Hari Muraleedharan

ISSN 0976-2272 J. B io s c i. Re s . , 2010. Vol. 1(2):108-117

Nanobiotechnology: BioInspired Devices and Materials of the future (A Review)

HARI MURALEEDHARAN Shri AMM Murugappa Chettiar Research Centre,Taramani,Chennai-113 Abstract Research and theoretical science, as we notice it today, has highly developed to a place in which, as an alternative of manipulating substances at the molecular level, we can manage them at the atomic level. This stirring operational space, where the laws of physics shift from Newtonian to quantum, provides us with novel discoveries, which hold the promise of future developments that, until in recent times, belonged to the territory of science fiction. Nanobiotechnology is a multidisciplinary field that covers an immeasurable and diverse array of technologies from engineering, physics, chemistry, and biology. It is expected to have a dramatic infrastructural impact on both nanotechnology and biotechnology. Its applications could potentially be quite diverse, from building faster computers to finding cancerous tumors that are still invisible to the human eye. As nanotechnology moves forward, the development of a nano-toolbox appears to be an inevitable outcome. This toolbox will provide new technologies and instruments that will facilitate molecular manipulation and fabrication via both top-down and bottomup approaches. Key words: Nanobiotechnology, nanomedicine, DNA, devices For correspondence: harimnair2001@gmail.com Introduction The term nano is derived from the Greek word nanos meaning dwarf, need and today it is used as a prefix describing 109 (one billionth) of a measuring unit. Therefore, nanotechnology is the field of research and fabrication that is on a scale of 1 to 100 nm. The nanometer has long been defined: it is one billionth of a meter or one thousandth of a micron, of the same order as the distance between two atoms in a solid (several tenths of a nanometer). What is new is the ability to manipulate matter on

scales ever closer to the nanometer. This new knows how, this new technology, was naturally given the name of nanotechnology. The fabrication of such small objects opened the way to a new field of scientific investigation. Using novel observational methods developed more or less simultaneously, abstract notions such as the wave function of the electron, the image of a single atom, or the presence of just one electron have become commonplace features of everyday experience. This newfound familiarity has indeed stimulated 108

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a rush of interest in those sciences that have benefited from it. The prime concept model was presented on December 29, 1959, when Richard Feynman presented a lecture entitled Theres Plenty of Room at the Bottom at the annual meeting of the American Physical Society, the California Institute of Technology. Back then, manipulating single atoms or molecules was not possible because they were far too small for available tools. Thus, his speech was completely theoretical and seemingly farfetched. He described how the laws of physics do not limit our ability to manipulate single atoms and molecules. Instead, it was our lack of the appropriate methods for doing so. From Biotechnology to Bionanotechnology Researchers are currently on the edge to broaden biotechnology into bionanotechnology. What is bionanotechnology, and how is it diverse from biotechnology? The two terms presently go halves an overlapped area of topics. Bionanotechnology defined as applications that necessitate human design and construction at the nanoscale level and will label projects as biotechnology when nanoscale understanding and design are not essential. Biotechnology grew from the use of natural enzymes to influence the genetic code, which was then used to revise whole organisms. The atomic informations were not really important, obtainable functionalities were combined to attain the end target. In the present day, we have the aptitude to work at a much better level with a more detailed level of perceptive and power. We have the gear to develop biological machines atom-by-atom according to our own plans. Presently, we must warm up our imagination and endeavor into the mysterious.

Bionanotechnology has many unusual faces, but all share a central conception: the aptitude to intend molecular machinery to atomic specifications. Today, individual bionanomachines are being designed and created to perform specific nanoscale tasks, such as the targeting of a cancer cell or the solution of a simple computational task. Many are toy problems, designed to test our understanding and control of these tiny machines. As bionanotechnology matures, we will redesign the biomolecular machinery of the cell to perform large-scale tasks for human health and technology. Macroscopic structures will be built to atomic precision with existing biomolecular assemblers or by using biological models for assembly. Looking to cells, we can find atomically precise molecule-sized motors, girders, random-access memory, sensors, and a host of other useful mechanisms, all ready to be harnessed by bionanotechnology. And the technology for designing and constructing these machines in bulk scale is well worked out and ready for application today. Nanomedicine will be the ubiquitous winner. Bionanomachines work best in the environment of a living cell and so are tailored for medical applications. Complex molecules that seek out diseased or cancerous cells are already a reality. Sensors for diagnosing diseased states are under development. Replacement therapy, with custom-constructed molecules, is used today to treat diabetes and growth hormone deficiencies, with many other applications on the horizon. Biomaterials are an extra foremost relevance of bionanotechnology. We already use biomaterials widely. Glance through the room and notice how coppice is used to build your home and furnishing and how much cotton, wool, and other natural fibers

