Introduction

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Introduction

  1. 1. BIO CHIP INTRODUCTION Bio(synthetic) Engineering is a fundamental approach to engineering based on an important lesson from biology: that the processes used to assemble or synthesize a complex system can make the resulting system more robust, evolvable, adaptive, and richly functional. Therefore, Bio(synthetic) Engineering aims to develop synthesis processes analogous to those occurring in biological growth, neural and cognitive development, and molecular scale self-assembly in living systems. Such developmental processes are also subject to evolutionary optimization. Importantly, however, these synthesis processes are not restricted to biological materials (such as proteins) or to mimicry of biological solutions to engineering problems (biomimetics): Transistors are much faster than nerve synapses, and jet engines are much more powerful than muscles. But the system design principles behind brains and muscles are much more advanced than anything in current engineering practice. Examples of biosynthesis in nature include the construction of wood, teeth, bones, hard shells, spider webs, and many other materials, minerals and mechanical structures. The same is true, on a grander scale, for the construction of nervous systems, brains, and cognition. Morphogenesis--the generation of multicellular form by signaling between cells that can grow, divide, and specialize--couples with molecular assembly at the cellular and subcellular scale to perform fabrication of organic, mineral, and computational structures in an efficient, adaptive and optimizable way from elementary building units. Upon injury, aspects of the developmental self-fabrication process can be restarted to effect repair, resulting in a robust and fault-tolerant system. Evolution takes 1
  2. 2. particular advantage of the developmental process to make large-scale, systematic improvements to a complex system by optimizing its growth rules, in addition to its individual components. With Bio(synthetic) Engineering, we seek to apply these system design principles to the best available technologies at every level of system organization from devices through distributed intelligence. This novel approach is expected to first become cost-effective for the extremely challenges that arise in space exploration. Table 1 contrasts conventional engineering, biomimetic, and our preferred biosynthetic approaches to engineering autonomous systems at different levels of design from molecular-scale devices to intelligent and distributed systems. airplane example Fixed-wing airplanes Flapping-wing airplanes Biofabricated, sensor-covered wings for airplanes Device level Si chip devices Si/Biomolecular doping experiments (Bell Labs) Modified PS1 proteins; self-assembled PS1 structures Fluid actuators Hydraulics Fractal hydraulics nanofluidics Fluid pumps Turbo pumps LVADS artificial heart Functional prestressed tubule for Computational level Chip design Artificial neural nets Evo-devo-neuro nets Artificial Brains Control software with human in the loop Standard structured networks with hidden layers and Hebbian learning Evolved networks grown with a developmental process . Cognitive systems Expert systems, Artificial intelligence Cognitive science, mind design Evolvable statistical inference systems Distributed systems Static, centrally controlled systems Flocking robots, without shared understanding of mission goals Simple bio- swarm agents and structures: dynamic, self-organizing, autonomic communication control and navigation Space applications of biosynthetic engineering will be systemic. They will include reduction of launch mass and power requirements for ambitious planetary exploration and space observatory projects. Increased autonomy, smarter spacecraft, and lighter and smarter mechanical, power, and instrument systems will also result. For human spaceflight, intelligent subsystems that support, understand, and cooperate with living systems from plants to astronauts will vastly amplify the capabilities of each human being in space. For robotic mission elements, eventually, launch mass will be nearly 2
  3. 3. eliminated by enabling self-fabrication to proceed in situ on other solid bodies in the solar system. HISTORY The development of biochips has a long history, starting with early work on the underlying sensor technology. One of the first portable, chemistry-based sensors was the glass pH electrode, invented in 1922 by Hughes . Measurement of pH was accomplished by detecting the potential difference developed across a thin glass membrane selective to the permeation of hydrogen ions; this selectivity was achieved by exchanges between H+ and SiO sites in the glass. The basic concept of using exchange sites to create permselective membranes was used to develop other ion sensors in subsequent years. For example, a K+ sensor was produced by incorporating valinomycin into a thin membrane Schultz, 1996. Over thirty years elapsed before the first true biosensor i.e. a sensor utilizing biological molecules emerged. In 1956, Leland Clark published a paper on an oxygen sensing electrode . This device became the basis for a glucose sensor developed in 1962 by Clark and colleague Lyons which utilized glucose oxidase molecules embedded in a dialysis membrane Clark, 1962. The enzyme functioned in the presence of glucose to decrease the amount of oxygen available to the oxygen electrode, thereby relating oxygen levels to glucose concentration. This and similar biosensors became known as enzyme electrodes, and are still in use today. In 