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Monday, February 15, 2010

NANOSCIENCE AND THEIR BIOLOGICAL IMPORTANCE: HUMAN HEALTH AND DISEASE

1. Introduction
Nano-science is well recognized as a revolutionary step in various field of science and a logical field of study for researchers in the coming years as it is, the study of fundamental principles of molecules and structures between one nanometer (one billionth of a meter) and 100nanometers in size. Due to the novel design and size-tunable optical properties of nano-materials .with new physico-chemical characteristics , their potential adverse impact on human health must be addressed.

Nano-materials are structurally and functionally prevalent in the organic, inorganic, and biological fields. Their unique size-dependent properties make these materials superior and indispensable in many areas of human activity. The biological application of nano-particles is a rapidly developing area of nanotechnology that raises new possibilities in the diagnosis and treatment of various diseases. Basically, the nano-meter length scale opens the way for the development of novel materials for use in highly advanced medical technology. As researchers are developing an ever-expanding toolkit of nano-particles for use as drug and imaging agent delivery vehicles, there is a growing need to understand how a given nano-particle's physical and chemical properties affect biological activity and toxicity. Now, various new methods have been developed for measuring the biological activity of nano-materials in a highly systematic manner that enables them to draw important insights about nano-material biologic activity.

2. Nanotechnology products


Nanotechnology has created a growing sense of excitement due to the ability to create and utilize materials, devices, and systems through the control of matter on the nanometer scale (1 to 50 nm). Current and near-future developments in medicine are of interest, because it can be projected beyond them to perceive what will be possible once inexpensive nano-scale manufacturing of highly functional products becomes a reality.Manufacturing with nanotechnology can solve many of the world's current problems.After more than twenty years of basic and applied research, nanotechnologies are gaining in commercial use. Nano-scale materials now are in electronic, cosmetics, automotive and medical products. Various investigations are continuing researches are now established in the area of nanomaterials, in which scientists use different cell lines for their assays and measured biological activity at different nano-particle doses. New concepts for regenerative medicine give hope to many patients with organ failure or severe injuries. Nano-particle reinforced polymers , orally applicable insulin , artificial
joints ] made from nano-particulate materials, and low-calorie foods with nano-particulate taste enhancers. Some products are already commercially available, such as surgical blades and suture needles, contrast-enhancing agents for magnetic resonance imaging , bone replacement materials , wound dressings , anti-microbial textiles, chips for in vitro molecular diagnostics, micro-cantilevers, and micro-needles. With the emergence of technologies to fabricate and mass-produce micro-scale tools and micro-machines, micro-surgery stands to potentially benefit through the development of a fundamentally new class of instruments. These new instruments may provide the surgeon with access to the smallest reaches of the body and perform operations that are currently not possible with manually operated tools . Nano-wires are tiny highways for electrons, transporting them quickly and efficiently through the solar cell. This analysis clearly showed that there were definite correlations between the physical and chemical properties of a nano-particle and biological activity.


3. Nanoscience and biotechnology


Nanotechnology will have an almost endless string of applications in biotechnology, biology, and biomedicine. The biotech world also has many real world applications currently in use or under development that are, or will be, affecting our quality of life. However, nanobiotechnology presents a promising research and development frontier with a tremendous future impact in the following areas:

Drug delivery: Novel therapeutic strategies include the development of targeted transport vehicles allowing drug delivery to specific cells or cell structures. Of particular interest are bioengineered nano-particles, which can be utilized as transport vehicles of diagnostic or therapeutic agents . Drugs with narrow therapeutic indexes create a major challenge for pharmaceutical scientists, during their developments. Application of nanotechnology for the delivery of such drugs can significantly overcome this problem . Nucleic acid ligands, also known as aptamers, are a class of macromolecules that are being used in several novel nanobiomedical applications, which collectively make them attractive molecules for targeting diseases or as therapeutics. These properties will enable aptamers to facilitate innovative new nanotechnologies with applications in medicine .

Magnetic nano-particles (MNPs) possess unique magnetic properties and the ability to function at the cellular and molecular level of biological interactions making them an attractive platform as contrast agents for magnetic resonance imaging (MRI) and as carriers for drug delivery. However, further development is required before nanotechnology can be applied clinically.

Gene therapy: Nanotechnology, using advanced polymers as a delivery mechanism, may revive genetic therapy as a tool for curing diseases. Problems with delivery systems for genes - often based on the use of viral vectors - have already caused researchers to pull gene therapy projects. Non-viral vectors, nano-particles, complexes between lipids, or polymers with DNA have been proposed as alternatives to viruses used to incorporate specific genes into target cells. Recent progress in nanotechnology has triggered the site specific gene delivery research and gained wide acknowledgment in contemporary DNA therapeutics . Recently the major challenge of gene therapy for researcher is to explore whether nano-particles can be delivered intravenously to attack metastatic tumour cells, which are found throughout the body in advanced stages of cancer.

Nano-biosensors/DNA nano-chips: Nano-materials are exquisitely sensitive chemical and biological sensors constructed of nano-scale components (e.g., nano-cantilevers, nano-wires, and nano-channels) can recognize genetic and molecular events and have reporting capabilities, thereby offering the potential to detect rare molecular signals associated with malignancy .

Rapid and sensitive drug screening, one of the limiting factors in combinatorial chemistry for drug discovery and development, is another important application of nano-biosensors. Because of the small dimension, most of the applications of nano-biotechnology in molecular diagnostics fall under the broad category of biochips/micro-arrays but are more correctly termed nano-chips and nano-arrays.The advancement of biotechnology has been facilitated the biotechnologist to have better understanding, characterization, and control of living cells.


