Progress of Molecular Nanotechnology in 2001

In 1959, the late Nobel Prize–winning physicist Richard P. Feynman presented a talk entitled “There’s Plenty of Room at the Bottom” at the annual meeting of the American Physical Society. Feynman proposed using machine tools to make smaller machine tools, which, in turn, would be used to make still smaller machine tools, and so on all the way down to the molecular level. He suggested that such nanomachines, nanodevices and nanorobots ultimately could be used to develop a wide range of atomically precise microscopic instrumentation and manufacturing tools. He concluded that this is “a development which I think cannot be avoided.” The vision of nanotechnology was born.

Forty years ago, this talk was greeted with astonishment and skepticism. However, since then, we have made remarkable progress toward realizing Feynman’s vision. From the dawn of the microcomputer era several decades ago, we have witnessed a significant increase in the speed and power of computers. This is due, in large measure, to the ever-decreasing size of the electronic components that can be packed at ever-increasing densities onto a single silicon chip. Transistor density has doubled every 18 months, an observation that has come to be known as Moore’s law. The size of features on computer chips has shrunk from a fraction of a millimeter in the first microprocessor chip to 0.1 to 0.2 micrometers (one millionth, or 10-6, of a meter) in the latest chips. Several companies have already been formed with the explicit goal of producing, within just a few years, molecular computer components using molecular parts at the nanometer scale (a nanometer is one-billionth, or 10-9, of a meter, about the width of 6 bonded carbon atoms).

Similar progress is under way in the related field of robotic miniaturization. The burgeoning field of microelectromechanical systems or MEMS was made possible by the fabrication of the first micromotors in the late 1980s and early 1990s. By 1994, engineers at Nippondenso Ltd. in Japan constructed a working electric car smaller than a grain of rice, a 1/1,000th-scale replica of a 1936 Model AA Toyota sedan that incorporated 24 parts, including a motor, wheels, body, spare tire, bumpers and even a 10-micrometer-thick license plate. In 1997, researchers at the Cornell Nanofabrication Facility produced a silicon guitar that was 10 micrometers in length and 2 micrometers wide, with six individual “strings” that were only 50 nanometers (approximately 200 atoms) thick.

The term “nanotechnology,” derived from the Greek word nanos, or “dwarf,” generally refers to engineering and manufacturing at the molecular or nanometer length scale. Nanotechnology aims to construct objects out of their most basic components – in sharp contrast to the typical industrial method of cutting, shaping and assembling products out of bulk materials, as is commonplace in modern computer chip lithography and the rest of microtechnology. Building objects molecule by molecule will offer an unprecedented degree of precision and control over the final product. And by using building blocks of molecular scale, devices of great complexity having thousands or even millions of different mechanical parts could be fabricated at microscopic size. The potential is enormous throughout all of society. In the coming decades, nanotechnology could make a supercomputer so small it could barely be seen in a light microscope. Medicine will be revolutionized by nanodevices that can interact with and repair individual living cells, leading to cures for most diseases, probably including aging. Clean factories could prevent new pollution, and remediate old pollution, that is traditionally caused by conventional manufacturing processes. Inexpensive and lightweight materials 50 times stronger than structural steel may give us easy personal access to space. New fabrics could be embedded with billions of tiny motors, sensors, and even computers, allowing our clothing to react instantly and intelligently to our ever-changing surroundings. Low cost solar cells and batteries could replace coal, oil and nuclear fuels with clean, cheap and abundant solar power. For instance, in 2001, Paul Alivisatos and his team at the University of California at Berkeley announced the first generation of plastic solar cells that eventually might be painted onto just about any surface. The first cells consisted of tiny cadmium selenide nanorods dispersed in plastic. Sandwiched between electrodes, the hair-thin layer produced about 0.7 volts. “This opens up all sorts of new applications,” said Janke Dittmer, a researcher on the team, “like putting solar cells on clothing to power LEDs (light-emitting diodes), radios or small computer processors.”

Molecular Self-Assembly

There are many different ways to build machines at the nanoscale. Self-assembly is the most common and near-term approach, and DNA – the same molecule that comprises our genes – is a useful building material for this purpose. Two decades ago, the pioneering nanotechnologist Nadrian Seeman at New York University recognized that a strand of DNA has many advantages as a construction material. These advantages include polymeric stiffness, easy manipulation by known enzymes, and intermolecular interaction with other strands that can be readily predicted and programmed due to the base-pair complementarity of nucleotides, the fundamental building blocks of genetic material. Arbitrary DNA sequences are readily manufactured using conventional biotechnological techniques. During the 1980s, Seeman worked to develop strands of DNA that would zip themselves up into more and more complex shapes – first tiny squares, then three-dimensional stick-figure cubes comprised of 480 nucleotides each, then a truncated octahedron containing 2550 nucleotides. By the mid-1990s, Seeman could fabricate nanoscale DNA stick figures of almost any regular geometric shape, by the billions per batch. In 1999, Seeman reported the construction of a mechanical DNA-based device that it was believed might serve as the basis for a nanoscale robotic actuator. The mechanism had two rigid double-stranded DNA arms a few nanometers long that could be made to rotate between fixed positions by introducing a positively charged cobalt compound into the solution surrounding the molecules, causing the bridge region to be converted from the normal B-DNA structure to the unusual Z-DNA structure. The free ends of the arms shift position by 2-6 nanometers during this fully reversible structural conversion, like a hinge opening and closing.