1953, Watson and Crick announced their discovery of the now familiar double helix structure of DNA molecules and set the stage for genetics research that continues to the present day Nelson, 2000. The development of sequencing techniques in 1977 by Gilbert Maxam, 1977 and Sanger Sanger, 1977 working separately enabled researchers to directly read the genetic codes that provide instructions for protein synthesis. This research showed how hybridization of complementary single oligonucleotide strands could be used as a basis for DNA sensing. Two additional developments enabled the technology used in modern DNA-based biosensors. First, in1983 Kary Mullis invented the polymerase chain reaction PCR technique Nelson, 2000, a method for amplifying DNA concentrations. This discovery made possible the detection of extremely small quantities of DNA in samples. Second, in 1986 Hood and coworkers devised a method to 3
  4. 4. label DNA molecules with fluorescent tags instead of radiolabels Smith, 1986, thus enabling hybridization experiments to be observed optically. The rapid technological advances of the biochemistry and semiconductor fields in the 1980's led to the large scale development of biochips in the 1990's. At this time, it became clear that biochips were largely a "platform" technology which consisted of several separate, yet integrated components. Figure shows the makeup of a typical biochip platform. The actual sensing component (or "chip") is just one piece of a complete analysis system. Transduction must be done to translate the actual sensing event (DNA binding, oxidation/reduction, etc.) into a format understandable by a computer (voltage, light intensity, mass, etc.), which then enables additional analysis and processing to produce a final, human-readable output. The multiple technologies needed to make a successful biochip -- from sensing chemistry, to microarraying, to signal processing -- require a true multidisciplinary approach, making the barrier to entry steep. One of the first commercial biochips was introduced by Affymetrix. Their "GeneChip" products contain thousands of individual DNA sensors for use in sensing defects, or single nucleotide polymorphisms (SNPs), in genes such as p53 (a tumor suppressor) and BRCA1 and BRCA2 (related to breast cancer) (Cheng, 2001). The chips are produced using microlithography techniques traditionally used to fabricate integrated circuits Biochips are a platform that require, in addition to microarray technology, transduction and signal processing technologies to output the results of sensing experiments. Today, a large variety of biochip technologies are either in development or being commercialized. Numerous advancements continue to be made in sensing research that enable new platforms to be developed for new applications. Cancer diagnosis through DNA typing is just one market opportunity. A variety of industries currently desire the ability to simultaneously screen for a wide range of chemical and biological agents, with purposes ranging from testing public water systems for disease agents to 4
  5. 5. screening airline cargo for explosives. Pharmaceutical companies wish to combinatorially screen drug candidates against target enzymes. To achieve these ends, DNA, RNA, proteins, and even living cells are being employed as sensing mediators on biochips. Numerous transduction methods can be employed including surface plasmon resonance, fluorescence, and chemiluminescence. The particular sensing and transduction techniques chosen depend on factors such as price, sensitivity, and reusability. MICROARRAY FABRICATION The micro array -- the dense, two-dimensional grid of biosensors -- is the critical component of a biochip platform. Typically, the sensors are deposited on a flat substrate, which may either be passive (''e.g.'' silicon or glass) or active, the latter consisting of integrated electronics or micro technology |micromechanical devices that performer assist signal transduction. Surface chemistry is used to covalent bond covalently bind]the sensor molecules to the substrate medium. The fabrication of micro arraysis non-trivial and is a major economic and technological hurdle that may ultimately decide the success of future biochip platforms. The primary manufacturing challenge is the process of placing each sensor at a specific position (typically on a Cartesian grid) on the substrate. Various mean sexist to achieve the placement, but typically roboticmicro- pipetting (Schema, 1995) or micro -printing (MacBeath, 1999) systems are used to place tinyspots of sensor material on the chip surface. Because each sensor is unique,only a few spots can be placed at a time. The low-throughput nature of this process results in high manufacturing costs. Fodor and colleagues developed a unique fabrication process later used byAffymetrix in which a series of microlithography steps is used toCombinatorial 5