4. Human health and disease
Nanotechnology is already starting to have an impact on the diagnosis, treatment and prevention of disease, especially by enabling early disease detection and diagnosis, as well as precise and effective therapy. It approaches in surgery, cancer diagnosis and therapy, bio-detection of molecular disease markers, molecular imaging, implant technology, tissue engineering, and devices for drug, protein, gene and radionuclide delivery. While many of these medical nanotechnology applications are still in their infancy. Nano-particles or nano-structures are utilizing as novel drug delivery systems . Systemic administration of chemotherapeutic agents, in addition to its anti-tumor benefits, results in indiscriminate drug distribution and severe toxicity. This shortcoming may be overcome by targeted drug-carrying platforms that ferry the drug to the tumor site while limiting exposure to non-target tissues and organs .
The rapid and sensitive detection of pathogenic bacteria is extremely important in medical diagnosis and measures against bioterrorism. Recent advances in the field of nanotechnology led several groups to recognize the promise of recruiting nano-materials to the ongoing battle against pathogenic bacteria . Rapid, selective, and sensitive detection of viruses is crucial for implementing an effective response to viral infection, such as through medication or quarantine.
Direct, real-time electrical detection of single virus particles can be achieved with high selectivity by using nano-wire field effect transistors .


5. Nanoscience and medical research

Research in nano-medicine will allow for a better understanding of the functioning of the human body at molecular and nano-metric level and it will thus give us the possibility to intervene better at pre-symptomatic, acute or chronic stage of illnesses. Some other nanotechnology applications which are currently under development in the biotech world are diabetic insulin biocapsules, pharmaceuticals utilizing “bucky ball” technology to selectively deliver drugs, and cancer therapies using targeted radioactive bio-capsules. Molecular manufacturing will have major effects on medical research, diagnosis, and treatment.

Other diseases, including influenza, hepatitis B virus (HBV) and pneumococcal infection are being at least partially controlled by vaccines, but there is still much that needs to be done to eliminate many such diseases, even in the developed world . With very few adjuvants currently being used in marketed human vaccines, a critical need exists for novel immunopotentiators and delivery vehicles capable of eliciting humoral, cellular and mucosal immunity. Nano-particle technology is also an attractive methodology for optimizing vaccine development because design variables can be tested individually or in combination .

6. Nanoscience and medicine
In recent years there has been a rapid increase in nanotechnology applications to medicine in order to prevent and treat diseases in the human body . Nano-medicine (the application of nanotechnology to health) raises high expectations for millions of patients for better, more efficient and affordable healthcare and has the potential of delivering promising solutions to many illnesses. Nano-medicine, an offshoot of nanotechnology, refers to highly specific medical intervention at the molecular scale for curing disease or repairing damaged tissues, such as bone , muscle, nerve chronic pulmonary diseases or coronary artery disease .

Nano-crystalline silver products (Acticoat) is effective against most common strains of wound pathogens; can be used as a protective covering over skin grafts; has a broader antibiotic spectrum activity; and is toxic to keratinocytes and fibroblasts. Animal studies suggest a role for nanocrystalline silver in altering wound inflammatory events and facilitation of the early phase of wound healing . Nano-sized cosmetic or sunscreen ingredients pose no potential risk to human
health, whereas their use in sunscreens has large benefits, such as the protection of human skin against skin cancer . It gives the hope of designing new, more efficient drugs with fewer or no side effects.

The development of novel materials and devices operating at the nano-scale range, such as nano-particles, provides new and powerful tools for imaging, diagnosis and therapy. The design of multifunctional nano-particles is suggested as an alternative system for drug and gene delivery,which has great potential for therapy in areas, such as cancer and neuro-pathologies .

Nano-medicine raises high expectations for millions of patients for better, more efficient and affordable healthcare and has the potential of delivering promising solutions to many illnesses.The aim is to identify a disease at the earliest possible stage. Ideally already a single cell with ill behavior would be detected and cured or eliminated.

7. Nano-science and cancer
The biological application of nano-particles is a rapidly developing area of nanotechnology that raises new promises in the diagnosis and treatment of various cancers. They can also facilitate important advances in detection, diagnosis, and treatment of human cancers and have led to a new discipline of nano-oncology . Nano-particles offer a new method of tumour targeting, already available in clinical practice, which can concomitantly improve the efficacy and decrease the toxicity of existing or novel anticancer agents. This makes them an ideal candidate for precisely targeting cancer cells. Molecular imaging has now considered as a high area in cancer diagnosis . Early assessment of nanotechnologies is also reported by Micro-array Analysis and Photodynamic Therapy implementation, which methodology can be extrapolated to other nanotechnologies in oncology. In the near future, the use of nanotechnology could revolutionize not only oncology, but also the entire discipline of medicine.

The development of resistance to variety of chemotherapeutic agents is one of the major challenges in effective cancer treatment. Nanotechnology could enhance the precision of drugs that have one highly specialized mission, like finding and killing cancer cells or tumors. Additionally, multi-functional nano-carriers are developed to enhance drug delivery and overcome MDR by either simultaneous or sequential delivery of resistance modulators (e.g., with P-glycoprotein substrates), agents that regulate intracellular pH, agents that lower the apoptotic threshold (e.g.,with ceramide), or in combination with energy delivery (e.g., sound, heat, and light) to enhance the effectiveness of anticancer agents in refractory tumors . A recent study showed that targeting of phage nano-medicines via specific antibodies to receptors on cancer cell membranes results in 145 endocytosis, intracellular degradation, and drug release, resulting in growth inhibition of the target cells in vitro with a potentiation factor of >1000 over the corresponding free drugs. These results define targeted drug-carrying filamentous phage nano-particles as a unique type of antibody-drug conjugates .
Optically efficient, cancer specific Quantum dots provide a new tool to enable noninvasive visualization of disease-specific molecular and tissue changes with subcellular spatial resolution . Nanotechnology is in a unique position to transform cancer diagnostics and to produce a new generation of fluorescent markers and medical imaging techniques with higher sensitivity and precision of recognition.