In 2001, Seeman announced his latest breakthrough – the molecular equivalent of a four-stroke engine, entirely built from and fuelled by DNA. While the motor can go round and round continuously, it has to be “stepped” a quarter turn at a time, which requires it to be flushed with a fluid containing the right sequence of DNA. The four-stranded DNA motor molecule is essentially a pair of double helixes of DNA connected at several points along their lengths. Adding molecules of control DNA to a solution full of the motor molecules causes the short, single-stranded control molecules to join with the larger molecules and rearrange them by connecting two of the double strands in one place and cutting them in another. The researchers then remove the control strands using fuel strands of DNA, which are also short single-stranded lengths of DNA. This leaves the motor molecule in a different physical shape than when it started – the end of one double strand of the DNA is rotated 180 degrees relative to the strands next to it. By flushing the motor with different short strands of DNA in sequence, it can be made to step forward, or to step in reverse, repeatedly. Seeman’s group is currently working on a method to insert the DNA devices into molecular lattices. The range of motion the molecular motors can produce ranges from 0.04 to 4 nanometers, but the researchers have produced motions as large as 35 nanometers using arrays. In just a few years, molecular motors based on this technology could power and control generations of molecular robots. “The incorporation of such devices into arrays could in principle lead to complex structural states suitable for nanorobotic applications, provided that individual devices can be addressed separately,” writes Seeman. “It could be used to configure a molecular pegboard or control molecular assemblers. Molecular machines could be used to assemble drugs molecule-by-molecule, and molecular robots may eventually work inside the human body.”

Other researchers are building biologically-based nanomotors using the techniques of self-assembly. Most notably, Carlo Montemagno of the California NanoSystems Institute at the University of California, Los Angeles, has modified a natural biomotor to incorporate nonbiological parts, creating the first artificial hybrid nanomotor. Montemagno started with natural ATPase, a ubiquitous enzyme found in the cells of virtually every living organism. The moving part of an ATPase molecule is a central protein shaft (or rotor, in electric-motor terms) that rotates in response to electrochemical reactions with each of the molecule’s three proton channels (comparable to the electromagnets in the stator coil of an electric motor). The universal cellular energy source, ATP (adenosine triphosphate), powers the molecular motor’s motion. Using the tools of genetic engineering, Montemagno added metal-binding amino acid residues to a modified ATPase that would allow each motor molecule to bind tightly to nanoscale nickel pedestals prepared by electron beam lithography. Properly oriented motor molecules 12 nanometers in diameter were then attached to the pedestals with a precision approaching 15 nanometers, and a silicon nitride bar a hundred nanometers long was bound to the rotor subunit of each motor molecule, all by self-assembly. In a microscopic video presentation, dozens of bars could be seen spinning like a field of tiny propellers. The group’s first integrated molecular motor ran for 40 minutes at 200 revolutions per minute, but subsequent motors have been operated for hours continuously by feeding them plenty of ATP. Researchers are measuring horsepower and motor efficiency, simple tests that would be familiar to any mechanical engineer designing an automobile engine.

Montemagno is now developing a chemical means of switching his hybrid motors on and off reliably. By engineering a secondary binding site tailored to a cell’s signaling cascade, he plans to use the sensory system of the living cell to control nanodevices implanted within the cell. Montemagno envisions tiny chemical factories operating inside living cells. He speculates that these nanofactories could be targeted to specific cells, such as those of tumors, where they would synthesize and deliver chemotherapy agents. The team is also trying to build a solar-powered, biomolecular motor-driven autonomous nanodevice. In this nanodevice, light energy is translated into chemical energy in the form of ATP, which then serves as a fuel source for the motor. It’s the first step towards creating truly autonomous nanodevices that don’t need outside chemical power supplies. “For a technology that wasn’t expected to produce a useful device before the year 2050,” remarked Montemagno, “I think we’ve made a pretty good start. But we have a long way to go before it’s safe to turn these little machines loose in the human body.”

