10-K Part 2:
DRUG DISCOVERY--GENOTYPING
THE GENOMICS SCIENCES MARKET
We are participating in the new field of high throughput genomics. By using
the knowledge of DNA (deoxyribonucleic acid) variations, genomics provides the
potential of discovering better, safer and more efficacious drugs. These
variations in DNA are believed to be the origin of many differences between
individuals, including disease predispositions and dissimilarity in drug
responses. A category of common variations in DNA are known as single nucleotide
polymorphisms, or SNPs. SNPs represent the smallest possible genetic change, and
occur where the DNA molecules of different individuals vary at a single
location. In the future, we believe that SNP analysis may play an essential role
in the development of drugs, diagnostics and other life science applications.
The process of determining the SNPs present in an individual is one method
of genotyping. It is generally estimated that there are millions of SNPs
inherited from each parent. Some SNPs may be genetic markers of inherited
diseases or responsible for individual differences in drug responsiveness.
Determining which patients have such markers is called patient stratification.
While most SNPs are believed to be of no medical consequence, thousands of SNPs
are expected to be medically relevant and correlate to disease susceptibility or
responsiveness to therapy. Establishing such a correlation is called an
association study. To capture this information, up to tens of thousands of SNPs
may have to be measured in each individual.
After a SNP is discovered, its potential relevance for human health must be
validated by determining how common the variation is in different segments of
the population. To identify the small subset of SNPs that occur with the
greatest frequency in human disease or are responsible for variations in drug
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responsiveness, hundreds of millions of SNP measurements must be made and
correlated with health and other physical and mental features of interest. SNPs
with a validated medical relevance may be useful in drug development and human
medical diagnostics. Identification of these SNPs will require a highly
accurate, cost-efficient, high throughput DNA analysis technology.
CURRENT SCREENING SYSTEMS
Many screening systems operate with varying degrees of automation. Full
automation--from sample dispensing to data collection--enables round-the-clock
operation, thereby increasing the screening rate. Fully automated high
throughput systems consist of assay analyzers, liquid handling systems,
robotics, a computerized system for data management, reagents and assay kits and
microplates. A microplate is a plastic plate that generally contains 96 wells,
384 wells or 1,536 wells, each well holding a mixture of a target, a compound
and reagents. In the automated high throughput process, a robot moves a
microplate among preparatory stations and then delivers the microplate to the
analyzer. In the case of fluorescence-based assays, after the microplate is
placed into the analyzer, the instrument directs a light source onto a well. The
intensity of the light emitted from the well in response to this light source is
then measured by the analyzer, showing the degree of the effect, if any, of the
compound on the target. In this manner, the analyzer detects and measures
possible bioactivity of a compound against a target.
Most screening systems utilize general-purpose assay analyzers, which were
not originally designed for high throughput use. We believe that most screening
systems in use today have the following limitations:
LACK OF ANALYTICAL FLEXIBILITY. Many general-purpose analyzers do not
provide sufficient analytical flexibility because they operate in only one
or a few types of assay detection modes. In order to perform assays using
different detection modes, researchers generally must physically move such
analyzers and reconfigure the high throughput line. Alternatively,
researchers may set up the high throughput line with multiple
general-purpose analyzers, which often results in critical space
constraints.
INADEQUATE SENSITIVITY. As researchers continue to use smaller assay
volumes to reduce reagents costs and increase throughput, many
general-purpose analyzers are inadequate because they are not sensitive
enough to read results based on these smaller volumes. Inadequate
sensitivity may result in:
- missed hits,
- limited research capabilities,
- increased costs of compounds, assays and reagents and
- lower throughput.
POOR HIGH THROUGHPUT SYSTEM INTEGRATION. Most analyzers have not been
designed specifically for a high throughput environment. They are difficult
and expensive to integrate into a high throughput automated line. Even after
the analyzer is integrated into the high throughput line, there are often
many problems, including:
- increased probability of system failures,
- loss of data,
- time delays and
- loss of costly compounds and reagents.
INABILITY TO REACH HIGH PERFORMANCE IN DENSER FORMATS. Many analyzers can
achieve high performance in the standard 96-well microplate format. However,
drug discovery companies are moving to the denser 384-well and 1,536-well
formats to reduce costs of reagents, assays and compounds, while increasing
throughput. Most existing analyzers cannot achieve high performance in this
denser format.
LIMITATIONS OF CURRENT ASSAYS. Many assays in use today are performed in a
complex, multi-step process and are expensive, time-consuming and difficult
to implement in a high throughput setting. In
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addition, certain assays use radioactive isotopes, which are hazardous and
result in expensive waste-disposal. Fluorescence-based assays are becoming
more accepted in high throughput settings due to the relative lack of
waste-disposal problems, as well as their sensitivity, versatility and
adaptability to high throughput. However, historically the use of many of
the fluorescence-based assays in high throughput was limited by the relative
insensitivity of available analyzers. Certain assays are also unsuitable for
high throughput because of the low sensitivity of both the assay and
general-purpose analyzer.
The high throughput laboratory today must balance the needs for performance,
such as dynamic range, sensitivity and analytical flexibility. The increasing
use of high throughput and the need for higher throughput further exposes the
limitations of current screening systems. These limitations result in higher
costs, lower throughput and lower productivity.
OUR SOLUTION
We design, produce and sell products under the CRITERION-TM- name
specifically targeted for both the current and evolving high throughput markets.
To develop these products, we have assembled an integrated team of scientists
and engineers with expertise in fluorescence chemistry, biophysics,
biochemistry, chemical and mechanical engineering, electronics and software.
Since our inception in 1988, we have designed, developed and manufactured high
performance clinical diagnostics analyzers and other automated instruments.
Starting in the second half of 1996, we began focusing on the high
throughput market. Since then our efforts have resulted in the achievement of
several key milestones.
- In May 1998, we began shipping Analyst-TM- HT, our first-generation
detection system for the high throughput market. This system was designed
specifically for the high throughput market and offers multi-mode
capability, flexibility and performs up to 70,000 screens per day.
- Later in 1998, we shipped our first ultra-high throughput system,
Acquest-TM-. Also multi-modal, the Acquest was designed to accept
microplates with both 384-well and 1,536-well formats. Assay throughput is
estimated at up to 200,000 tests per day.
- In June 1999, we began shipping Analyst AD, which was designed
specifically for assay development and is fully compatible with Analyst
HT.
We believe that the Analyst and Acquest product lines provide several
important customer benefits, including:
- increased throughput,
- improved analytical performance and flexibility, especially in higher
density formats,
- lower reagents costs and
- the ability to be quickly integrated into existing high throughput
laboratories and to evolve with changing high throughput needs.
We have developed and are developing value-added, application-specific
reagents, assay kits and microplates, which are being optimized for use in high
throughput systems and specifically for use with our Analyst and Acquest product
lines.
- In 1998, we introduced and shipped our first value-added consumable
product, the TKX-TM-, or Tyrosine Kinase Fluorescence Polarization assay
kit.
- In September 1998, we started marketing our High Efficiency (HE) line of
microplates.
- In September 1999, we started marketing four additional assay and reagent
products including:
- DPX-TM- for dopamine receptor screening,
- cyclic AMP (cAMP) for a general cell signaling molecule,
- ProteasePX-TM- for protease inhibitor screens and
- a new proprietary fluorescent reagent, Sunnyvale Red-TM-.
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In addition, we are currently developing several other consumable products,
including additional assays, which will be optimized to perform with our
instruments. We believe that customers will prefer to purchase consumables and
instruments from a single source for convenience, ongoing support and
accountability. |