Nanoparticles make biofuel production more efficient

Biofuel production currently involves a complex mixture of hydrophilic and hydrophobic liquids, along with one or more catalysts. Getting them all together and separating out the fuel can be a time-consuming challenge. Researchers have now used carbon nanotubes and oxidized metals to create a solid that is both hydrophilic and hydrophobic and sits between oil and alcohol layers, mediating their interactions.

Making biofuel using current methods can be a bit tedious. Recipes generally involve mixing some kind of bio-oil, often vegetable oil, with an alcohol, usually methanol, along with a catalyst such as lye. Once these have all been combined, they react to form the desired biofuel, glycerine, and some excess soap, water, and alcohol. All of these will, for the most part, separate into layers like with a vinaigrette dressing if allowed to sit for a long enough time.

The glycerine can be drained off easily enough, and most of the impurities will settle between the glycerine and biofuel, but the biofuel must be "washed" a few times to extract any errant soap particles and other impurities that are suspended in it, and boiled to remove the water. All told, the process can take between a couple of days and a week, depending on how much you're making. There are machines that will carry out the mixing and washing, but the process can't be shortened much because of the impurities that are introduced due to the use of lye as a catalyst.

Researchers set out to solve this problem by finding a catalyst that would not introduce any impurities that would be difficult to remove. They also wanted to find one that would that could stabilize an oil and water emulsion, which would help the reaction components form a stable mix, in the same way that egg yolks stabilize mayonnaise. A stabilized emulsion would significantly increase the surface area where the two substances can react—typically, this function is performed by the solid catalysts. Ideally, the newly engineered catalysts would also be reusable.

The researchers' solution involved a combination of hydrophilic and hydrophobic materials that would both emulsify the oil/water mixture by sitting at the interface of the two substances, and facilitate their reaction to form biofuels. To accomplish this, they grew hydrophobic carbon nanotubes on small pellets of hydrophilic oxidized metals that contained enough palladium catalyst to speed up the reaction.

They found this combination helped the aqueous and organic phases emulsify, and would remain at the boundary between the two substances; the palladium facilitated the hydrogenation, hydrogenolysis, and decarbonylation reactions. Hydrogenation was the dominant reaction at around 100ºC, hydrogenolysis at 200ºC, and decarbonylation at 250ºC. Each of these reactions is useful for the conversion of different combinations of alcohols and oils, and because of the increased surface area. Thanks to the inclusion of palladium, these reactions happen at a much faster rate than when performed using lye.

Once the reactions had occurred, the authors found that all of the desired products had moved into the organic phase, or what was once just bio-oil, leaving any waste and water in the aqueous phase, where it was still bound by the catalytic nanoparticles.

To separate the catalyst and waste, they strained the liquid through a regular paper filter, which managed to catch most of the catalyst. They then passed the organic liquid through a polytetrafluoroethylene filter to catch the nanoparticles that had gotten through the paper filter, leaving them with purified biofuel.

These solid nanohybrid particles seem to be a strong candidate for fuel production, given the greater amount of precision and control they provide fuel makers and the speedier reaction times they enable. But they do still require a filtration process, an aspect of the experiment that was not extensively studied. Since reducing production time and increasing purity would be beneficial to the future of biofuel, streamlining the waste-removal step in this process will be critical. The paper also made no mention of whether their chosen nanoparticles were reusable after their initial reaction. Still, the basic principles seem solid, provided that these aspects of the catalysts can be optimized.

Nanoparticle

A nanoparticle is a microscopic particle with at least one dimension less than 100 nm.

Nanoparticle research is currently an area of intense scientific research, due to a wide variety of potential applications in biomedical, optical, and electronic fields. Nanoparticles are of great scientific interest as they are effectively a bridge between bulk materials and atomic or molecular structures.

A bulk material should have constant physical properties regardless of its size, but at the nano-scale this is often not the case.

Size-dependent properties are observed such as quantum confinement in semiconductor particles, surface plasmon resonance in some metal particles and superparamagnetism in magnetic materials. The properties of materials change as their size approaches the nanoscale and as the percentage of atoms at the surface of a material becomes significant.

For bulk materials larger than one micrometre the percentage of atoms at the surface is minuscule relative to the total number of atoms of the material.

The interesting and sometimes unexpected properties of nanoparticles are not partly due to the aspects of the surface of the material dominating the properties in lieu of the bulk properties. Nanoparticles exhibit a number of special properties relative to bulk material.

For example, the bending of bulk copper (wire, ribbon, etc.) occurs with movement of copper atoms/clusters at about the 50 nm scale.

Copper nanoparticles smaller than 50 nm are considered super hard materials that do not exhibit the same malleability and ductility as bulk copper.

The change in properties is not always desirable.

Ferroelectric materials smaller than 10 nm can switch their magnetisation direction using room temperature thermal energy, thus making them useless for memory storage.

Suspensions of nanoparticles are possible because the interaction of the particle surface with the solvent is strong enough to overcome differences in density, which usually result in a material either sinking or floating in a liquid.

Nanoparticles often have unexpected visible properties because they are small enough to confine their electrons and produce quantum effects.

For example gold nanoparticles appear deep red to black in solution. Nanoparticles have a very high surface area to volume ratio.

This provides a tremendous driving force for diffusion, especially at elevated temperatures.

Sintering can take place at lower temperatures, over shorter time scales than for larger particles.

This theoretically does not affect the density of the final product, though flow difficulties and the tendency of nanoparticles to agglomerate complicates matters.


Nanomaterials

Nanomaterials is a field which takes a materials science-based approach to nanotechnology. It studies materials with morphological features on the nanoscale, and especially those which have special properties stemming from their nanoscale dimensions. Nanoscale is usually defined as smaller than a one tenth of a micrometer in at least one dimension, though this term is sometimes also used for materials smaller than one micrometer.