Molecular Positional Assembly

For more the most complex structures, such as complete molecular robots having thousands or millions of parts, getting all the pieces to spontaneously assemble themselves in the right order will become maddeningly difficult. To build such structures, it could make more sense to design a manufacturing mechanism, called a molecular assembler, that can assemble a molecular structure using positional assembly – that is, picking and placing molecular parts exactly where you want them. A device capable of positional assembly would work much like the robot arms that manufacture cars on automobile assembly lines in Detroit, or which insert electronic components onto computer circuit boards with blinding speed in Silicon Valley, California. Using the positional assembly approach, the robot manipulator picks up a part, moves it to the workpiece, installs it, then repeats the procedure over and over with many different parts until the final product is fully assembled. In biology, a familiar example of positional assembly is offered by the ribosome, which assembles amino acids one by one into proteins in our cells.

Serious experiments in nanoscale pick-and-place operations may be said to have begun in 1989 when a group of engineers at IBM managed to spell out their employer’s name using precisely-positioned individual xenon atoms, creating the smallest-ever company logo, using a scanning probe microscope (SPM) that had earlier won its inventors the 1986 Nobel prize in physics. Today, nanotechnologists are learning how to pick and place, and even chemically bond, individual molecules at known positions on surfaces. For example, two years ago, Wilson Ho and Hyojune Lee of the University of California at Irvine used an SPM to pick up a carbon monoxide molecule from a prepared surface, move it to a new position, and then bond it to the surface at that new position. These researchers used an SPM with a nanoscale tip to locate two carbon monoxide (CO) molecules and one iron (Fe) atom adsorbed on a silver surface in vacuum, at the very cold temperature of 13 K. Next, they lowered the tip over one CO molecule and increased the voltage and current flow of the instrument to pick up the molecule. Then they moved the tip-bound molecule over the surface-bound Fe atom and reversed the current flow, causing the CO molecule to covalently bond to the Fe atom, forming an iron carbonyl or Fe(CO) molecule bound at the particular spot on the silver surface. Finally, the researchers repeated the procedure, returning again to the exact site of the first Fe(CO) and adding a second CO molecule to the Fe(CO), forming a molecule of Fe(CO)2. In subsequent images of the surface, the iron dicarbonyl could be seen as a tiny “rabbit ears” structure, covalently bound to the silver surface.

Another step toward positional assembly was taken by Philip Kim of the University of California at Berkeley and Charles Lieber at Harvard University, who created the first general-purpose nanotweezer in 1999. Its working end is a pair of electrically controlled carbon nanotubes made from a bundle of multiwalled carbon nanotubes. (Nanotubes are long, hollow cylinders of carbon atoms arranged in a “chicken-wire” configuration of hexagons, typically several nanometers in diameter or larger.) To operate the tweezers, a voltage is applied across the electrodes, causing one nanotube arm to develop a positive electrostatic charge and the other to develop a negative charge. The attractive force can be increased or decreased by varying the applied voltage – 8.5 volts completely closes the arms, while lower voltages give different degrees of grip. Using the tool, Kim and Lieber successfully grasped 500-nanometer clusters of polystyrene spheres, about the same size scale as structures inside living cells. They were also able to remove a semiconductor wire 20 nanometers wide from a mass of entangled wires. Each of the original tweezer’s arms is about 50 nanometers wide and 4 micrometers long. But by growing single-walled nanotubes directly onto the electrodes, the researchers hope to produce nanotweezers small enough to grab individual macromolecules.

The Kim-Lieber nanotweezer is very good at pinching and releasing objects, but the technique creates a large electric field at the tweezer tips which can alter the objects being manipulated, and the tweezers must be constructed one at a time which makes the manipulation of large numbers of nano-objects a slow and tedious process. To try to improve on this, in 2001 a group led by Peter Boggild of the Technical University of Denmark in Lyngby used standard micromachining processes to carve from a tiny slab of silicon an array of cantilevered micro-pliers which could be opened and closed electrically. Boggild then used an electron beam to grow a tiny carbon nanotweezer arm from the end of each cantilever, angled so that the tips were only 25 nanometers apart, making a better-controlled nanotweezer. Experiments are continuing with this approach.

Microscale devices could also be used to pick and place nanoscale parts. In 2001, the MEMS Research Group of Agilent created an ultra-high-precision micro-mover platform capable of providing linear two-dimensional movement in steps of 1.5 nanometers, the width of about 9 bonded carbon atoms. The core of the micro-mover is a stepper actuator or linear motor that does not rotate, but instead steps right to left or front to back. The platform can travel a total of 30 micrometers in each direction in 2.5 milliseconds; since each micrometer is made up of 1,000 nanometers, the micro-mover would take approximately 20,000 steps to traverse 30 micrometers, a distance which is about half the width of a single human hair. Another group led by Sylvain Martel at the Bio-Instrumentation Laboratory at the Massachusetts Institute of Technology is working on a similar nano-positioning device called the Nano-Walker.