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Hari Muraleedharan are used in your clothing and books. Biomaterials address our growing ecological sensitivity-biomaterials are strong but biodegradable. Biomaterials also integrate perfectly with living tissue, so they are ideal for medical applications. The production of hybrid machines, part biological and part inorganic, is another active area of research in bionanotechnology that promises to yield great fruits. Bionanomachines, such as light sensors or antibodies, are readily combined with silicon devices created by microlithography. These hybrids provide a link between the nanoscale world of bionanomachines and the macroscale world of computers, allowing direct sensing and control of nanoscale events. Finally, Drexler and others have seen biological molecules as an avenue to reach their own goal of mechanosynthesis using nanorobots. Certainly, biology provides the tools for building objects one atom at a time. Perhaps as our understanding grows, bionanomachines will be coaxed into building objects that are completely foreign to the biological blueprint. Major areas of Nanobiotechnology One of the strategic objectives of nanotechnology is the development of new materials having nanometer sizes which have entirely new physical properties with respect to bulk systems and, therefore, new functionalities. The main scientific question which can be asked regarding nano concept is: what new properties or behavior we can expect from nanomaterials which they do not have in a larger size scale. There are many examples of nanomaterials which indeed demonstrate unusual and frequently unexpected properties: metal nanoparticles, carbon nanostructures, semiconductor quantum dots or nanocrystals etc. At first sight, one might wait for the interface between silicon and oxygen to be no more than a simple oxidation process resulting in formation of SiO2. However, we discovered that, at the nanoscale, the interaction becomes much more subtle, interesting and handy. In this review we would like to explain on the property of Si nanostructures to act as facilitators for indirect photoexcitation of adsorbed molecules via; energy transfer from electronic excitations confined in Si nanocrystals (excitons) to the surrounding molecules. The photo excitation mechanism is likely to be universally applicable to a wide range of other inorganic and organic molecules. 1. Nanomedicine- Biomedical Application of Nanotechnology While major advancement has been achieved in recent years, modern medicine is limited by both its knowledge and its treatment tools. It is only in the last 50 yr that medicine has started looking at diseases at the molecular level, and todays drugs are thus fundamentally single-effect molecules. The probable force of nanotechnology on medicine stems directly from the dimension of the devices and materials that can interact directly with cells and tissues at a molecular level. On first sight, nanomedicine is the rather more well-defined application of nanotechnology in the areas of healthcare and disease diagnosis and treatment. But here, too, one encounters a bewildering array of programmes and projects. Artificial bone implants already benefit from nanotechnologically improved materials. Nanostructured surfaces can serve as scaffolding for controlled tissue-growth. Applied nanobiotechnology in medicine is in its infancy. However, the breadth of current nanomedicine research is extraordinary. It includes three major research areas: diagnostics, pharmaceuticals, and prosthesis and implants. Nowadays, nanomedicine is one of the leading and foremost fields of nanobiotechnology. 110

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2. Nanocomputing An assessment of biological systems to computers demonstrated that both process information that is stored in a sequence of symbols taken from an unchanging alphabet, and both operate in a stepwise fashion. In recent years, immense interest has arisen amid researchers on developing new computers inspired from biological systems. Performing calculations employing biomolecules and using genetic engineering technology may soon find use as a tool for computation. The greatest promise of biological computers is that they can operate in biochemical environments. 3. Biological Research at the Nanoscale The introduction of research tools at the nanolevel and nanomanipulation techniques stemming from the material world has initiated a new paradigm of biomolecular research. Living organisms and biomolecules are far more multifaceted than engineered materials. In the last few decades, research has focused on the connection between structure, mechanical response, and biological function at the macro- and microlevels. Nanoresearch tools are capable of analyzing and visualizing properties of single molecules, thereby providing the opportunity to examine bioprocesses of single cells and molecular motors. 4. Nanoelectronics and DNA-Based Nanotechnology DNA-based nanotechnology is essential to all of the nanotechnological approaches mentioned thus far. An escalating number of scientists within nanoscience are using nucleic acids as building blocks in the bottom-up fabrication approach in order to produce novel structures and devices. The basic drive of this application is the well established DNA double helical structure by Watson-Crick