An aspect of nanotechnology is the vastly increased ratio of surface area to volume present in many nanoscale materials which makes possible new quantum mechanical effects, for example the “quantum size effect” where the electronic properties of solids are altered with great reductions in particle size. This effect does not come into play by going from macro to micro dimensions. However, it becomes pronounced when the nanometer size range is reached. A certain number of physical properties also alter with the change from macroscopic systems. Novel mechanical properties of nanomaterials is a subject of nanomechanics research. Catalytic activities also reveal new behaviour in the interaction with biomaterials.
Nanotechnology can be thought of as extensions of traditional disciplines towards the explicit consideration of these properties. Additionally, traditional disciplines can be re-interpreted as specific applications of nanotechnology. This dynamic reciprocation of ideas and concepts contributes to the modern understanding of the field. Broadly speaking, nanotechnology is the synthesis and application of ideas from science and engineering towards the understanding and production of novel materials and devices. These products generally make copious use of physical properties associated with small scales.


As mentioned above, materials reduced to the nanoscale can suddenly show very different properties compared to what they exhibit on a macroscale, enabling unique applications. For instance, opaque substances become transparent (copper); inert materials attain catalytic properties (platinum); stable materials turn combustible (aluminum); solids turn into liquids at room temperature (gold); insulators become conductors (silicon). Materials such as gold, which is chemically inert at normal scales, can serve as a potent chemical catalyst at nanoscales. Much of the fascination with nanotechnology stems from these unique quantum and surface phenomena that matter exhibits at the nanoscale.


Uniformity

The chemical processing and synthesis of high performance technological components for the private, industrial and military sectors requires the use of high purity ceramics, polymers, glass-ceramics and material composites. In condensed bodies formed from fine powders, the irregular sizes and shapes of nanoparticlesin a typical powder often lead to non-uniform packing morphologies that result in packing density variations in the powder compact.
Uncontrolled agglomeration of powders due to attractive van der Waals forces can also give rise to in microstructural inhomogeneities. Differential stresses that develop as a result of non-uniform drying shrinkage are directly related to the rate at which the solvent can be removed, and thus highly dependent upon the distribution of porosity. Such stresses have been associated with a plastic-to-brittle transition in consolidated bodies, and can yield to crack propagation in the unfired body if not relieved.


In addition, any fluctuations in packing density in the compact as it is prepared for the kiln are often amplified during the sintering process, yielding inhomogeneous densification. Some pores and other structural defects associated with density variations have been shown to play a detrimental role in the sintering process by growing and thus limiting end-point densities. Differential stresses arising from inhomogeneous densification have also been shown to result in the propagation of internal cracks, thus becoming the strength-controlling flaws.
It would therefore appear desirable to process a material in such a way that it is physically uniform with regard to the distribution of components and porosity, rather than using particle size distributions which will maximize the green density. The containment of a uniformly dispersed assembly of strongly interacting particles in suspension requires total control over particle-particle interactions. It should benoted here that a number of dispersants such as ammonium citrate (aqueous) and imidazoline or oleyl alcohol (nonaqueous) are promising solutions as possible additives for enhanced dispersion and deagglomeration. Monodisperse nanoparticles and colloids provide this potential.


Monodisperse powders of colloidal silica, for example, may therefore be stabilized sufficiently to ensure a high degree of order in the colloidal crystal or polycrystalline colloidal solid which results from aggregation. The degree of order appears to be limited by the time and space allowed for longer-range correlations to be established. Such defective polycrystalline colloidal structures would appear to be the basic elements of submicrometer colloidal materials science, and, therefore, provide the first step in developing a more rigorous understanding of the mechanisms involved in microstructural evolution in high performance materials and components.

What are Nanorobots

Nanorobots are theoretical microscopic devices measured on the scale of nanometers (1nm equals one millionth of 1 millimeter). When fully realized from the hypothetical stage, they would work at the atomic, molecular and cellular level to perform tasks in both the medical and industrial fields that have heretofore been the stuff of science fiction.

A few generations from now someone diagnosed with cancer might be offered a new alternative to chemotherapy, the traditional treatment of radiation that kills not just cancer cells but healthy human cells as well, causing hair loss, fatigue, nausea, depression, and a host of other symptoms. A doctor practicing nanomedicine would offer the patient an injection of a special type of nanorobot that would seek out cancer cells and destroy them, dispelling the disease at the source, leaving healthy cells untouched. The extent of the hardship to the patient would essentially be a prick to the arm. A person undergoing a nanorobotic treatment could expect to have no awareness of the molecular devices working inside them, other than rapid betterment of their health.

Nanomedicine's nanorobots are so tiny that they can easily traverse the human body. Scientists report the exterior of a nanorobot will likely be constructed of carbon atoms in a diamondoid structure because of its inert properties and strength. Super-smooth surfaces will lessen the likelihood of triggering the body's immune system, allowing the nanorobots to go about their business unimpeded. Glucose or natural body sugars and oxygen might be a source for propulsion, and the nanorobot will have other biochemical or molecular parts depending on its task.

According to current theories, nanorobots will possess at least rudimentary two-way communication; will respond to acoustic signals; and will be able to receive power or even re-programming instructions from an external source via sound waves. A network of special stationary nanorobots might be strategically positioned throughout the body, logging each active nanorobot as it passes, then reporting those results, allowing an interface to keep track of all of the devices in the body. A doctor could not only monitor a patient's progress but change the instructions of the nanorobots in vivo to progress to another stage of healing. When the task is completed, the nanorobots would be flushed from the body.

Molecular nanotechnology (MNT), the umbrella science of nanomedicine, envisions nanorobots manufactured in nanofactories no larger than the average desktop printer. The nanofactories would use nano-scale tools capable of constructing nanorobots to exacting specifications. Design, shape, size and type of atoms, molecules, and computerized components included would be task-specific. Raw material for making the nanorobots would be nearly cost-free, and the process virtually pollution-free, making nanorobots an extremely affordable and highly attractive technology.