Perhaps the leading proponent of positional assembly at the molecular scale is Zyvex Corp., a privately-held nanotechnology research and development corporation headquartered in Richardson, Texas. Zyvex is the first engineering company with the explicit goal of creating a molecular assembler that uses positional assembly to manufacture atomically precise structures. As a first step toward this goal, in 1998 Zyvex demonstrated the ability to use three independently-controlled inch-long robotic arms to manipulate tiny carbon nanotubes in three dimensions, under the watchful eye of a scanning electron microscope that can monitor objects and motions as small as 6 nanometers at near-video scan rates.

In 2001, Zyvex was awarded a $25 million, five-year, National Institute of Standards and Technology (NIST) Advanced Technology Program government contract – to develop prototype microscale assemblers using microelectromechanical systems (MEMS), extend the capabilities to nanometer geometries, and then to develop nanoelectromechanical systems (NEMS) for prototype nanoscale assemblers. Along with its commercial partners and its university collaborators (Rensselaer Polytechnic Institute Center for Automation Technologies, the University of Texas at Dallas, and the University of North Texas), Zyvex hopes to accelerate the production and commercialization of low-cost assemblers for micro- and nanoscale components and subsystems. The ultimate program goal through 2006 is nothing less than automated micro- and nano-manufacturing – the design and construction of assemblers capable of handling thousands of sub-micrometer components at high speed, using MEMS to prototype systems which could then be built at relatively low cost. Zyvex engineers are conceiving and testing various manufacturing architectures that someday may enable the massively parallel construction of large batches of identical molecular machines simultaneously. This would allow vast numbers of nanodevices and nanorobots to be produced to precise molecular specifications, relatively inexpensively.

Nanoelectronics

The biggest news in nanotechnology in 2001 was the major progress achieved in the field of molecular electronics. The U.S. scientific journal Science named the wiring up of the first molecular scale circuits as the “breakthrough of the year” for 2001. Recent advances at numerous independent laboratories suggests that a fantastic miniaturization of computer circuits could happen within just a few years. This would bring us close to the limits allowed by physics, with very tiny hardware components made of precise assemblages of individual atoms. Nanoelectronics researchers appear to be converging on viable circuit-fabrication methods, including several approaches to building circuits with molecules using self-assembly that reached the stage of at least rudimentary logic or simple devices in 2001, including a wide range of molecular electronics components such as wires, diodes, and transistors. Computation speed and memory capacity could soon make enormous leaps, sharply reducing the cost and difficulty of manufacturing. All devices currently under development rely on some form of self-assembly, rather than positional assembly, for their manufacture.

One important potential building block for molecular electronics may be the carbon nanotube, and the most important component in electronics is the transistor. Transistors are electronic switches that form the heart of electronic computers. In the simplest transistor, current flow between source and drain electrodes is controlled by a small voltage applied to an intervening gate, providing substantial gain much greater than 1. (The phenomenon of “gain” is essential for assembling gates and other circuit elements into useful microprocessors – circuits with a gain less than one are ultimately useless because the electrical signal becomes so faint that it cannot be detected.) To make a simple nanotube transistor, single-walled nanotubes in solution are spread on top of prefabricated electrode arrays. A very low surface coverage ensures that one nanotube at most connects a source and drain electrode. Cees Dekker and his coworkers at Delft University of Technology in the Netherlands were the first to build a working carbon nanotube transistor in 1999. However, the controlling gate contact in that experiment consisted of the entire supporting silicon chip, so that all nanotube devices on each chip had to be switched simultaneously, and the gain was less than 1 because the silicon oxide insulator between the gate contact and the nanotube was too thick. In 2001, the team used electron beam lithography to pattern local aluminum gate contacts which were then exposed to air to form very thin insulating layers on the aluminum leads. This thin insulation allowed the new nanotube transistors to operate independently with a gain ratio in excess of 10. By wiring nanotube transistors together with gold interconnects made by lithography, the team has succeeded in constructing a variety of logic circuits, including a memory cell that could serve as part of a random access memory. Says Dekker: “Molecular logic has been one of the holy grails of nanotube research. Now we have done it. Intrinsically, these circuits will run anywhere from megahertz to terahertz speeds.”

Depending on the orientation of the carbon hexagons with respect to the tube axis in the nanotube chickenwire geometry, carbon nanotubes can be either metallic (conducting) or semiconducting. Early in 2001, a team at the IBM Thomas J. Watson Research Center in Yorktown Heights, New York, led by Phaedon Avouris reported a new technique for producing dense random arrays of carbon nanotube transistors, bypassing the need to manually separate metallic and semiconducting nanotubes, or to prealign or orient them. To fabricate such arrays, single-walled carbon nanotube ropes containing a mixture of conducting and semiconducting nanotubes are deposited on an oxidized silicon wafer, and an array of electrodes is fabricated lithographically on top of the ropes. By applying a heavy current between metal electrodes, the conducting nanotubes can be selectively burned away, leaving only the semiconducting ones between the electrodes.