Hari Muraleedharan hybridization of complementary nucleicacid strands. This force has been shown to be efficient in the construction of nanodevices, nanomachines, DNA-based nanoassemblies, DNAprotein conjugated structures, and DNA-based computation 5. Biomimetics, Biotemplating, and De NovoDesigned Structures One of the central goals of nanobiotechnology is the design and creation of novel materials on the nanoscale. Biomolecules, through their unique and specific interaction with other biomolecules and inorganic molecules, natively control complexed structures at the tissue and organ levels. With recent progress in nanoscale engineering and manipulation, along with developments in molecular biology and biomolecular structures, biomimetics and de novo designed structures are entering the molecular level. The promise in biomimetics and biotemplating lies in the potential use of inorganic surfacespecific proteins for controlled material assembly in vivo or in vitro. 6. Bionanoarrays Patterned arrays of biomolecules, such as DNA, proteins, viruses, and cells, have been utilized as powerful tools in a variety of biological studies. Microarrays, in particular, have led to significant advances in many areas of medical and biological research, opening up avenues for the combinatorial screening and identification of single-nucleotide polymorphisms (SNPs), high-sensitivity expression profiling of proteins, and high-throughput analysis of protein function. With the advent of powerful new nanolithographic methods, such as dip-pen nanolithography (DPN), there is now the possibility of reducing the feature size in such arrays to their physical limit, the size of the structures from which they are made of, and the size of the structures they are intended to interrogate

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Hari Muraleedharan Such massive miniaturization not only allows one to increase the density of combinatorial libraries, to increase the sensitivity of such structures in the context of a biodiagnostic event, and to reduce the required sample analyte volume, but also to carry out studies that are not possible with the more conventional microarray format. Arrays with features on the nanometerlength scale open up the opportunity to study many biological structures at the single particle level. Such features can be used to immobilize and orient individual virus particles and to study many important processes such as cell infectivity and virus proliferation and transmission. These miniaturized features allow one to contemplate the creation of the equivalent of an entire combinatorial library (e.g., a gene chip or complex protein array) underneath a single cell, thus opening new possibilities for the study of important fundamental, multivalent, processes such as cell-surface recognition, adhesion, differentiation, growth, proliferation, and apoptosis. 7. Nanomotors : Biological Nanomotors. The increase in cell size that characterizes eukaryotic cells was accompanied by the elaboration of molecular machineries that stabilize cell shape, power cell movement, secure segregation of the genetic material, and deliver goods to specific destinations within the cell. These tasks are accomplished by a special class of machines termed molecular motors, which use polymers of two classes of cytoskeletal fiber as tracks on which to move: (i) microfilaments composed of actin subunits; and (ii) microtubules made from tubulin dimers. Whereas relatives of these cytoskeletal polymers already form part of the prokaryotic make-up, motors apparently are novel inventions of the eukaryotic
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cell. Three classes of these linear molecular motors are known to date myosins, which use actin filaments as tracks; and kinesins and dyneins, which move on microtubules. For almost a century, myosin from skeletal muscle was the only protein known to be involved in force generation and movement, but it was joined in 1965 by dynein, an ATPase present in flagella and cilia . Many biologists at the time probably were quite happy with the view of one motor (myosin) being responsible for cytoplasmic movements, and a second (dynein) for ciliary and flagellar beating. However, many cellular movements could not clearly be associated with either myosin or dynein, and this eventually led to the discovery of a new type of cytoplasmic motor, kinesin, in 1985 . With respect to different motor categories, this seemed to be the end of the line, but subsequently further complexity arose within each group. A combination of biochemical, molecular genetic and genomic approaches revealed that each of the three motor classes comprises superfamilies of motors of strikingly varied make-up and function. Today, we can distinguish at least 24 different classes of myosins , 14 different families of kinesins , and two groups of dyneins (axonemal and cytoplasmic). Current Status and Future Trends Nanobiotechnology is still in the premature stages of growth; nevertheless, its development is multidirectional and fastpaced. Nanobiotechnology research centers are being established and supported at an elevated occurrence, and the numbers of papers and patent applications is also rising rapidly. In addition, the nanobiotechnology tool box is being speedily packed with new and practical tools for bionanomanipulations that will accelerate novel applications. As a final point, an analysis of the total investment in nanobiotechnology