  6. 6. chemistry|combinatorially synthesize hundreds of thousands of unique, single- strandedDNA sensors on a substrate one nucleotide at atime (Fodor, 1991; Pease, 1994). One lithography step is needed per base type; thus, a totalof four steps is required per nucleotide level. Although this technique isvery powerful in that many sensors can be created simultaneously, it iscurrently only feasible for creating short DNA strands (15-25 nucleotides).Reliability and cost factors limit the number of photolithography steps thatcan be done. Furthermore, light-directed combinatorial synthesis techniquesare not currently possible for proteins or other sensing molecules. As noted above, most microarrays consist of a Cartesian grid of sensors. Thisapproach is used chiefly to map or "encode" the coordinate of each sensorto its function. Sensors in these arrays typically use a universal signalingtechnique (''e.g.'' fluorescence), thus making coordinates their onlyidentifying feature. These arrays must be made using a serial process(''i.e.'' requiring multiple, sequential steps) to ensure that each sensoris placed at the correct position. Random" fabrication, in which the sensors are placed at arbitrarypositions on the chip, is an alternative to the serial method. The tedious and expensive positioning process isnot required, enabling the use of parallelized self-assembly techniques. Inthis approach, large batches of identical sensors can be produced; 1998) Each bead was uniquelyencoded with a fluorescent signature. However, this encoding scheme is limited in the number of unique dye combinations that be can be used andsuccessfully differentiated." sensors from each batch are then combined and assembled into an array. Anon-coordinate based encoding scheme must be used to identify each sensor. Asthe figure shows, such a design was first demonstrated (and later commercialized by Illumina) using functionalized beads placed randomly in thewells of an etched fiber opticcable Protein Biochip Array and Other Micro array Technologies Microarrays are not limited to DNA analysis; protein microarrays, antibody microarray, Chemical Compound Microarray can also be produced using biochips. 6
  7. 7. Randox Laboratories Ltd. launched Evidence®, the first protein Biochip Array Technology analyzer in 2003. In protein Biochip Array Technology, the biochip replaces the ELISA plate or cuvette as the reaction platform. The biochip is used to simultaneously analyze a panel of related tests in a single sample, producing a patient profile. The patient profile can be used in disease screening, diagnosis, monitoring disease progression or monitoring treatment. Performing multiple analyses simultaneously, described as multiplexing, allows a significant reduction in processing time and the amount of patient sample required. Biochip Array Technology is a novel application of a familiar methodology, using sandwich, competitive and antibody-capture immunoassays. The difference from conventional immunoassays is that the capture ligands are covalently attached to the surface of the biochip in an ordered array rather than in solution. In sandwich assays an enzyme-labelled antibody is used; in competitive assays an enzyme-labelled antigen is used. On antibody-antigen binding a chemiluminescence reaction produces light. Detection is by a charge-coupled device (CCD) camera. The CCD camera is a sensitive and high-resolution sensor able to accurately detect and quantify very low levels of light. The test regions are located using a grid pattern then the chemiluminescence signals are analysed by imaging software to rapidly and simultaneously quantify the individual analytes BIOETHICS When the question of ethics come up there is never a clear cut answer, nor should there be. Since no one has actually implemented many types of future biotechnology, interpreting moral issue at this point is very difficult. However, this debate is relevant today and it is critical to begin debate now. Arthur Caplan of University of Pennsylvania School of Medicine explains that “Crossing into this area will be so startling, so momentous, and so socially unnerving that the prospect of doing so demands proactive ethical, theological, and scientific discussion.” 7
  8. 8. Bioethics is the collaborative investigation of biology, scientific technology, and ethical issues. Van Potter’s definition in 1971 states that bioethics is “biology combined with diverse humanistic knowledge forging a science that sets a system on medical and environmental priorities for acceptable survival.” Genetic research has many life altering benefits. Genetic research can be used to prevent genetic defects, eliminate disease and replace vital organs. This will save many lives. However, we must realize the potential impact on life itself. Scientists are advised to come up with plans and submit these plans to associated groups with both scientific and ethical expertise for review, before entering into development of new biotechnology. Reviews should be conducted nationally and or internationally. As well, the development should be contained in strict biological confinement until the implications are understood. Ethics is concerned with what is morally good and bad or right and wrong. Obviously,with regards to bioethics there is a thin line between what is ethical and what is not. Scientists have an ethical obligation as do individuals to do what is right. There is no question whether or not biotechnology is a powerful new tool for modifying living organisms to benefit humankind. However, because biotechnology is so new to us we have yet to understand the risks involved with altering organisms.. BIO CHIP The development of biochips is a major thrust of the rapidly growing biotechnology industry, which encompasses a very diverse range of research efforts including genomics, proteomics, computational biology, and pharmaceuticals, among other activities. Advances in these areas are giving scientists new methods for unraveling the complex biochemical processes occurring inside cells, with the larger goal of understanding and treating human diseases. At the same time, the semiconductor industry has been steadily perfecting the science of microminiaturization. The merging of these two fields in recent years has enabled biotechnologists to begin packing their traditionally bulky sensing tools into smaller and smaller spaces, onto so-called biochips. These chips are essentially miniaturized laboratories that can perform hundreds or thousands of simultaneous biochemical reactions. Biochips enable researchers to quickly screen large 8