Later in 2001, the IBM group used a similar technique to construct an elementary computing circuit known as a voltage inverter or “NOT” logic gate, encoding the entire inverter logic function along the length of a single carbon nanotube to form the world’s first intra-molecular (or single-molecule) logic circuit. In the binary digital world of zeros and ones, a voltage inverter changes a “1” into a “0” and a “0” into a “1”. This is a crucial step, because the processors at the heart of today’s computers can be viewed as vast and intricate combinations of the NOT gate, coupled with two other basic logic circuits, “AND” and “OR” gates, which perform related logic functions. Voltage inverters typically are comprised of two types of transistors with different electronic properties – n-type (in which electrons carry the electrical current) and p-type (in which electron-deficient regions called “holes” carry the electrical current). All previous carbon nanotube transistors have been p-type only, which are fine for scientific studies but are not sufficient to build logic-performing computer circuits. Scientists at IBM and elsewhere have been able to alter the properties of nanotube transistors by adding atoms of another element, such as potassium, to the carbon nanotube. However, Avouris’ team discovered a new, simpler way to convert p-type nanotube transistors into n-type transistors: simply heating p-type transistors in a vacuum turns them into n-type transistors, and exposure to air reverses the process. The team also discovered that in addition to converting an entire nanotube from p-type to n-type, they could also selectively convert part of a single nanotube to n-type, leaving the remaining part of the single nanotube p-type.

Thus in one experiment in 2001, the IBM researchers deposited two p-type nanotube transistors onto a substrate that was wired up to serve as a NOT gate. Then they coated one of the nanotubes with a protective polymer, and vacuum annealed the entire assembly, converting both nanotubes to the n-type. The team then exposed the device to low-pressure oxygen, causing only the unprotected nanotube to revert to p-type. The result was a fully functioning voltage inverter fashioned out of separate p- and n-type nanotube transistors. In a second experiment, the IBM scientists deposited a single-walled carbon nanotube bundle on an oxidized silicon substrate that had been prepatterned with three gold electrodes. Then they coated the entire assembly with a protective polymer. Finally, the group doped a region of the nanotube with potassium through a small window in the polymer that had been opened using electron-beam lithography. The procedure yielded a voltage inverter fabricated from a single nanotube bundle. IBM’s nanotube circuit has a gain of 1.6, so Avouris is hopeful that even more complex circuits can be made along single nanotubes. The IBM team is now working to create these more complex circuits, which is the next step toward molecular computers. In addition, the team is working to further improve the performance of individual nanotube transistors, and further integrate them into more complex circuits.

The most intricate nanoelectronics circuits might require thousands or millions of nanotube components properly placed on the same device. Researchers at Stanford University in California have coaxed massive arrays of single-walled carbon nanotubes to form at specific sites on the 4-inch silicon wafers commonly used to make computer chips. Growing nanotubes in an orderly fashion on silicon wafers might make it possible for manufacturers to use existing chipmaking technology to connect the nanotubes into circuits, eventually producing massive transistor arrays for computer processors, memory chips and chemical and biological sensors. To make the nanotubes grow on a wafer, Hongjie Dai and his fellow Stanford researchers used photolithography to place an array of 10 to 100 million microscopic dots on the silicon wafer which served as catalysts to initiate the growth of carbon nanotubes. When the researchers exposed the wafer to a hot vapor containing carbon in the presence of an electric field, the carbon atoms condensed to form nanotubes and began their growth from the catalyst dots, all oriented parallel to the field. One, two or three single-walled nanotubes grew from each dot, with the nanotubes ranging from 1 to 3 nanometers in diameter and growing as long as 10,000 nanometers, about twice as long as a red blood cell. The chemistry that yields the nanotubes is independent of the size of the catalyst islands, so this technique could theoretically produce a nanotube for every 100 square nanometers of surface area on a wafer, or about 800 million on a 4-inch wafer. The next step will be to use standard chip-making techniques to place metal contacts over the nanotubes to connect them into circuits, with this patterned nanotube growth technique possibly finding practical applications in 1 to 5 years, according to Dai.

Charles Lieber’s group at Harvard University has been working on a different type of nanoscale wire, which they call a semiconductor nanowire. The nanowire is roughly comparable in size to a carbon nanotube, about 10-30 nanometers in diameter, but its chemical composition is easier to manipulate precisely. Nanowires are synthesized by starting with a metal catalyst, which defines the diameter of the growing wire and serves as the site where molecules of the desired material (usually silicon or gallium nitride) tend to collect. Chemical dopants are added as the nanowires grow, which controls whether the nanowires are n-type (having extra electrons) or p-type (having a shortage of electrons). Lieber has used his nanowires to assemble both major types of transistors (field-effect and bipolar), and also inverters, diodes, and a memory element using crisscrossing n- and p-type nanowires. The memory element can store information for 10 minutes or longer by trapping charge at the interface between the crossing nanowires.

