. Experiments show that the nanoparticles kill various species of bacteria, including MRSA, in addition to some pathogenic fungi. Tests on mice showed no apparent problems, but many more tests are necessary before human trials even warrant consideration.

DARPA (the Defense Advanced Research Projects Agency), the US military-research wing, is also interested in the potential of nanoparticles to combat bacterial infections. In its program to "develop a platform capable of rapidly synthesizing therapeutic nanoparticles targeted against evolving and engineered pathogens," DARPA envisages developing small-interfering RNA– or siRNA-loaded nanoparticles to target bacterial infections. DARPA hopes to avoid the use of conventional antibiotics that become useless as bacterial strains develop resistance to them. Instead, different siRNAs targeting different genes or strains are attachable to the nanoparticles if resistance develops or new bacterial species necessitate targeting.

Researchers at King Saud University (Riyadh, Saudi Arabia) are combining nanotechnology with conventional antibiotics to fight bacterial pathogens. Their technology uses nanofibers comprising polyvinyl alcohol and polyethylene oxide to hold antibiotics. According to Mohamed H. El-Newehy, leader of the nanofibers research team, "When treated with antibiotics wrapped in nanofibers, the microbes were severely damaged and many cells were enlarged, elongated, fragmented, or left as just empty ghosts. The fibers by themselves, without antibiotic did not affect the bacteria. They seem to work by boosting the power of the antibiotics. By wrapping the anti-microbial agents in the fibers, it makes the drug action more focused and the agents are effective for longer period of time than with conventional delivery techniques." The scientists tested their antibiotic-infused nanofibers and found that the fibers could kill a range of pathogenic bacteria and fungi, including E. coli and Pseudomonas aeruginosa. The scientists envisage that the antimicrobial fibers could find use in wound dressings, medical textiles, and drug delivery, among other applications.

Magnetic Nanoparticles

Magnetic nanoparticles are finding wide use in therapeutics and diagnostics. Their ability to separate from their medium—which is most likely body fluids—by means of magnets enables their recovery and concentration. Magnetic nanoparticles are also functionalizable with other materials that widen their application.

Scientists at the University of Zurich (Switzerland) are developing magnetic nanoparticles that could remove toxic compounds from bodily fluids such as blood. According to "Tiny Magnets Could Clear Diseases from the Blood" in Technology Review, the magnetic nanoparticles comprise a coating of carbon and antibodies, of which the latter are targeted to the molecules that need removal from the fluids. Inge Herrmann, who is leading the research, describes how the technology works: "The nanomagnets capture the target substances, and right before the nanoparticles would be recirculated, the magnetic separator accumulates the toxin-loaded nanomagnets in a reservoir and keeps them separated from the recirculating blood." In February 2011, the scientists published details of their success in removing 75% of the heart drug digoxin in a single pass using their technology and 90% of the drug after an hour and a half of cleansing.

Scientists at the Massachusetts General Hospital (Boston) and their collaborators are developing a cancer-detector device that is linkable to a smartphone to analyze and record data. The technology uses a miniature nuclear-magnetic-resonance (NMR) scanner to identify specific proteins—for example, biomarkers for tumor cells—that are labeled with magnetic nanoparticles. Current cancer-diagnosis methods involve taking needle samples from tumors, which a pathology laboratory will assess with selective staining to reveal cancer biomarkers and irregular cell shape to indicate the presence of cancer. This process may take several days, and results are often inconclusive. An article on the website compares the traditional pathology-laboratory process with the new NMR scanner that provides results within an hour. A test evaluating the efficacy of the device resulted in accurate diagnosis in 48 of the 50 tested patients. A further test showed 100% accuracy with 20 patients. In comparison, conventional pathology analyses are accurate in only 74% to 84% of cases.

Look for These Developments in 2012

  • Although 2011 was a quiet year for nanotechnology safety concerns, the public and regulators should not become complacent about such risks, and one hopes that further consumer products containing nanotechnology for no other reason than marketing will not reach the market.
  • Few nanobiotechnology-based innovations (apart from gene sequencing) will reach commercialization in 2012. If they do, they will most likely be diagnostic devices.
  • Whole-genome-sequencing technology faces another exciting year. We will see whether Ion Torrent's machine lives up to its hype and if its low price tag will enable its deployment into a wide range of smaller life-science laboratories, increasing their productivity enormously. We may also see the first $1000 genome, which looks likely to be claimed by either Ion Torrent or Illumina. The $10 Million Archon Genomics X Prize—which requires the sequencing of 100 centenarians' genomes within 30 days with an error rate of no more than one per million base pairs and a cost of less than $1000 per genome—may also find a claimant in 2012.