BBI Contributing Writer

LAS VEGAS, Nevada – Surgeons have advanced from stitching wounds and amputating limbs to repairing hearts and reattaching limbs – sometimes with robotic assistance. Using microscopes and fine tools, they join delicate blood vessels and nerves. Yet even the best microsurgeon cannot cut and stitch some tissue structures. Modern scalpels and sutures are simply too coarse for repairing capillaries, cells and molecules. Some experts believe nanosurgery – shrinking surgical robots to the molecular level – may be possible in the near future. As results begin to emerge from the Human Genome project, understanding of human life will continue its advance from knowledge of organs, to tissues, to cells and finally to molecules. Mapping of the human genome will provide a complete catalog of all human proteins, lipids, carbohydrates, nucleoproteins and other molecules.

Speaking at the 7th International Congress on Anti-Aging & Biomedical Technologies, held here in December, Robert Bradbury, president of Aeiveos (Seattle, Washington), said he believes combining knowledge of the genome with biochemistry, molecular modeling and combinatorial chemistry will allow creation of drugs that treat infections in highly specific manners. He added, "Genome technologies will provide the foundation for the construction of biobots, then nanobots – allowing us to create therapies that expand treatment windows during strokes or heart failure. Eventually, nanobots may help us resist aging or survive typically fatal accidents."

Familiarity with the human body added to advances in molecular engineering may set the stage for a shift for molecular manipulation of the body's atoms to provide desired results, Bradbury said. Expanding on the concept of current surgical robots, these tiny surgeon's assistants will be sent on missions of cellular inspection, repair and reconstruction – a shift from medical science to medical engineering.

Biobots are described by Bradbury as bacteria and eukaryotic cells with programmed genomes. He expects biobots to be developed before 2010. Biobots will enable therapies that include genome augmentation with a moderate number of genes to designer organs with a subset of the natural genome.

Bradbury describes nanobots as "bacteria-sized machines assembled with molecular nanotechnology that have significantly enhanced physical properties over biobots. I expect to see them developed during the period from 2010 to 2020."

No 'pie in the sky' thinking

The precursors to nanotechnology – microelectromechanical systems (MEMS), molecular engineering and biochips – exist today.

To manufacture machines of any kind generally requires two primary capabilities – fabrication of parts, and assembly of parts. In 1998, primitive parts fabrication and assembly capabilities were demonstrated at the molecular level using three different enabling technologies: biotechnology, supramolecular chemistry and scanning probes.

Microelectromechanical systems (MEMS) – a relatively new engineering field – is an extension of chip-etch technology. MEMS led to the development of microgrippers that can manipulate individual 2.7 micron polystyrene spheres, dried red blood cells of similar size and various protozoa. In terms of system size, micromachined MEMS devices (typically -10-13 m3 in volume) lie intermediate between the macroscale world (-10-4 m3) and the nanoscale world (-10-22 m3). Molecular manufacturing could enable the construction of giga-ops computers smaller than a cubic micron; cell repair machines; personal manufacturing and recycling applications.

In 1997, a panel of U.S. Department of Defense health science experts known as Military Health Service Systems 2020 concluded in its final report: "If a breakthrough to a molecular assembler occurs within 10 to 15 years, an entirely new field of nanomedicine will emerge by 2020. Initial applications will be focused outside the body in areas such as diagnostics and pharmaceutical manufacturing. The most powerful uses would eventually be within the body.

"Possible applications include programmable immune machines that travel though the bloodstream, supplementing the natural immune system; cell herding machines to stimulate rapid healing and tissue reconstruction; and cell repair machines to perform genetic surgery."

Biochips today

Once relegated to science fiction, chips that analyze biological material to diagnose disease, aid in drug discovery and deliver medicine inside the body may provide the basis for major research and commercial breakthroughs in the 21st century. In 2010, a patient may go to a doctor's office for a blood test with a lab-on-a-chip device that uses the patient's DNA to tell the doctor in real time if a patient's illness will respond well to a drug. The chip could also confirm the patient's identity, diagnose disease and even be used to establish paternity. These are heady times for electronics engineers and researchers marrying semiconductor technologies and techniques with biology, chemistry and genetics.

