Words and phrases in
bold are [or can
be] defined in
the text.
Like the web, in the short run, genomics and bioinformatics
have been overhyped and subject to unrealistic expectations. But in the long run
both are bringing about truly profound changes, within the
pharmaceutical industry, increasingly, to individual patients and health
professionals and spillover into agriculture, food, the environment and other
sectors. Progress is a mix of incremental improvements, and truly new
paradigms.
Scalability and ramping up for high throughput and automation
remain challenging. It is clear that identifying genes and sequence is not synonymous with interpretation and understanding
of gene
functions. Learning how to use biological insights to alter human physiology at the molecular and biochemical
levels requires integrating biology, chemistry and informatics.
Scope:
These
sections focus on the use of genomics and proteomics in drug discovery
and
development, on current and potential uses in pre- clinical, and clinical
trials, and research use in patients, and the quickly growing, but still evolving
role of molecular medicine. Biopharmaceutical
manufacturing is not a major focus, but the efforts involved in ramping up to
higher throughput and scaling in going from the lab into clinical use are not
inconsequential.
Biotechnology
Biotechnology started as a means for producing biopharmaceuticals.
It has only recently become an integral part of the drug discovery and development
process. Use of genomics and proteomics is still primarily at the earliest stages of
the drug discovery pipeline.
"Biotechnology" is not an industrial sector, but rather a set of
methods useful in many industrial sectors (usually established ones such as
drugs and biologics, devices, or agriculture), but also for some entirely new
applications (e.g., DNA forensics). Many firms, almost 1500 listed by the
various online services, are called "biotechnology" firms because they
are largely built around technologies developed since 1980. These firms are
generally competing in established markets, however, even when they compete by
using novel products, services, and technical approaches. Robert Cooke- Deegan
et. al., World Survey of Funding for Genomics Research: Final Report to the
Global Forum for Health Research and the World Health Organization,
September 2000 http://www.stanford.edu/class/siw198q/websites/genomics/finalrpt.htm
That the biotechnological innovations of the 1970’s took until the 1990’s to
integrate into big pharma is outlined in "The Pharmaceutical Industry and the Revolution in Molecular
Biology: Exploring the Interactions between Scientific, Institutional and
Organizational Change, Iain M. Cockburn, Rebecca Henderson, Scott Stern, 1999. http://www.cid.harvard.edu/cidbiotech/events/henderson.htm
More
definitions of the "biotechnology industry"
Information resources
Business
Biology
Genomics definitions
Generation of information about living things by systematic
approaches that can be performed on an industrial scale. Roger Brent
"Genomic biology" Cell 100: 169-183 Jan 2, 2000 http://www.molsci.org/files/Cell_v100_p169-83.pdf
The systematic study of the complete DNA sequences (GENOME) of
organisms. MeSH, 2001
More
terminology Genomics
How does genomics differ from
genetics?
Genetics looks at single genes, one at a time, as a snapshot. Genomics is trying
to look at all the genes as a dynamic system, over time, to determine how they
interact and influence biological pathways, networks and physiology, in a much
more global sense. A dynamic process, 2D vs. 3D and 4D.
Genomics
overviews and introductions
AMA, Human Genome http://www.ama-assn.org/ama/pub/category/2398.html
Access Excellence, National Health Museum, US
http://www.accessexcellence.org/
Provides high school biology and life science teachers access to their
colleagues, scientists, and critical sources of new scientific information.
Originally developed and launched by Genentech Inc.
Bringing the Genome
to You, NHGRI, April 2003
http://www.genome.gov/page.cfm?pageID=10506366
Webcast of celebration of the 50th anniversary of DNA and the double
helix.
Cold Spring Harbor, DNA
Learning Center, http://vector.cshl.org/
A clearinghouse for information on DNA science, genetic medicine, and
biotechnology, to provide an interactive learning environment for students,
teachers, and nonscientists, extending the Laboratory's traditional research and
postgraduate education mission to the college, precollege, and public levels
DOE Dept. of Energy, Genomes
to Life, http://doegenomestolife.org/
Genomics and Its Impact on Science and Society: The Human Genome Project
and Beyond, Human Genome Program, DOE http://www.ornl.gov/sci/techresources/Human_Genome/publicat/primer2001/index.shtml
Glossary, Includes impact on medicine
EBI European
Bioinformatics Institute, UK Quick introduction to elements of biology –
cells, molecules, genes, functional genomics, microarrays, Alvis Brazma,
Helen Parkinson, Thomas Schlitt, Mohammadreza Shojatalab, EMBL-EBI, European
Bioinformatics Institute, Oct. 2001 http://www.ebi.ac.uk/microarray/biology_intro.htm
Intended for scientists, engineers, computer programmers, or anybody with
background or strong interest in science, but without background in biology ...
we have tried to distil the content down to the absolute minimum needed to make
some sense of bioinformatics, while on the other to leave in enough to show why
it is interesting
NHGRI,
National DNA Day
April
25, 2003 teaching tools http://www.genome.gov/10506367
NCBI, NLM, NIH: Science
Primer http://www.ncbi.nlm.nih.gov/About/primer/index.html
Bioinformatics, genome mapping, molecular modeling, SNPs, ESTs, microarray
technology, molecular genetics, pharmacogenomics, phylogenetics
A
User's guide to the
Human Genome, Nature Genetics, 32 (1): supp 2002 http://www.nature.com/genomics/post-genomics/index.html
more
genomic overviews See also Human
genome websites
Functional genomics
Definitions
The development and application of global (genome- wide or system- wide)
experimental approaches to assess gene function by making use of the information
and reagents provided by structural genomics [in the original more limited sense
of construction of high- resolution genetic, physical and transcript maps of an
organism]. It is characterized by high throughput or large- scale experimental
methodologies combined with statistical and computational analysis of the
results. The fundamental strategy is to expand the scope of biological
investigation from studying single genes or proteins to studying all genes or
proteins at once in a systematic fashion. Phil Hieter and Mark Boguski
"Functional Genomics: It's All How You Read It" Science 278: 601- 602,
October 24, 1997
Functional
genomics' insights
can be biochemical, genetic, metabolic and or
physiological. Comparative genomics is the practice of uncovering the functions of human genes
and other DNA regions by studying their parallels in nonhumans.