“One of the next big things is making advances in the assembly area,” explained Lieber in early 2002. His group is investigating how to assemble his nanowires into larger two-dimensional arrays or nanocircuits using fluid flows. Just as sticks and logs can flow down a river, short nanowires suspended in ethanol can be drawn into parallel lines as they flow through channels in polymer blocks. The process can be used to create interconnections in the direction of the fluid flow. For example, to produce a right-angle grid, Lieber first lays down a series of parallel nanowires less than 100 nanometers apart, then rotates the direction of flow by 90 degrees and lays down another series. By using wires of different compositions for each layer, he can rapidly assemble an array of functional nanodevices. In 2001, Lieber’s group fabricated functional OR, AND, and NOR logic gates. He has also interconnected multiple AND and NOR gates to implement basic computation – first, in the form of an XOR gate which corresponds to the binary logic function SUM, and second, in the form of a logical half-adder (with carry) which corresponds to the addition of two binary bits. Combining a series of half-adder circuits would allow the construction of primitive basic computers able to perform elementary arithmetic, the earliest true nanocomputers.

Another large-scale component assembly technique being investigated by Thomas Mallouk and his team at Pennsylvania State University is to use DNA to encourage gold nanowires to take up specific positions on a gold surface, bringing self-wiring nano-circuitry within the bounds of possibility. The researchers first cast the gold wires, 200 nanometers wide and 6,000 nanometers long, inside the narrow channels of a porous membrane, and tag them with short strands of DNA. Then they cover a gold film with DNA strands that match the strands on some of the nanowires. (Single DNA strands “match” one another when their sequences are complementary, like a key and lock or like the north and south poles of magnets.) Just like magnets, when complementary strands find each other they adhere, making the wires stick to the surface. The wires whose DNA strands match those on the surface are up to four times more likely to become attached than those with non-complementary DNA tags. Discrimination is not yet perfect, because mis-tagged or even non-tagged nanowires also have a slight tendency to stick. Mallouk’s researchers hope to improve on this, and make self-wiring nanoscale electronic circuits, using surface-bound DNA tags to guide the components into place. They also imagine linking the wires to one another by giving them complementary tags at their ends, having already shown a way to tag just the wires’ tips. Suitably programmed, the components might then gather spontaneously into a complex circuit.

Hendrik Schon and colleagues at Lucent Bell Labs in Murray Hills, New Jersey, are also pursuing an organic pathway to nanoelectronics. Schon has demonstrated an inverter (a logical NOT gate) assembled from field-effect transistors based on an organic semiconductor monolayer of small sulfur-containing hydrocarbon molecules called thiols, each only 2 nanometers long. The main challenges in making molecular-scale transistors are, first, fabricating electrodes that are separated by only a few molecules and, second, attaching electrical contacts to the tiny devices. The Bell Labs researchers overcame both these hurdles by using a self-assembly technique and a clever design in which each electrode is shared by many transistors. “We solved the contact problem by letting one layer of organic molecules self-assemble on one electrode first, and then placing the second electrode above it,” explained one of the Bell Labs chemists. “For the self assembly, we simply make a solution of the organic semiconductor, pour it on the base, and the molecules do the work of finding the electrodes and attaching themselves.”

Like Lieber’s group at Harvard, Fraser Stoddart and James Heath of the University of California at Los Angeles (UCLA), in collaboration with Hewlett-Packard (HP), are investigating nanoelectronics devices made from a simple grid of nanoscale wires connected by electronic switches a single molecule thick. In 1999, the UCLA group constructed the first chemically-assembled rotaxane-based logic gate. Rotaxane is a molecular shuttle switch consisting of a ring-shaped molecule that encircles and slides along a shaft-like chain molecule between two stations located near either end of the chain. Residence of the ring at one station or the other can be switched electrically, providing reversible “0” and “1” states. According to patents filed by HP in 2001, the researchers can now lay down a set of 2-nanometer-diameter erbium disilicide wires parallel to each other, then lay a similar set of nanowires just above the first set, but crossways. The resulting crossbar grid is washed with a solution of rotaxane molecules. These molecules automatically position and attach themselves exactly at each cross point, making each cross point an addressable molecular switch. “It’s basically a ‘shake and bake’ approach to semiconductor processing,” says Phil Keukes, an HP scientist. “Chemical reactions, rather than computer-defined masks, determine the circuit and assemble it.” In 2001, the UCLA/HP group demonstrated the first working 16-bit molecular memory made up of just a few molecules per memory cell.