The first generation of nanorobots will likely fulfill very simple tasks, becoming more sophisticated as the science progresses. They will be controlled not only through limited design functionality but also through programming and the aforementioned acoustic signaling, which can be used, notably, to turn the nanorobots off.

Robert A. Freitas Jr., author of Nanomedicine, gives us an example of one type of medical nanorobot he has designed that would act as a red blood cell. It consists of carbon atoms in a diamond pattern to create what is basically a tiny, spherical pressurized tank, with "molecular sorting rotors" covering just over one-third of the surface. To make a rough analogy, these molecules would act like the paddles on a riverboat grabbing oxygen (O2) and carbon dioxide (CO2) molecules, which they would then pass into the inner structure of the nanorobot.

The entire nanorobot which Freitas dubbed a respirocyte, consists of 18-billion atoms and can hold up to 9-billion O2 and CO2 molecules, or just over 235 times the capacity of a human red blood cell. This increased capacity is made possible because of the diamond structure supports greater pressures than a human cell. Sensors on the nanorobot would trigger the molecular rotors to either release gasses, or collect them, depending on the needs of the surrounding tissues. A healthy dose of these nanorobots injected into a patient in solution, Freitas explains, would allow someone to comfortably sit underwater near the drain of the backyard pool for nearly four hours, or run at full speed for 15 minutes before taking a breath.

While potential medical and even military applications seem obvious for this one simple type of nanorobot, implications for every-day life are also intriguing. Imagine scuba diving without tank or regulator, but a swarm of respirocytes in your bloodstream; or the 2030 Olympics when, perhaps, super-athletes will not be scanned for drugs, but for nanorobotic augmentation.

Although nanorobots applied to medicine hold a wealth of promise from eradicating disease to reversing the aging process (wrinkles, loss of bone mass and age-related conditions are all treatable at the cellular level), nanorobots are also candidates for industrial applications. In great swarms they might clean the air of carbon dioxide, repair the hole in the ozone, scrub the water of pollutants, and restore our ecosystems.

Early theories in The Engines Of Creation (1986), by "the father of nanotechnology," Eric Drexler, envisioned nanorobots as self-replicating. This idea is now obsolete but at the time the author offered a worst-case scenario as a cautionary note. Runaway microscopic nanobugs exponentially disassembling matter at the cellular level in order to make more copies of themselves - a situation that could rapidly wipe out all life on Earth by changing it into "gray goo." This unlikely but theoretically feasible ecophage triggered a backlash and blockade to funding. The idea of self-replicating nanobugs rapidly became rooted in many popular science fiction themes including Star Trek's nanoalien, the Borg.

Over the years MNT theory continued to evolve eliminating self-replicating nanorobots. This is reflected in Drexler's later work, Nanosystems (1992). The need for more control over the process and position of nanomachines has led to a more mechanical approach, leaving little chance for runaway biological processes to occur.


Nanorobots are poised to bring the next revolution in technology and medicine, replacing the cumbersome and toxic Industrial Age and opening humankind up to incredible possibilities. But while gray goo is no longer a central concern, more potential dangers and abuses of nanotechnology remain under serious consideration by scientists and watchdog groups alike.

Nanorobotics

Nanorobotics is the technology of creating machines or robots at or close to the microscopic scale of a nanometer (10−9 meters). More specifically, nanorobotics refers to the still largely hypothetical nanotechnology engineering discipline of designing and building nanorobots, devices ranging in size from 0.1-10 micrometers and constructed of nanoscale or molecular components. As no artificial non-biological nanorobots have yet been created, they remain a hypothetical concept. The names nanobots, nanoids, nanites or nanomites have also been used to describe these hypothetical devices.

Another definition sometimes used is a robot which allows precision interactions with nanoscale objects, or can manipulate with nanoscale resolution. Following this definition even a large apparatus such as an atomic force microscope can be considered a nanorobotic instrument when configured to perform nanomanipulation. Also macroscale robots or microrobots which can move with nanoscale precision can also be considered nanorobots.

Nanomachines are largely in the research-and-development phase[1], but some primitive molecular machines have been tested. An example is a sensor having a switch approximately 1.5 nanometers across, capable of counting specific molecules in a chemical sample. The first useful applications of nanomachines, if such are ever built, might be in medical technology, where they might be used to identify cancer cells and destroy them. Another potential application is the detection of toxic chemicals, and the measurement of their concentrations, in the environment. Recently, Rice University has demonstrated a single-molecule car which is developed by a chemical process and includes buckyballs for wheels. It is actuated by controlling the environmental temperature and by positioning a scanning tunneling microscope tip.

More specifically, nanorobotics refers to the still largely theoretical nanotechnology engineering discipline of designing and building nanorobots.

Nanorobots (nanobots or nanoids) are typically devices ranging in size from 0.1-10 micrometres and constructed of nanoscale or molecular components.

As no artificial non-biological nanorobots have so far been created, they remain a hypothetical concept at this time.

Another definition sometimes used is a robot which allows precision interactions with nanoscale objects, or can manipulate with nanoscale resolution.

Following this definition even a large apparatus such as an atomic force microscope can be considered a nanorobotic instrument when configured to perform nanomanipulation.

Also, macroscale robots or microrobots which can move with nanoscale precision can also be considered nanorobots.



Molecular Manufacturing

Molecular manufacturing is the hypothetical future use of reprogrammable nanoscale "assemblers" to build products atom by atom. A molecular assembler would be a nanoscale robotic manipulator capable of placing single atoms, for example carbon, onto a surface with atomic precision. An everyday person would experience this technology in the form of a "nanofactory," a self-contained desktop molecular manufacturing unit that uses a purified feedstock material, such as propane gas.

For a molecular assembler to be useful to humans, it would have to be able to make copies of itself. Otherwise, it would take too long for a single assembler to build anything of significant size or value. If a large array of assemblers could be made to cooperate, they could construct macroscale products with atomic precision, using a fully automated process with high throughput. This is significant enough that, if the technical obstacles are overcome, the technology would launch another Industrial Revolution, probably more transformative than the first two put together.