  9. 9. numbers of biological analytes for a variety of purposes, from disease diagnosis to detection of BIOTERRORISM agents. bio - combining form ( Environment ) (Health and Fitness) (Science and Technology) Part of the words biology and biological, widely used as the first element of compounds relating to biology or biotechnology; frequently used as a shortened form of biological(ly). Etymology: Formed by abbreviating biology and biological; in both words this part is ultimately derived from Greek bios 'life'. History and Usage: Compounds relating to 'life' have been formed on bio- in English for over three centuries, and even the ancient Greeks used it as a combining form. During the second half of the twentieth century, however, advances in biotechnology and the increasing interest in green issues caused a proliferation in popular language of compounds in these areas, alongside the continuing use of bio- in scientific terminology . Like eco-, bio- was particularly productive in the late sixties and early seventies, and many of the compounds which had been well known then came back into fashion during the eighties, often undergoing further development. The development of plastics and other synthetic products which were biodegradable, that is, those that would decompose spontaneously and hence not become an environmental hazard , led during the eighties to the verb biodegrade. Biomass, originally a biologists' term for the total amount of organic material in a given region, was later also used of fuel derived from such matter (also called biofuel, or, in the case of the mixture of methane and other gases produced by fermenting biological waste, biogas; this was burnt to produce what became known as bioenergy). By contrast, biofeedback, the conscious control of one's body by 'willing' readings on instruments (such as heart-rate monitors) to change , reappeared in the eighties as one of the techniques used in autogenic training. Computer scientists continued to speculate that micro-organisms could be developed that would function like the simple logic circuits of conventional microelectronics, thus paving the way for biocomputing with biochips. 9
  10. 10. Biological warfare, a more disturbing application of biotechnology, became sufficiently familiar to be abbreviated as biowar. Concern about the effect of even peaceful technology on the biosphere (the component of the environment consisting of living things) was expressed in the philosophy of biocentrism, in which all life, rather than just humanity, is viewed as important ( much as in Gaia theory). Direct and sometimes violent Chip and inductor inside of glass container, less than 1/4 of inch long opposition to such aspects of biological research as animal experimentation and genetic engineering was organized by biofundamentalists. As a result of the Green Revolution, the public was made more aware of the threat posed by intensive cultivation of particular species to biodiversity, the richness of variety of the biosphere. Towards the end of the decade bio- began to be used indiscriminately wherever it had the slightest relevance, either frivolously or because of its advertising potential (just as biological had once been a glamorous epithet for washing powder). The prefix is sometimes even used as a free-standing adjective in this sense, meaning little more than 'biologically acceptable'. Examples include biobeer, biobottom (an 'eco-friendly nappy cover'), bio house, bio home, bioloo, bioprotein, and bio yoghurt. The term bio-chip, coined only about four years ago, already means different things to different people. BIOCHIP DEFINITION A biochip is a collection of miniaturized test sites (microarrays) arranged on a solid substrate that permits many tests to be performed at the same time in order to achieve higher throughput and speed. Typically, a biochip's surface area is no larger than a fingernail. Like a computer chip that can perform millions of mathematical operations 10
  11. 11. in one second, a biochip can perform thousands of biological reactions, such as decoding genes, in a few seconds. A genetic biochip is designed to "freeze" into place the structures of many short strands of DNA (deoxyribonucleic acid), the basic chemical instruction that determines the characteristics of an organism. Effectively, it is used as a kind of "test tube" for real chemical samples. A specially designed microscope can determine where the sample hybridized with DNA strands in the biochip. Biochips helped to dramatically accelerate the identification of the estimated 80,000 genes in human DNA, an ongoing world-wide research collaboration known as the Human Genome Project. The microchip is described as a sort of "word search" function that can quickly sequence DNA. Human chip In addition to genetic applications, the biochip is being used in toxicological, protein, and biochemical research. Biochips can also be used to rapidly detect chemical agents used in biological warfare so that defensive measures can be taken BIOCHIP IMPLANTS "We're from the government and we are here to help you." The dangers of incrementalism and sub-dermal biochip implants is becoming increasingly clear. It is also increasingly clear that privacy has become an anachronism. The privacy the founding fathers so cherished is about to become a footnote in history. Many are aware of the unbridled abuse of the alleged single-purpose Social Security number. The persistent push for a national identification card (complete with biometric elements) is barely a step away from sub-dermal biochip implants. 11