John Santini Jr., PhD, a former Massachusetts Institute of Technology (Cambridge, Massachusetts) researcher, heads MicroChips (also Cambridge), a start-up developing controlled-release microchips that deliver drugs inside or outside the body. The company is in the early stage of developing technology, but its goal is to develop a silicon chip with tiny wells filled with drug compounds that can be released in the body in a controlled manner via a preprogrammed microchip.

Santini admits the idea of such a device was science fiction years ago – especially a microchip device that could operate on its own in the body. "It's kind of the way people felt about tissue engineering many years ago," he said. (Tissue engineering involves growing an entire organ from a few living cells.) "But with the advances that have been made to date, we can envision using chips to replace faulty systems in the body," he added.

Researchers at Argonne National Laboratory are working with Russian scientists in an effort to combat tuberculosis (TB) on a nano level. The teams hope to develop inexpensive microchips that can rapidly identify the specific strain of TB affecting a patient. Using the patient's genetic material, the microchips could select the most effective therapy. Experts note that diagnostic biochips for TB are already on the market, but their high cost – $50 and up – is prohibitive for Russia and other cash-strapped nations.

Nanogen (San Diego, California) is among the companies marrying the power of molecular biology and microelectronics. Nanogen's technology incorporates a semiconductor chip into an automated molecular analysis system.

The system analyzes molecules by taking advantage of the naturally occurring positive and negative charges associated with most biological molecules. The chip contains test sites arranged in an array that can be individually manipulated electronically from the instrument controls. Each chip is coated with a layer that functions as the interface between the electrochemical surface of the microchip and the biological test environment.

The system is used for medical diagnostics, genetic testing, genomic research and drug discovery. For research applications, Nanogen delivered a benchtop instrument system based on its NanoChip cartridge in 1999 and expects to follow with a PC-sized instrument and a hand-held device in five years.

Nanogen co-founder and chief technical officer Michael Heller, PhD – whose own work in co-founding the company derived from his background in biochemistry – credits microelectromechanical systems as an enabling technology for such biochips as DNA chips, microfluidics and lab-on-a-chip devices. Heller also credits the advancing field of biochips to the achievements in materials science and lithography, atomic force microscopy, nanotechnology, and closer interaction than ever before among engineers, biologists and chemists.

Today's biochip developments are focused on diagnostic applications and drugs. This is a typical path for medical and surgical advances. Historically, diagnostic applications come first and surgical applications follow. For example, diagnostic laparoscopy preceded laparoscopic cholecystectomy.

Nanosurgery will evolve from nanotechnology. Nanoassemblers (or nano-surgical robots) will be capable of holding and positioning reactive compounds in order to control the precise location at which chemical reactions take place. This general approach should allow the construction of large, atomically precise objects by a sequence of precisely controlled chemical reactions, building objects molecule by molecule. Experts predict nanoassemblers will be able to build copies of themselves. They will require a detailed sequence of control signals – a nanocomputer.

Chemical computer reported

DNA computing could satisfy the requirements for a nanocomputer. It has the potential to be much faster than conventional computing methods, and could make it possible to solve problems too large for normal computers. Lloyd Smith and colleagues from the University of Wisconsin (Madison, Wisconsin) reported in the Jan. 13, 2000, issue of Nature that DNA not only can hold, but also process, information. They have used it as a chemical computer to solve a computational problem. Among the hardest of all computational problems are those belonging to the class called "NP-complete." In these tasks, the number of possible answers, and so the time required to find the correct one, increases exponentially as the number of independent variables increases. Smith's group has applied DNA computing to such a problem, called the "satisfiability" problem, or SAT. They systematically try out every possible route and then see which of them is shorter.

The researchers conducted a process of elimination on possible solutions encoded in strands of DNA, for a relatively small-scale SAT-type problem for which there were just 16 possible solutions. They translated these into DNA sequences of eight base pairs (the chemical components of DNA) each. To keep track of every sequence, the researchers fixed one end of each strand to a gold surface. They eliminated the wrong solutions by exposing the tethered strands to free-floating strands carrying sequences complementary to those that satisfy each one of the criteria met by the correct solution. On each step, an enzyme was added that destroyed all the DNA that was single-stranded (and therefore contradicted one of the criteria). The surviving single strands could then be regenerated simply by gentle heating. Those that survived all of these steps satisfied all the criteria. Their sequences could then be decoded to deduce the correct solution.