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Computers and biotechnology have united in a new field known as 'bioinformatics', which provides faster research in drug discovery. Instead of the tedious process of trial and error in finding DNA sequence matches, a computer can reassemble the DNA, accelerating the whole process. The creation of vast genetic libraries is a major driving force for bioinformatics. Bioinformatics provides informational framework that integrates data obtained from mapping and sequencing. This information then can be used as a starting point for development of new or improved molecules of therapeutic or clinical importance. Bioinformatics encompasses:
The use of software, databases and networks for gene and open-reading frame (ORF)
identification;
Database homology and pattern searching with both DNA and protein sequences;
Comparative sequence analysis (which can pinpoint specific regions against which
to target drugs) and multiple sequence alignment;
Protein structure prediction and the mapping of functional sites;
Protein homology modelling and 'inverse' folding as a means of probing protein
structure and function; and
The discovery or design of drugs against genes or their products.
Comprehensive library of genes and protein sequences is required for above work.
Many databases are accessible and searchable via the Internet (see Table below).
Information
Database in Europe, Japan
Gene sequences GenBank, Genome Sequence Database (GSDB), European Molecular
Biology Laboratory (EMBL), DNA Databank of Japan (DDBJ)
Protein sequences Protein Information Resource (PIR) (SWISS-PROT)
Sequence-tagged site database Database of Sequence-tagged Sites) dbSTS
Expressed sequence tag database (cDNA sequences) Database of Expressed Sequence
Tags (dbEST)
Polymorphic markers in human families Centre d'Etudes Polymorphism Humaine (CEPH)
(France)
Patented DNA & protein sequences GENESEQ (published by Derwent, Inc./
IntelliGenetic)
Japan archives DNA sequences obtained on the Asian subcontinent in DNA Databank
of Japan (DDBJ). GenBank, EMBL, and DDBJ exchange sequence data among each other
regularly.
Human Genome Project (HGP) is currently generating 250 to 500 kbases per day and
this is expected to increase to 10 Mbases per day within the next five years.
Analysis of this data requires data centres both nationally and internationally
to collect, manage and distribute this data. As the project is generating
information of a new type, novel electronic publishing systems (bulletin boards
- the BIOSCITM newsgroups and hypertext links) are being developed.
Collaboration has also been established between database centres. In the US, the
National Center for Biotechnology Information (NCBI) has been established to
oversee all aspects of Human Genome Initiative. Similarly in Europe, the EMBL
has established European Bioinformatics Center in Cambridge, England.
There is now so much information available that it is impossible for scientists
to conduct experiments without the use of a computer. It is the only way to
provide access to the huge amount of data floating around. Also, interestingly
it is difficult to know how important the information is.
However, for drug companies, bioinformatics offers the prospect:
of finding better drug targets
saving time in drug development process, and
decreasing overall costs of the drug development programme.
A search for compounds that bind to and have the desired effect on drug targets
takes place mainly in a biochemist's traditional 'wet' lab, where evaluations
for activity, toxicity and absorption can take years. But with new tools of
bioinformatics and the growing data on protein structures and bio-molecular
pathways, this aspect of drug development will also shift to computers.
A biomedical researcher is now equipped with a workstation, suitable software,
databases and Internet. Bioinformatics has rapidly emerged as critical to gene
based drug discovery.
Although the basic work of getting a draft copy of entire human genome is
complete, the task ahead is still more difficult. With genetic data available on
the human genome (and 30 other organisms), the correlation between gene and
functional proteins coded by them has become necessary. Assigning function to a
novel protein requires the integration of many techniques and is currently the
bottleneck in the drug discovery process. There may be as few as 1,000 drug
targets for major diseases in 100,000 genes that make up the human genome, and
finding these validated targets is a considerable challenge.
A number of commercial concerns are also sequencing portions (cDNA fragments) of
the human genome for commercial gains. Their proprietary database is not
accessible to the public. There is a lot of debate on maintaining sequence
information proprietary (and to allow patenting of genes or gene fragments for
which function may not be known). The competitive value of genetic information
is exemplified by the acquisition of rights by Amgen Corporation (for US $20 mn)
to commercialisation of therapeutic agents developed from the discovery of the
leptin gene (conferring predisposition to obesity).
The Institute for Genomic Research (TIGR) is a non-profit privately funded
organisation that is performing cDNA sequencing of fragments of human genome.
They have sequenced about 100,000 genetic fragments, which correspond to half
the genes of the human genome. They aim to identify functions of the genes and
to develop potential therapeutics.
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There are other commercial companies who have developed novel diagnostics and
therapeutics from human genome technology. Some of these are:
Genomyx and Hyseq (rapid sequencing technology)
Mercator Genetics (chromosome mapping), (work on cardiovascular disease, some
cancers, endocrine disorders, psychiatric disorders)
Incyte Pharmaceuticals (cDNA and EST sequencing)
Seqana, Inc. and Myriad Genetics, Inc. (diagnostics from gene markers) (work on
diagnostic kit for breast cancer, melanoma, prostate and colon cancer, heart
disease, hypotension)
Darwin Molecular Corp. (large scale sequencing and directed molecular evolution
of targets to T-cell receptor genes)
Millennium Sciences, Inc. (mapping and sequencing of multifactorial gene
disorders such as diabetes).
Various genome databases store data in incompatible formats. Synergy uses CORBA
to communicate with them. CORBA is a software architecture becoming widely
accepted as a method for handling diverse database formats in standard ways.
Synergy is designed to run on a computer behind a company firewall (a gateway to
the Internet that keeps out electronic intruders). Pharmaceutical companies will
be able to access the software's functions via familiar Web browsers.
While many pharmaceutical companies are developing ties with genomics and
bioinformatics companies for information access, some large pharma companies
have sought to establish their own in-house bioinformatics investment. This will
make their drug discovery more efficient and can save money in software support.
Pharmaceutical giants are also forging strategic alliances, entering into
licensing agreements and acquiring smaller biotechnology companies so as to
integrate bioinformatics throughout their operations.
Some examples of these strategies are as below:
Glaxo Wellcome and Affymetrix, the company that has developed the GeneChip to
assay the gene sequences, are undertaking a new approach to the treatment of
AIDS. Glaxo Wellcome will use the GeneChip to produce a database that correlates
the genetic sequences of the HIV virus with sensitivity to various drug regimes.
There are three classes of drugs, which can be used in combination therapies:
Protease inhibitors, Nucleoside analogue reverse transcriptase inhibitors, and
Non-nucleoside analogue reverse tanscriptase inhibitors. The initiative of Glaxo
Wellcome should enable clinicians to make sense of the vast number of different
combinations of therapies that are possible.
A drug research company, which focuses entirely on the use of human tissue, has
been established in the Royston, Herts (UK). This company, Pharmagene
Laboratories, is first of its kind, and will work in collaboration with the
pharmaceutical industry to discover new medicines through the expression and
function of genes and gene products in human tissue. The company has been
functional since Dec. 1996, and is busy with collecting pre-clinical data for
their drug discovery programmes.
Abbott Laboratories is investing $42.5 mn in genomics company, Genset. The joint
venture in the new virgin field of 'pharmacogenomics', aims to develop new drugs
through study of genetic differences within different groups of populations.
Axys has drug discovery programs in infectious diseases and cancer therapeutics.
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