  12. 12. All the assaults on our privacy have a "reasonable" rationalization. Now we have a classic example of the "reasonable" rationalization of incrementalism. Foreign executives and other individuals who are frequent kidnapping targets in Latin America will soon be able to use implantable ID chips and personal GPS devices in an attempt to thwart their abductors. Gosh-oh-gee-golly! Thanks! Applied Digital Solutions announced recently it had reached an agreement with a distributor to sell its VeriChip and Digital Angel products in three South American countries. Of course, for security reasons, the company refuses to discuss any particulars including the names of the countries or the distributor. This isn't black helicopter stuff folks, and it's not far off in the future evil disguised as benign assistance is knocking on the door NOW. Digital Angel is set to fly soon. Implant technology (as in sub-dermal biochip implants) is about to be beta tested on humans. Applied Digital Solutions will begin beta testing on humans an implant technology capable of allowing users to emit a homing beacon, have vital bodily functions monitored and confirm identity when making e-commerce transactions. So notwithstanding the protestations of privacy advocates or religious critics who warn of the Bible's book of Revelation and the mark of the beast, the first production run of Digital Angel devices has begun. Applied Digital Solutions snatched up the patent rights to the miniature digital transceiver it has named Digital Angel. Now they are ready to kick off a sea-change marketing blitzkrieg. The company plans to market the device for a number of uses, including as a tamper-proof means of identification for enhanced e- business security. If you've just returned from the Amazon or depend on the mainstream media to inform you, you may not be up to speed yet. Or, if you are a liberal socialist democrat you might be in denial. Here's the deal. Digital Angel sends and receives data and can be continuously tracked by global positioning satellite technology. When implanted within a body, the 12
  13. 13. device is powered electromechanically through the movement of muscles and can be activated either by the wearer or by a monitoring facility. According to ADS Chairman and Chief Executive Officer Richard Sullivan, "We believe its potential for improving individual and e-business security and enhancing the quality of life for millions of people is virtually limitless Although we're in the early developmental phase, we expect to come forward with applications in many different areas, from medical monitoring to law enforcement. However, in keeping with our core strengths in the e-business-to-business arena, we plan to focus our initial development efforts on the growing field of e-commerce security and user ID verification." This is better than any national ID card. This whiz-bang little device will send a signal from the person wearing Digital Angel to either a computer or the e-merchant with whom he is doing business in order to verify his identity. But e-commerce is only the tip of the invasion-of-privacy iceberg. According to the patent on this hoped-to-be ubiquitous sliver of silicon, it is described as a rescue beacon for kidnapped children and missing persons. The implant will save money by reducing resources used in rescue operations for athletes, including mountain climbers and skiers. Already they are spinning and manufacturing reality: Law enforcement can use the implant to keep track of criminals under house arrest. It will reduce emergency response time by immediately locating individuals in distress. The device also has the capacity to monitor the user's heart rate, blood pressure and other vital functions. Beyond just mere medical readouts, could it also analyze variances and become an ipso facto lie detector? Peace of mind is a big selling point for this so-called "advancement." They tell us, "Your doctor will know the problem before you do," provided someone is monitoring your 13
  14. 14. medical data when you get sick. We've been cautioned that our would-be controllers would incrementally introduce this ID/tracking/monitor/locator: First, It's been suggested, they would implant those who could not refuse (prisoners, and the military). Then, they would build a case for potential or feared kidnap victims. At first, it would be voluntary. Then, it would be required for "certain services." Eventually, it would be mandatory, and probably implanted at birth. Referring to the threat of kidnapping, the patent itself says, "Adults who are at risk due to their economic or political status, as well as their children who may be at risk of being kidnapped, will reap new freedoms in their everyday lives by employing the device." According to Digital Angel executives, one inquirer/prospect is the U.S. Department of Defense, not directly but through a contractor. American soldiers may be required to wear the implant so their whereabouts and health conditions can be accessed at all times. HEALTH CHIPS This chip is used for the health purpose to identify the disease DOCTORS are to implant computerised sensors into patients to enable them to monitor chronic conditions minute- by-minute from miles away. The sensors detect tiny changes in metabolism and transmit data, via a mobile phone, to the patient’s doctor. Scientists at Imperial College London who invented the device believe it will enable some patients to lead a normal life while being kept under constant watch. It has the potential to be developed into a complete body sensor that could be implanted into normally healthy people to pick up early signs of disease. The sensor, which includes a Pentium microprocessor just 2mm square, will initially be implanted in diabetics. Trials will begin by Christmas at St Mary’s hospital, London. The implant will be programmed to send an emergency text message via a mobile phone, alerting medical staff to changes in blood-sugar levels. 14
