Biochip
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 numbers of biological analytes for a variety of
purposes, from disease diagnosis to detection of bioterrorism agents.

# History
The development of biochips was 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 (Hughes, 1922). 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
-ther 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 (Clark, 1956_41).
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
-f 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
-ligonucleotide strands could be used as a basis for DNA sensing. Two
additional developments enabled the technology used in modern DNA-based
biosensors. First, in 1983 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 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 1980s led to the large scale development of biochips in the 1990s.
At this time, it became clear that biochips were largely a "platform"
technology which consisted of several separate, yet integrated components.
Figure 1 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 (see below).
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
-f 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 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 microarray -- 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 micromechanical devices that perform or assist signal transduction. Surface chemistry is used to covalently bind the sensor molecules to the substrate medium. The fabrication of microarrays is 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 means exist to achieve the placement, but typically robotic micro-pipetting (Schena, 1995) or micro-printing (MacBeath, 1999) systems are used to place tiny spots 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 by
Affymetrix) in which a series of microlithography steps is used to
combinatorially synthesize hundreds of thousands of unique, single-stranded
DNA sensors on a substrate one nucleotide at a
time (Fodor, 1991; Pease, 1994). One lithography step is needed per base type; thus, a total
-f four steps is required per nucleotide level. Although this technique is
very powerful in that many sensors can be created simultaneously, it is
currently only feasible for creating short DNA strands (15-25 nucleotides).
Reliability and cost factors limit the number of photolithography steps that
can be done. Furthermore, light-directed combinatorial synthesis techniques
are not currently possible for proteins or other sensing molecules.
As noted above, most microarrays consist of a Cartesian grid of sensors. This
approach is used chiefly to map or "encode" the coordinate of each sensor
to its function. Sensors in these arrays typically use a universal signaling
technique (e.g. fluorescence), thus making coordinates their only
identifying feature. These arrays must be made using a serial process
(i.e. requiring multiple, sequential steps) to ensure that each sensor
is placed at the correct position.
"Random" fabrication, in which the sensors are placed at arbitrary
positions on the chip, is an alternative to the serial method. The tedious and expensive positioning process is
not required, enabling the use of parallelized self-assembly techniques. In
this approach, large batches of identical sensors can be produced; sensors
from each batch are then combined and assembled into an array. A
non-coordinate based encoding scheme must be used to identify each sensor. As
the figure shows, such a design was first demonstrated (and later
commercialized by Illumina) using functionalized beads placed randomly in the
wells of an etched fiber optic
cable (Steemers, 2000; Michael, 1998) Each bead was uniquely
encoded with a fluorescent signature. However, this encoding scheme is
limited in the number of unique dye combinations that be can be used and
successfully differentiated.

# Protein Biochip Array and Other Microarray Technologies
Microarrays are not limited to DNA analysis; protein microarrays, antibody microarray, Chemical Compound Microarray can also be produced using biochips.  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.
Details about other array technologies can be found in the following pages: Antibody microarray and Chemical Compound Microarray.

# 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.
Bioethics is the collaborative investigation of biology, scientific technology, and ethical issues. Van Potters 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. Until all the safety issues are resolves and ethical standards are put into stone government oversight is crucial.