Molecular assemblers and molecular manufacturing are nothing new. We have trillions of them in our bodies: organelles called ribosomes. Working in large numbers, ribosomes synthesize every protein in every organism in nature, from extremophile microbes to the blue whale. Their basic design is all the same, because every living thing evolved from a common ancestor that already had the basic protein synthesis machinery in place. Of course, ribosomes are also self-replicating.

If an inorganic molecular assembler were created capable of making copies of itself, it could create a new form of "life," albeit a type controlled directly by programming. This idea has been called molecular manufacturing, and some of the technical details for it have actually been worked out. Theorists have designed physically-viable nanoscale gears, motors, batteries, wires, moving rods, sorters, shafts, and more. Some of these nanoscale devices have already been fabricated, others are being actively worked on.


Molecular manufacturing has the potential to turn society upside-down, but barely anyone has heard of it. Often, the ideas of molecular manufacturing are combined or conflated with other possible applications of the wider field of nanotechology in general, which makes it difficult to come up with regulation policies for the latter. One study found that public opinions on nanotechnology could easily be manipulated by changing just a few sentences in the way the topic is introduced. These gaps in knowledge are worrisome to some futurists and policymakers, who would like to see more discussion on the futuristic possibilities of molecular manufacturing, and the way it might be regulated.

Molecular Nanotechnology

Molecular nanotechnology is an anticipated manufacturing technology that would allow precise control and positional assembly of molecule-sized building blocks through the use of nano-scale manipulator arms. Molecular nanotechnology is usually considered distinct from the more inclusive term "nanotechnology", which is now used to refer to a wide range of scientific or technological projects that focus on phenomena or properties of the nanometer scale (around 0.1-100nm). Nanotechnology is already a blossoming field, but molecular nanotechnology — the goal of productive, molecular-scale machine systems — is still in the preliminary research stage.


Nanotechnology was first introduced in 1959, in a talk by the Nobel Prize-winning physicist Richard Feynman, entitled "There's Plenty of Room at the Bottom". Feynman proposed using a set of conventional-sized robot arms to construct a replica of themselves, but one-tenth the original size, then using that new set of arms to manufacture an even smaller set, and so on, until the molecular scale is reached. If we had many millions or billions of such molecular-scale arms, we could program them to work together to create macro-scale products built from individual molecules — a "bottom-up manufacturing" technique, as opposed to the usual technique of cutting away material until you have a completed component or product — "top-down manufacturing".

Feynman's idea remained largely undiscussed until the mid-80s, when the MIT-educated engineer K. Eric Drexler published "Engines of Creation", a book to popularize the potential of molecular nanotechnology. Because MNT would allow manufacturers to fabricate products from the bottom up with precise molecular control, a very wide range of chemically possible structures could be created. Since MNT systems could put every molecule in its specific place, molecular manufacturing processes could be very clean and efficient. Also, because every little bit of matter in an molecular nanotechnology system would be part of a nano-scale manipulator, nanotechnological systems could be far more productive and maintain much higher throughputs than modern manufacturing techniques, which use macro-scale manipulators to fabricate products.


To initiate an MNT revolution would require an "assembler" — a reprogrammable nano-scale manipulator capable of creating a wide range of molecular structures, including a complete copy of itself. The first assemblers will only function effectively in lab-controlled environments, such as a vacuum. The advent of self-replicating molecular nanomachines could quickly lead to "desktop nanofactories", tabletop appliances that consume modest amounts of power and contain the software required to manufacture an interesting range of useful products. The arrival of MNT would revolutionize wide sectors of human activity, including manufacturing, medicine, scientific research, communication, computing, and warfare. When full-blown molecular nanotechnology will arrive is currently unknown, but some experts foresee its arrival sometime between 2010 and 2030.

Wednesday, February 3, 2010

Biotechnology as a route to nanotechnology

Introduction
Nanotechnology is creating a growing sense of excitement because we see an opportunity of unprecedented magnitude looming on the horizon: the ability to arrange and rearrange molecular structures in most of the ways consistent with physical law. This will have a pervasive impact on how we manufacture almost everything -- what is manufacturing but a way to arrange atoms? If we can arrange atoms with greater precision, at lower cost, and with greater flexibility then almost all the familiar products in our world will be revolutionized. To name just three: we'll pack more computational power into a sugar cube than exists in the world today, we'll make inexpensive structural materials that are as light and strong as diamond (which will have a major impact on the aerospace industry), and we'll make surgical tools and instruments that are molecular in their size and precision, able to intervene directly at the fundamental level where most sickness and disease are caused.


Underlying the excitement is a very simple fact: while atoms can be arranged in almost infinite permutations, today we can make only an infinitesimal fraction of what is possible. Very roughly, if we can pack 100 atoms into a cubic nanometer, and each atom can be any of the approximately 100 elements, then there are something like 100100 different ways we can arrange the atoms in just a single cubic nanometer. A cubic micron expands this to 100100000000000, while an object the size of you or me makes even this number seem vanishingly small. The goal that now seems possible: to take a healthy bite out of this enormous range of possibilities; to make most of the things that are possible, rather than an infinitesimally small fraction.
In 1959 Feynman said: "The principles of physics, as far as I can see, do not speak against the possibility of maneuvering things atom by atom. It is not an attempt to violate any laws; it is something, in principle, that can be done; but in practice, it has not been done because we are too big." More recently, Smalley said "Most interesting structures that are at least substantial local minima on a potential energy surface can probably be made one way or another."
The breathtaking magnitude of this opportunity is attracting interest. Neal Lane, the Director of NSF, said: "The possibilities of nanotechnology are endless. Entirely new classes of incredibly strong, extremely light and environmentally benign materials could be created" and went on to discuss inexpensive superconductors and medical applications. NSF is backing up this rhetoric with grants. NASA has a computational molecular nanotechnology research group examining the ways in which this technology can be used to advance the exploration and human habitation of space. IBM is doing pathbreaking research to revolutionize computing. Storing one bit in a few atoms no longer seems outlandish, and molecular switches will someday replace the bulky devices made today using optical lithography.