  15. 15. If the problem is serious, the patient will be given immediate medical advice. Once patients become familiar with the system, they could monitor their condition themselves The only restriction is that the computer’s low power output means that it needs a receiver — generally a mobile phone — to be within a metre of the patient to pick up the sensor’s wireless signal from its miniaturised antenna. Chris Toumazou, director of the Institute of Biomedical Engineering at Imperial, is hoping eventually to link the sensor to an insulin pump that can be operated remotely by a doctor. The sensor could also be used to protect people with heart and respiratory diseases. The researchers are exploring ways to detect chemical changes in a patient’s blood. “The computer in your body can take away anxiety and allow medics to take control of your care from miles away,” said Toumazou. More than 17.5m people in Britain have one or more chronic diseases of varying severity figure that is set to soar as the elderly population grows over the coming decades. If many of these patients could be turned into experts monitoring their own conditions with minimal intervention by doctors or nurses, it could free up significant NHS resources. 15
  16. 16. The aim is also to develop the system so that the sensor can provide prompts to patients to take medication.Pathology departments are under particular pressure because of the increase in the number of chronically ill patients who need regular blood tests. Oracle, the technology company that is backing the project, has designed the software to be compatible with the NHS’s new £6.5 billion computer system. This will allow the data to be stored on a patient’s record and accessed by healthcare staff nationwide. DRUG DISCOVERY biochips and systems that are being used for accelerating the research processes and capabilities of bio-pharmaceutical drug discovery. This study has found that the total biochip market size in 2001 is about $740 million and may more than triple in revenues, to about $2.47 billion in 2006. The 5-year CAGR is 27.3%. This market includes biochip systems, Lab-on-a chip devices, microarrays, protein chips and other related technologies. In particular, biochip technologies will continue to help pharma companies. Facing near term product pipeline challenges, Pharma companies have seen their R&D costs explode as their delivery of new drug products have declined. Many of their current high priced $billion -plus blockbuster drugs will reach their patent expirey dates by 2005-2006 and draw competition from generic drug makers. These companies have tried growing through M&As, but their growth has not increased. As a result, pharma companies have increasingly become a source of strong research and financial partners with many of the companies in the biotechnology industry. Pharma companies are motivated to become customers and partners of biochip companies because these companies have technologies that might help the big pharma companies become more productive and deliver more than one product, in a shortened time frame rather than in the current 10-15 year drug development process. 16
  17. 17. Accelerating the drug making process means turning to modern industrialization of R&D, using genomics and proteomics technologies, and other capabilities that bio-chip companies can provide. This report targets these important issues with interesting and useful findings. This study uses more than 46 figures and tables to illustrate the findings The wealth of data in the tables summarizes 90 alliance deals, over 375 patents, reviews recent patent disputes, includes categorized lists of microarray products, technologies and 75 web links. BIO CHIP TECHONOGOLY Current Trends Biochip technology is currently experiencing a series of rapid growth spurts that promise to propel biochips to the forefront of medical and practical applications. "The explosion of genetic sequence information and its availability in both public and corporate databases has resulted in the gradual shift towards gene function-oriented studies. Gene sequence data alone is of relatively little clinical use unless it is directly linked to disease- relevant information that has diagnostic or therapeutic value. For gene function studies, what is required is information regarding gene function, which begins by analyzing the actual patterns of transcription and translation of the genetic message." DNA-based biochips are used primarily for analysis. "One type of application focuses on the detection of mutations in specific genes obtained from test tissue. Such mutations can be a marker of the onset of a particular disease, such as cancer, and their detection serves as a diagnostic tool". Some examples of applications come from one of the founding companies in the development of biochip technology, Affymentrix. The Affymetrix GeneChips, are the only commercially viable biochips on the market. "The p53 17