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Hari Muraleedharan start-ups exposed that nearly 50% of the venture capital investments in nanotechnology is addressed to nanobiotechnology. One of the strongest driving forces in this research area is the semiconductor industry. Computer chips are quickly shrinking according to Moores law, i.e., by a factor of four every 3 yr. However, this simple shrinking law cannot continue for much longer, and computer scientists are therefore looking for solutions. One approach is moving to single-molecule transistors. This shift is critically dependent on molecular nanomanipulations to form molecular computation that will write, process, store, and read information within the single molecule where proteins and DNA are some of the alternatives. As medical research and diagnostics steadily progresses based on the use of molecular biomarkers and specific therapies aimed at molecular markers and multiplexed analysis, the necessity for molecular-level devices increases. Technology platforms that are reliable, rapid, low-cost, portable, and that can handle large quantities are evolving and will provide the future foundation for personalized medicine. These new technologies are especially important in cases of early detection, such as in cancer. Future applications of nanobiotechnology will probably include nanosized devices and sensors that will be injected into, or ingested by, our bodies. These instruments could be used as indicators for the transmission of information outside of our bodies or they could actively perform repairs or maintenance. Nanotechnology-based platforms will secure the future realization of multiple goals in biomarker analysis. Examples for such platforms are the use of cantilevers, nanomechanical systems (NEMS), nanoelectronics (biologically gated nanowire), and nanoparticles in diagnostics imaging and therapy. The art of nanomanipulating materials and biosystems is converging with information technology, medicine, and computer sciences to create entirely new science and technology platforms. These technologies will include imaging diagnostics, genome pharmaceutics, biosystems on a chip, regenerative medicine, on-line multiplexed diagnostics, and food systems. It is clear that biology has much to offer the physical world in demonstrating how to recognize, organize, functionalize, and assemble new materials and devices. In fact, almost any device, tool, or active system known today can be either mimicked by biological systems or constructed using techniques originating in the bio-world. Therefore, it is plausible that in the future, biological systems will be used as building blocks for the construction of the material and mechanical fabric of our daily lives. 1. Current status of nanotechnology approaches for cardiovascular disease Nanotechnology is poised to have an increasing impact on cardiovascular health in coming years. Diagnostically, multiplexed point-of-care devices will enable rapid genotyping and biomarker measurement to optimize and tailor therapies for the individual patient. Nanoparticle-based molecular imaging agents will take advantage of targeted agents to provide increased insight into disease pathways rather then simply providing structural and functional information. Drug delivery will be impacted by targeting of nanoparticleencapsulated drugs to the site of action, increasing the effective concentration and decreasing systemic dosage and side effects. Controlled and tailored release of drugs from polymers will improve control of pharmacokinetics and bioavailability. The application of nanotechnology 113

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Hari Muraleedharan to tissue engineering will facilitate the fabrication of better tissue implants in vitro, and provide scaffolds to promote regeneration in vivo taking advantage of the bodys own repair mechanisms. Medical devices will benefit from the development of nanostructured surfaces and coatings to provide better control of thrombogenicity and infection. Taken together, these new technologies have enormous potential for improving the diagnosis and treatment of cardiovascular diseases. 2. Nanoscale imaging of microbial pathogens using atomic force microscopy. The nanoscale exploration of microbes using atomic force microscopy (AFM) is an exciting research field that has expanded rapidly in the past years. Using AFM topographic imaging, investigators can visualize the surface structure of live cells under physiological conditions and with unprecedented resolution. In doing so, the effect of drugs and chemicals on the fine cell surface architecture can be monitored. Real-time imaging offers a means to follow dynamic events such as cell growth and division. In parallel, chemical force microscopy (CFM), in which AFM tips aremodified with specific functional groups, allows researchers to measure interaction forces, such as hydrophobic forces, and to resolve nanoscale chemical heterogeneities on cells, on a scale of only 25 functional groups. Lastly, molecular recognition imaging using spatially resolved force spectroscopy, dynamic recognition imaging or immunogold detection, enables microscopists to localize specific receptors, such as cell adhesion proteins or antibiotic binding sites. These noninvasive nanoscale analyses provide new avenues in pathogenesis research, particularly for investigating the action mode of antimicrobial drugs, and for elucidating the molecular basis of pathogenhost interactions. 3. Commercialization of Nanotechnology The emerging and potential commercial applications of nanotechnologies clearly have great potential to significantly advance and even potentially revolutionize various aspects of medical practice and medical product development. Nanotechnology is already touching uponmany aspects of medicine, including drug delivery, diagnostic imaging, clinical diagnostics, nanomedicines, and the use of nanomaterials in medical devices. This technology is already having an impact; many products are on the market and a growing number is in the pipeline. Momentum is steadily building for the successful development of additional nanotech products to diagnose and treat disease; the most active areas of product development are drug delivery and in vivo imaging. Nanotechnology is also addressing many unmet needs in the pharmaceutical industry, including the reformulation of drugs to improve their bioavailability or toxicity profiles. The advancement of medical nanotechnology is expected to advance over at least three different generations or phases, beginning with the introduction of simple nanoparticulate and nanostructural improvements to current product and process types, then eventually moving on to nanoproducts and nanodevices that are limited only by the imagination and limits of the technology itself. This review looks at some recent developments in the commercialization of nanotechnology for various medical applications as well as general trends in the industry, and explores the nanotechnology industry that is involved in developing medical products and procedures with a view toward technology commercialization.