As we move beyond the vision and start asking how we are going to do this and how long it will take, opinions begin to diverge. Should we make ever better scanning probe microscopes (SPM's)? These remarkable instruments have already demonstrated an ability to move atoms and molecules on a surface in a controlled way (often spelling out names of interest to the researchers or their sponsors), but have so far been confined to two dimensions. Stacking molecules one on top of another is the next obvious goal, which will no doubt be accomplished in the next few years. Could these versatile instruments go on to make molecular machines?
Or perhaps the design and modification of proteins and their self assembly will provide the key to progress? Living systems already use many molecular machines, such as molecular motors. Could we adapt them to our own uses, perhaps using them to power tiny pumps or open and close tiny valves?1

There are many novel uses of existing biopolymers that could provide us with new tools. DNA, for example, is known primarily for its ability to encode information. But it can also produce structures as complex as a truncated octahedron2 and even provide power when it's chemical conformation changes in response to changes in its environment3.
The great diversity of proposals, ideas, and experimental capabilities makes it very difficult to predict exactly how we will proceed towards the more general goals of nanotechnology. Yet there are a few principles that seem both powerful enough and clear enough that they can provide some sort of framework for orienting ourselves. The first principle we consider is that of positional assembly.
Positional assemblyThere are two main ways to assemble parts. In self assembly, the parts move randomly under the influence of thermal noise and explore the space of possible mutual orientations. If some particular arrangement is more stable, then it will be preferred. Given sufficient time, this preferred arrangement will be adopted. For example, two complementary strands of DNA in solution will eventually find each other and stick together in a double-helical configuration.

In positional assembly, some restoring force keeps the part positioned at or near a particular location, and two parts are assembled when they are deliberately moved into close proximity and linked together. While common at the scale of humans (we commonly hold, position and assemble parts with our hands) this ability is still quite novel at the molecular scale. Thermal noise still plays a significant role, as "holding" a molecular part does not provide absolute certainty about its position but instead imposes a bias on the range of positions it can adopt. Using a linear approximation, an object might be subjected to a restoring force F which is proportional to its distance from the desired location, i.e., F = ks x, where x is the distance between the part and its desired location, and ks is the restoring force.
Restoring forces on the order of 10 N/m (Newtons/meter) or better can be achieved with scanning probe microscopes, which can position an object quite accurately. The fundamental equation relating positional uncertainty, temperature and stiffness is4:
s2 = kbT/ks

Where s is the mean error in position, kb is Boltzmann's constant, T is the temperature in Kelvins, and ks is the "spring constant" of the restoring force. If ks is 10 N/m, the positional uncertainty s at room temperature is ~0.02 nm (nanometers). This is accurate enough to permit alignment of molecular parts to within a fraction of an atomic diameter. It is important to remember, however, that the actual error could be many times s. The probability that the actual error is xerr is exp[-ks xerr2/(2s2)] / (s sqrt(2p)). Errors of a few times s are common, but errors of 20 times s would be extremely unlikely.

The distinction between self assembly and positional assembly is not binary, but moves continuously along a scale depending on the positional uncertainty (which is a function of the restoring force and the temperature). When the positional uncertainty s is large, we are near the self assembly end of the spectrum. When s is small, we are at the positional assembly end of the spectrum. Intermediate points along this spectrum are occupied by, for example, a molecule "tethered" to an SPM tip by a polymer; or an object held by optical tweezers (a restoring force of 10-4 N/m implies a positional uncertainty s at room temperature of ~6 nm).

While the SPM provides programmable positional control (you can adjust x, y and z to essentially any values), a simple form of positional assembly can also be seen in enzymes which bind two substrate molecules. The two bound molecules are positioned with respect to each other, thus facilitating their assembly. A limited form of positional assembly is also used in the ribosome, which can position the end of a growing protein adjacent to the next amino acid to be incorporated into that protein5.

This combination of positional assembly and self assembly can also be seen at the macroscopic scale. The vibratory bowl feeder6 is commonly used in manufacturing to position parts with sizes on the order of a centimeter. The bowl is shaken by a motor, causing parts in the bowl to bounce onto and along a spiral track leading out of the bowl. By careful design of the track, parts in the right orientation continue to move along it, out of the bowl and into further assembly steps. Parts in the wrong orientation are bounced back into the bowl, where they can try again to move up the spiral path leading out of the bowl.

While the power of self assembly has been amply demonstrated by the wide range of complex molecular structures it has made (including a remarkable range of biological structures), we have barely begun to explore the power of positional assembly at the molecular scale. Despite this, it seems clear that this new capability will play a major role in our future ability to synthesize molecular structures. The power of positional assembly has been amply demonstrated at the macroscopic scale in today's factories and by our own ability to make things with our hands. While its application at the molecular scale will differ in many details, it will provide a new and remarkably powerful tool for extending the range of structures that we can make.

Biotechnology and programmable positional control

Schematic illustration of a Stewart platform. The lower (blue) triangle forms the base, while the upper (green) triangle froms the platform.
The position and orientation of the platform with respect to the base can be controlled in six degrees of freedom (X, Y, Z, rool, pitch, and yaw) by adjusting the lengths of the six gray struts.

Today's SPMs are large, relatively slow, and will never make mole quantities of product. If we really want positional assembly to make products in the volume that ribosomes make proteins, we must have small, fast positional devices7. Yet it seems unlikely that biotechnology will directly give us a molecular robotic arm.