  18. 18. GeneChip is designed to detect single nucleotide polymorphisms of this tumor-suppressor gene. The HIV GeneChip is designed to detect mutations in the HIV-1 protease and also the reverse transcriptase genes. Finally, the P450 GeneChip focuses on mutations of key liver enzymes that metabolize drugs". Moreover, "Affymetrix has a number of additional GeneChips in development, including ones for the breast cancer gene BRCA1, for bacterial pathogen identification, and also second-generation HIV biochips for the detection of additional HIV genes". Other applications also utilize biochip technology. In addition to biochips that identify and categorize diseases, biochips are being used for a variety of operations that stretch beyond medical applications. An example of said application is "Caliper's (Palo Alto, CA) LabChip, which uses microfluidics technology to manipulate minute volumes of liquids on chips with no moving parts. Applications include chip-based PCR, as well as high throughput screening assays based on the binding of drug leads with known drug targets. Orchid BioComputer (Princeton, NJ) is another microfluidics chip company that has developed a technology it calls Chemtel, which integrates microfluidic distribution, temperature modulation, detection system and drive electronics on a single chip. Potential applications are in drug screening and clinical diagnostic areas, as well as in DNA mutation and expression analysis". In tandem with the electronic assays Orchid BioComputer and Caliper are developing, wide ranges of companies are using biochip technology to investigate "expression profile analysis and broader screening and diagnostics applications". These functions include the use of biochip technology in forensics, applying DNA from a particular crime scene on a biochip and using suspect DNA to connect a culprit to the crime scene. In addition, biochips are being investigated for possible use in organ match identification, general identity testing, and ecological testing. "Companies involved in the development of the technical aspects of chip design, structure and function itself, such as microfluidic applications that are essential for the miniaturization of the large number of assays carried out on chips". The leadership these companies take in developing second and third generation biochips are paramount for the continued development of novel uses for biochip technology. 18
  19. 19. One of the challenges to the biochip industry continues to be consistent standardization of materials used to interpret results. This is important because "when genetic diagnostic applications are at stake, important clinical decisions (should be based) on the interpretation of gene chip readouts, and these results need to be independent of the manufacturer of the biochip". However, there is work being done to address issues of standardization. "An example of an effort to address this issue is the formation of the Genetic Analysis Technology Consortium (GATC) by Affymetrix and Molecular Dynamics Inc. (Sunnyvale, CA). The aim of this group is to establish an industry standard for the reading and analysis of multiple types of chips by the same chip readers and detection reagents. Other companies in the field are considering whether to join or not. An important factor in the current debate is that different chips have different characteristics and therefore strengths and weaknesses, and are useful for different things, which may attenuate somewhat the need for absolute standardization". Market Analysis For years industries have been using Michael Porters five forces to define industry competition. While Biochip technology is only a decade old it has quickly emerged as a technological force. As a result of the relative youth of this industry we have taken a novel approach to determining the competitive landscape. Many of the current participants are recent start-ups, yet some key members of this group are already publicly traded. As such, they post quarterly reports that include an analysis of what they believe to be their key threats, opportunities, strengths, and weaknesses. By surveying several of these players it becomes clear that certain competitive trends have already developed. This type of analysis is particularly important because it allows firms to see how they can strategically manage their businesses in ways that play to their strengths. Please use the subheadings to explore how the biochip industry has developed with regards to each of Michael Porter's five forces. As you peruse these sections keep in mind that strategic 19
  20. 20. positioning can be as important as innovation in determining success and failure of any business endeavor. CONCLUSION "Biochips will evolve both in terms of their physical characteristics and also in terms of the assays they carry out". Biochips will consistently grow smaller and more powerful with each new generation of biochip created. Additionally, with the development of specialty biochips, based from various organic materials can lead to new developments and utilizations. One encouraging development is protein-based biochips. "The so-called patterning of proteins on various chip substrates is the focus of intense research, with examples including the development of 3-dimensional patterning vs. nano-patterning on single layers. These biochips would be used to array protein substrates for drug lead screening, antibodies for diagnostic purposes, where the biochip then is also a biosensor, enzymes for catalytic reaction analysis and other applications".A broad "technology platform", biochip technology will redefine "genetic diagnostics, because of their reproducibility, low cost and speed. 20

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