Yet another interesting approach is being pursued by James Tour, head of the molecular electronics effort at the Center for Nanoscale Science and Technology at Rice University in Houston, Texas. Tour’s project involves the production of logic circuits based on randomly assembled collections of active molecular electronics molecules in very small areas, with each area comprising a single “nanocell.” Each nanocell is thought to contain all the intermolecular connections necessary to produce common logic circuits such as NOT, AND, and NAND gates, as well as adder circuits. While the Harvard and UCLA groups are trying to assemble deterministic arrays of individual circuit elements with a certain predictable behavior from the start, Tour’s approach is to allow blocks of devices and wires to interconnect at random, in large numbers. Later, each ensemble can be analyzed to determine how it might be used for storage or computation, after which one particular circuit path within each nanocell can be selected and burned in by using electrical pulses to turn molecular switches on and off. Tour intends first to prove that it is possible to program the nanocell after assembly (using simulations); second, to actually program a real nanocell; and third, to package and deliver the programmed nanocells in commercially useful devices. His group, along with collaborators from several other universities, has already demonstrated switching in a single phenylene ethynylene oligomer molecule by changing the spatial arrangement of its atoms and thereby its conductance. The molecules are two nanometers long, half a nanometer across, and can retain the change for as long as 26 hours.

One of Europe’s leading specialist consultancies, CMP Científica, now believes that nanoelectronics devices could reach the wider market within three to seven years, against a previously estimated 10 to 15 years. According to its Nanotechnology Opportunity Report, issued in early 2002: “The market is around five years away from the introduction of major disruptive technologies, such as terabyte non-volatile memories based on nanotubes. Científica believes these technologies could make a large part of the hard disk industry redundant.”

Nanomedicine

Burgeoning interest in the medical applications of nanotechnology is leading to the rapid emergence of a new field called nanomedicine. Most broadly, nanomedicine is the science and technology of diagnosing, treating, and preventing disease and traumatic injury, of relieving pain, and of preserving and improving human health, using molecular tools and molecular knowledge of the human body. But it is more than just an extension of modern “molecular medicine.” Nanomedicine will solve most of today’s medical problems using nanoscale-structured materials, biotechnology and genetic engineering, and eventually complex molecular machine systems and nanorobots.

Nanomedicine can best be viewed as a set of three mutually overlapping and progressively more powerful technologies. First, in the relatively near term, certain nanoscale-structured materials and devices can address many important medical problems and can be manufactured today. Second, over the next 5–10 years, biotechnology will allow even more remarkable advances in molecular medicine, genetic engineering and gene therapies, and biobotics (artificial microbes). Third, in the longer term, perhaps 10–20 years from today, the earliest molecular machine systems and nanorobots may join the medical armamentarium, finally putting the most potent healing tools imaginable in the hands of physicians.

Dendrimers are one example of a nanostructured material or device that may soon find its way into medical therapeutics. These tree-shaped synthetic molecules have a regular branching structure emanating outward from a core, with an outermost layer that can be made to form a dense field of molecular groups that serve as hooks for attaching other useful molecules, such as DNA. Dendrimers grow nanometer by nanometer, so the number of synthetic steps or “generations” dictates the exact size of the particles in a batch. Each molecule is typically a few nanometers wide although some have been constructed up to 30 nanometers wide, incorporating more than 100,000 atoms.

James Baker of the Center for Biologic Nanotechnology at the University of Michigan is pioneering the use of dendrimers as a safer and more effective genetic therapy agent. Dendrimers are attractive because they can sneak DNA into cells while avoiding triggering an immune response. Donald Tomalia, at the same center, has reported using glycodendrimer “nanodecoys” to trap and deactivate influenza virus particles. The glycodendrimers present a surface that mimics the sialic acid groups normally found in the mammalian cell membrane, causing virus particles to adhere to the outer branches of the decoys instead of the natural cells. These are only the first in what is expected to become a vast array of medical nanodevices using these components. A dendrimer-based generalized “smart” therapeutic agent will have multiple components which may perform the following functions: (1) diseased cell recognition, (2) diagnosis of disease state, (3) drug delivery, (4) reporting location, and (5) reporting outcome of therapy. Tecto-dendrimers under development will have all five of these functions – specific molecules which perform each of these functions have already been made and tested. Once the Center has a working component which can recognize apoptosis (cell death), then that component can be used as part of a larger nanodevice to report successful therapy delivery to any kind of diseased cell, such as a cancer cell or a cell infected with a virus.