Which brings us to the Stewart platform8,9,10. This device, basically an octahedron six of whose struts can be lengthened or shortened under programmatic control (see illustration), provides six degree of freedom positional control for the "platform," (the green triangle at the top of the octahedron) with respect to its base (the blue triangle at the bottom of the octahedron). The ability to make an octahedron does not seem beyond the capabilities of biotechnology (in the broad sense of the term), particularly when the ability to self assemble a truncated octahedron has already been demonstrated by Seeman2.

All we need are twelve stiff struts, some way to make their ends stick together, and some way to lengthen or shorten six of those struts. As the latter seems the harder problem, we discuss one possible approach to solving it.

Consider a single strut: how can we change its length? One way would be to use two struts that overlap, and then make them slide past each other in a controlled fashion. Suppose that the first strut is made of three repeat units, ABCABCABCABCABC...., while the second strut is also made of three repeat units, XYZXYZXYZXYZ.... If we want to combine these two struts into one long strut, then we have to join them together. Suppose we use "joiners" that have two ends: one end binds to the A units of the first strut, while the other end binds to the X units of the second strut. Then, as illustrated above, the two struts would be held together by this a-x joiner to form a single longer strut.


But how can we change the position of the ABC strut with respect to the XYZ strut? First, we add a c-y joiner. These new joiners will bridge between the C and Y units of the ABC and XYZ struts. They will at first be strained, but as we add more and more c-y joiners they will start to balance out the a-x joiners. If we now wash the a-x joiners out of solution (the simplest arrangement would be to anchor the octahedron in place by a tether, and flow a solution with an appropriate concentration of joiners past them), then the c-y joiners will dominate the linkage between the two struts leading to the results in the final illustration, below. At this point, the ABC and XYZ struts have moved past each other by one monomer.

If we repeat the whole process again, this time washing in a b-z joiner and washing out the c-y joiner, we can again move the two struts over by one monomer. Finally, if we wash in an a-x joiner and wash out the b-z joiner, we are back where we started. By repeating the whole cycle, we can move the ABC strut past the XYZ strut as much as we want. By running the cycle in reverse, we can reverse the motion. In essence, we have a three-phase linear motor. While this is slow (it's limited by the speed at which we can wash the joiners into and out of position) it does provide a flexible means of controlling the length of the strut, and does not seem hopelessly difficult.

The essential point here is not that this particular approach is the right one or even necessarily a good one, but that biotechnology and self assembly can be used to make positional devices. This is just one possible way: there are a great many more.
Building blocksIf we are to use positional assembly, we must have something to assemble. In biotechnology and self assembly, the most common building blocks are monomers that are built into polymers. Each monomer has two linkage groups which let it become part of a chain. The best known polymers are proteins, DNA, and RNA5. Proteins and RNA form complex three dimensional structures because the monomers from which they are made have strong preferences in how they bind to each other. By appropriately arranging the linear sequence of monomeric units, it is possible to indirectly control the three dimensional structure of the resulting polymer.

While the demonstrated capabilities of this approach are remarkable, if we could hold and position building blocks in three dimensions we should be able to assemble complex three dimensional structures much more directly from building blocks. To this end, we require building blocks that have more than two linking groups (as two linking groups would give us polymers, which provide only indirect control over three dimensional structure). Three points define a plain, and so three groups are frequently found in two-dimensional structures. In graphite, for example, each carbon atom is joined to three neighbors. Four points define a three-space, so four linking groups in tetrahedral symmetry are well suited to the formation of three dimensional structures, much as the carbon atoms in diamond are each bonded to four neighbors.

In the near term, building blocks that are relatively large (many atoms) and which can be readily manipulated in solution are more likely to be experimentally accessible. While synthetic methodologies and reactions for arranging carbon atoms in desired patterns have been proposed4,11,12,13, these approaches require very controlled conditions, extremely good absolute positioning capbabilities, and very clean ultra-high vacuum environments. While these conditions should be achievable in the future, at present they present formidable experimental challenges. Molecular building blocks made from many atoms can be designed that are easier to manipulate, easier to link, less susceptible to contaminants, and more easily positioned. We need to start with large, easy to use building blocks.

If we are to build large, stiff structures then the building blocks themselves should be stiff. Drexler has proposed the use of artificially designed proteins in which simultaneous use of many stabilization techniques produces a protein that is much more stable than naturally occuring proteins14. The recent explosion of interest in fullerenes has produced not only functionalized C60, which is both large and stiff, but also long fullerene tubes which can be functionalized at the ends. Adamantane, essentially a small fragment of diamond, is a tetrahedrally symmetric molecule with a 10-carbon framework which is very stiff. Over 20,000 substituted or functionalized variants of adamantane are known, and even more are possible.

The linking groups between building blocks should also be strong and stiff. Krummenacker15 proposed the use of dienes and dieneophiles as linking groups which would combine in a Diels-Alder cycloaddition. Because the diene and dienophile are selectively reactive, molecular building blocks with these groups would be relatively immune to contaminants and the reaction could take place in any of a wide range of solvents.

The requirements for building blocks designed for positional assembly are not the same as the requirements for building blocks that self assemble. For example, positionally assembled building blocks must not only link with each other, they must also bind and release from the positional device. Drexler proposed the use of antibody-derived proteins bound to an SPM tip to provide a flexible method of binding to and positioning a wide range of building blocks4.
A second difference is that the linkage groups between positionally assembled building blocks can be much stronger. In self assembly, the use of many weak bonds (such as hydrogen bonds) provides a high degree of specificity in the inter-building-block reactions5. More reactive moieties (radicals, for example) would tend to combine promiscously, and so cause the self assembled building blocks to "clump" in random patterns rather than forming the desired structures. By contrast, positionally controlled building blocks can be more reactive, provided that encounters between building blocks are controlled. Rather than stirring positionally controlled building blocks together in solution, they could be introduced while bound to a surface. The positional device would pick them up from the surface and then move them to a work area where they would be joined to other building blocks which had already been formed into a partial structure. At no point would the positionally assembled building blocks be allowed to encounter each other in uncontrolled or random orientations, thus eliminating undesired side reactions.