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Hari Muraleedharan 4. Nanostructured polymer scaffolds for tissue engineering and regenerative medicine. The structural features of tissue engineering scaffolds affect cell response and must be engineered to support cell adhesion, proliferation and differentiation. The scaffold acts as an interim synthetic extracellular matrix (ECM) that cells interact with prior to forming a new tissue. In this review, bone tissue engineering is used as the primary example for the sake of brevity. We focus on nanofibrous scaffolds and the incorporation of other components including other nanofeatures into the scaffold structure. Since the ECM is comprised in large part of collagen fibers, between 50 and 500nmin diameter, welldesigned nanofibrous scaffoldsmimic this structure. Our group has developed a novel thermally induced phase separation (TIPS) process in which a solution of biodegradable polymer is cast into a porous scaffold, resulting in a nanofibrous porewall structure. These nanoscale fibers have a diameter (50500 nm) comparable to those collagen fibers found in the ECM. This process can then be combined with a porogen leaching technique, also developed by our group, to engineer an interconnected pore structure that promotes cell migration and tissue ingrowth in three dimensions. To improve upon efforts to incorporate a ceramic component into polymer scaffolds by mixing, our group has also developed a technique where apatite crystals are grown onto biodegradable polymer scaffolds by soaking them in simulated body fluid (SBF). By changing the polymer used, the concentration of ions in the SBF and by varying the treatment time, the size and distribution of these crystals are varied. Work is currently being done to improve the distribution of these crystals throughout three-dimensional scaffolds and to create nanoscale apatite deposits that better mimic those found in the ECM. In both nanofibrous and composite scaffolds, cell adhesion, proliferation and differentiation improved when compared to control scaffolds. Additionally, composite scaffolds showed a decrease in incidence of apoptosis when compared to polymer control in bone tissue engineering. Nanoparticles have been integrated into the nanostructured scaffolds to deliver biologically active molecules such as growth and differentiation factors to regulate cell behavior for optimal tissue regeneration. Ethical Considerations Bionanotechnology carries with it a grave responsibility. As with any technology, the potential for misuse is enormous. We have seen in the past several decades an explosion of technology at all levelsmachinery, electronics, information, and biology. Many people have reservations about this fast pace. Some are discouraged by the compulsion toward novelty. Many scientists and engineers explore new technologies simply because they are possible, without spending the time to think about the implications and consequences. Also, many new technologies are the domains of experts and large corporations, which may be pursuing developments for personal motives that do not reflect goals that best benefit humanity or the global environment. The governments of many countries are becoming increasingly aware of the reservations of their populace and are enacting regulations to control the more controversial applications, such as human cloning and embryonic stem cell research. But, of course, it is difficult to decide where to draw the line between morally acceptable technology and applications that are morally reprehensible. As we decide where to draw our own personal line, we might think