Other simple but effective nanostructured devices may soon be clinically available. For instance, Tejal Desai of the University of Illinois has fabricated silicon-based immunoisolation microcapsules perforated with a high density of uniform nanopores as small as 20 nanometers in diameter. These pores are large enough to allow small molecules such as oxygen, glucose, and insulin to pass, but are small enough to impede the passage of much larger immune system molecules such as immunoglobulins (antibodies) and graft-borne virus particles. Microcapsules containing easily-harvested piglet islet cells could be implanted beneath the skin of some diabetes patients, temporarily restoring the body’s delicate glucose control feedback loop without the need for powerful immunosuppressants that can leave the patient at serious risk for infection. Live animal studies on diabetic rats were underway in 2001. Supplying encapsulated new cells to the body could also be a valuable way to treat other enzyme or hormone deficiency diseases, including encapsulated neurons which could be implanted in the brain and then be electrically stimulated to release neurotransmitters, possibly as part of a future treatment for Alzheimer’s or Parkinson’s diseases.

Another kind of nanodevice might make it possible to swiftly read our individual genomes. Daniel Branton at Harvard University uses an electric field to drive a variety of RNA and DNA polymers through the central nanopore of an alpha-hemolysin protein channel mounted in a lipid bilayer similar to the outer membrane of a living cell. Polymer strands pass single-file through the 2.6 nanometer-wide nanopore, allowing changes in ionic current to be used to measure polymer length and to discriminate between pyrimidine and purine segments (the two types of nucleotide bases) along a single RNA molecule. Last year, Branton’s group demonstrated the ability to distinguish between DNA chains of similar length and composition that differ only in base pair sequence, but a more robust nanopore, probably solid-state, will be required for routine ultra-fast DNA sequencing. Branton envisions a future diagnostic chip containing 500 operational pores, each pore reading at a rate of 1000 base pairs per second, which could sequence an entire human genome in less than two hours, or the entire genome of a viral biological agent in seconds.

The greatest power of nanomedicine will emerge in a decade or two when we learn how to design and construct complete artificial nanorobots using strong diamond-like materials, nanometer-scale parts, and onboard subsystems including sensors, motors, manipulators, power plants, and molecular computers. One example is my design for an artificial mechanical red cell called a respirocyte. Still entirely theoretical, the respirocyte is a micrometer-wide spherical nanorobot made of 18 billion atoms precisely arranged in a diamondoid structure to form a tiny tank for compressed gas, that can be safely pressurized up to 1,000 atmospheres. Several billion molecules of oxygen and carbon dioxide can be absorbed or released from the tank in a controlled manner using computer-controlled molecular pumps powered by serum glucose and oxygen. External gas concentration sensors allow respirocytes to mimic the action of the natural hemoglobin-filled red blood cells, with oxygen released and carbon dioxide absorbed in the tissues, and vice versa in the lungs. Each respirocyte can hold 236 times more gas per unit volume than a natural red cell, so a few cubic centimeters injected into the human bloodstream would exactly replace the gas carrying capacity of the patient’s entire 5.4 liters of blood. A half-liter dose could keep a patient’s tissues safely oxygenated for up to 4 hours in the event that a heart attack caused the heart to stop beating. Or this large dose would enable a healthy person to sit quietly at the bottom of a swimming pool for four hours, holding his breath, or to sprint at top speed for at least 15 minutes without breathing.

Other proposed medical nanorobots could offer equally astonishing performance improvements over nature. In 2001, I completed a theoretical technical scaling study of nanorobotic phagocytes (white cells) called microbivores that would patrol the bloodstream, seeking out and digesting unwanted pathogens including bacteria, viruses, or fungi. Each one of these nanorobots could completely destroy one pathogen in just 30 seconds – about 100 times faster than natural leukocytes or macrophages – releasing a harmless effluent of amino acids, mononucleotides, fatty acids and sugars. It will not matter that a bacterium has acquired multiple drug resistance to antibiotics or to any other traditional treatment. The microbivore will eat it anyway, achieving complete clearance of even the most severe septicemic infections in minutes to hours, as compared to weeks or even months for antibiotic-assisted natural white cell defenses – and without increasing the risk of sepsis or septic shock. Related nanorobots could be programmed to recognize and digest cancer cells, or to mechanically clear circulatory obstructions in a time scale on the order of minutes, thus quickly rescuing the stroke patient from ischemic damage.

Although nanotechnology is still in its infancy, researchers are steadily making major breakthroughs. If we can learn to harness and precisely control the ability to manipulate molecules, then many aspects of our lives will change forever. Indeed, the ability to carry out medical procedures at the molecular level will revolutionize current medical practice.

Robert A. Freitas Jr. is a Research Scientist at Zyvex Corp. in Texas and a Research Fellow at the Institute for Molecular Manufacturing in California. He is the author of Nanomedicine (Landes Bioscience, 1999), the first technical book on medical nanorobotics.

Last updated on 23 September 2003