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Hari Muraleedharan carefully about two topics: the respect for life and possible dangers. The potential dangers of nanotechnology are a favorite topic in current science fiction. In particular, the concept of the rogue disassemble /assembler has been widely discussed, both in fiction and by speculative scientists. We have abundant precedents for how to proceed (and warnings of how not to proceed) from other technologies that pose dangers when used improperly. These include regulations on research in nuclear science and viral research that may be applied to sensitive applications in bionanotechnology. Addressing potential dangers can lead to additional moral complications. Take, for instance, the incorporation of terminator genes into genetically modified seeds that make them sterile and productive only for a single generation. Although this provides a ready solution to the possible spread of the engineered plant, it has been criticized as a method to ensure continued sales, as farmers will require new seed for each years crop. This provides a significant hardship for farmers in developing countries, where seed is typically saved from one season to the next, despite the fact that this is the market often advertised as the major winners for these modified crops. On a more familiar level, one is faced with the question of the need for intervention. Just because we have a technology, we are not obligated to useparticular, provides immediate moral problems. The genetic engineering of children, particularly for cosmetic reasons or to improve native ability, raises severe problems for most people, using the argument that children are not commodities to be picked and sorted through on the department store shelf. However, the ability to remove hereditary diseases, permanently and for all successive generations, has an undeniable appeal. Of course, this dilemma is not, at its heart, anything new. For centuries, agriculture and medicine have modified biology in profound ways. By selective breeding, we have changed livestock, grains, flowers, dogs, cats, and countless other organisms into grossly different shapes to provide more food and to please our senses. To our own bodies, we add substances to change blood pressure, to fight microorganisms, to relieve pain, and thus extend our life span by decades. Perhaps, in a few decades, the advances of nanotechnology will feel as familiar as a hybrid tea rose. References Adar R., Benenson, Y., Linshiz, G., Rosner, A., Tishby, N., Shapiro E. Stochastic computing with biomolecular automata. Proc. Natl. Acad. Sci. USA 2004;101:99609965. Arora, P.S., Kirshenbaum K. Nanotailoring; stitching alterations on viral coats. Chem Biol 2004;11:418420. Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., Walter, P. Molecular Biology of the Cell, 4th ed. New York: Garland Science, 2001. Benenson Y., Adar R., Paz-Elizur T., Livneh Z., Shapiro E. DNA molecule provides a computing machine with both data and fuel. Proc. Natl. Acad. Sci. USA. 100(2003):pp 21912196. Benenson, Y., Gil, B., Ben-Dor, U., Adar, R., Shapiro, E. An autonomous molecular computer for logical control of gene expression. Nature,429 (2004);pp423 429. Brenning, H. T., Kubatkin, S. E., Erts, D., Kafanov, S. G., Bauch, T, Delsing P. A single electron transistor on an atomic

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Hari Muraleedharan force microscope probe. Nano. Lett. 6(2006) pp 937941. Cheng, M .M, Cuda, G., Bunimovich, Y. L,. Nanotechnologies for biomolecular detection and medical diagnostics. Curr Opin Chem Biol 10.(2006):1119. Cox J. C., Ellington A.D. DNA computation function. Curr. Biol.11( 2001)11:R336. Cox J. P., Long-term data storage in DNA. Trends Biotechnol. 2001; 19:247250. DAmico, S., Maruccio, G., Visconti, P., DAmone, E., Bramanti, A., Cingolani, R., Rinaldi, R. Ambipolar transistors based on azurin proteins. IEE Proc Nanobiotechnol 151(2004):pp 173175. Fortina, P., Kricka, L., J., Surrey, S., Grodzinski, P. Nanobiotechnology: the promise and reality of new approaches to molecular recognition. Trends. Biotechnol., 2005;23:168173 Freitas, R A, Jr. Nanomedicine, vol. I: Basic . Capabilities. Georgetown, TX: Landes Bioscience., 1999. . Freitas, R .A, Jr. Nanomedicine, vol. Iia: Biocompatibility. Georgetown, TX: Landes. Bioscience, 2003. Kricka, L. J, Park, J. Y., Li, S. F., Fortina, P. Miniaturized detection technology in molecular diagnostics. Expert. Rev. Mol. Diagn .5 (2005)pp549559. Parker, J. Computing with DNA. EMBO Rep 4(2003):pp 710. Unger R., Moult J. Towards computing with proteins. Proteins 63(2006)pp:5364. Soreni, M., Yogev, S., Kossoy, E., Shoham, Y., Keinan, E. Parallel biomolecular computation on surfaces with advanced finite automata. J. Am. Chem. Soc. 127 (2005) pp 39353943. Roco, M. C. Nanotechnology: convergence with modern biology and medicine. Curr. Opin. Biotechnol. 2003; 14 pp 337346.

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