But even
defining "function" is problematic.
"The vagueness of the
term 'function' when applied to genes or proteins emerged as a particular
problem, as this term is colloquially used to describe biochemical activities,
biological goals and cellular structure. Gene Ontology Consortium "Gene
Ontology: tool for the unification of biology Nature Genetics 25: 25-29 May 2000
Genomics by itself cannot usually determine even the biochemical, much less
the cellular or physiological functions of a protein. Structural biology can
determine the shape of the protein but cannot reliably determine its function;
the coupling between overall structure and function is a loose one. Given a
structure, one cannot determine where on the surface of a protein the likely
binding sites for ligands are located and what those ligands are likely to be.
Genomewide experiments have many false positives and false negatives and often
do not distinguish indirect effects from direct ones. The consequences of the
expression of a given gene sequence can only be determined by integrating the
results from many different types of experiments, and the best way to carry out
this integration is not obvious. "From Sequence to Consequence: The Problem
of Determining the Functions of Gene Products in the Age of Genomics" Dr.
Gregory A. Petsko, Brandeis Univ. Cambridge Healthtech Chemogenomics/ Chemical
Genomics conference, Nov. 18- 19, 2002, Boston MA
As the
pressure mounts to produce validated targets and reduce late- stage attrition,
functional analysis and characterization of drug targets and disease pathways is
becoming key in pharmaceutical research. Understanding the role of specific
genes in disease requires a highly parallelized and multidisciplinary approach.
Armed with more- powerful, higher- throughput tools for gene knock- out/ knock-
down, protein characterization, metabolic profiling, high- content
screening, and data management, researchers are now in a position to acquire and
integrate genomic, proteomic, metabolite, phenotype, and clinical data to
provide a systems- wide view of biological function and disease pathways/
mechanisms.
Comparative
genomics
"We believe that the problem of the genome- phenotype connection,
which, in a sense, is the central theme of biology, can be solved only through
an experimental program strategically planned on the basis of comparative-
genomic results. Much of the biological research of the next few decades is
likely to develop along these lines. E. Koonin et al "The Impact of
Comparative Genomics on our Understanding of Evolution" Cell 101:573-576
June 9, 2000
A useful way to tackle noise and
complexity of functional genomics information is to average the data from many
different genes into broad 'omic categories (Jansen & Gerstein
2000. For instance, instead of looking at how the level of expression of an
individual gene changes over a time- course, we can average all the genes in a
functional category (e.g. glycolysis) together. This gives a more robust answer
about the degree to which a functional system changes over the time- course. Dov Greenbaum, Mark Gerstein et. al. "Interrelating Different Types of
Genomic Data" Dept. of Biochemistry and Molecular Biology, Yale Univ. 2001 http://bioinfo.mbb.yale.edu/e-print/omes-genomeres/text.pdf.
Information
resources Genomics
Proteomics
Definitions
The most useful definition of proteomics is likely to be the
broadest: proteomics represents the effort to establish the identities,
quantities, structures and biochemical and cellular functions of all proteins in
an organism, organ, or organelle, and how these properties vary in space, time
and physiological state. .. A much broader field than would be apparent
from early efforts, which have focused on cataloging levels of protein
expression. Ideally it should encompass efforts to obtain complete functional
descriptions for the gene products in a cell or organism. Defining the Mandate
of Proteomics in the Post- Genomics Era, National Academy of Sciences, 2002 http://www.nap.edu/books/NI000479/html/R1.html
The
analysis of complete complements of proteins. Proteomics includes not only the
identification and quantification of proteins, but also the determination of
their localization, modifications, interactions, activities, and, ultimately,
their function. Initially encompassing just two- dimensional (2D) gel
electrophoresis for protein separation and identification, proteomics now refers
to any procedure that characterizes large sets of proteins. The explosive growth
of this field is driven by multiple forces - genomics and its revelation of more
and more new proteins; powerful protein technologies, such as newly developed
mass spectrometry approaches, global [yeast] two- hybrid techniques, and
spin-offs from DNA arrays; and innovative computational tools and methods to
process, analyze, and interpret prodigious amounts of data. Stanley Fields
"Proteomics in Genomeland" Science 291: 1221-1224 Feb. 16, 2001 http://www.sciencemag.org/cgi/content/full/291/5507/1221
The
systematic study of the complete complement of proteins (PROTEOME) of organisms.
MeSH 2003
A subset of genomics in a sense, but also much broader in that
the function(s) of proteins change over time and in different cells and tissues.
[temporal spatial localization]
The
Central Dogma (DNA makes RNA makes protein(s) is still essentially valid --
except that given the unexpected prevalence of alternative splicing and our
still fragmentary knowledge of post- translational modifications it is clear that
DNA and RNA (singular) makes proteins (plural) and that these proteins may have
multiple functions, at various times during the cell cycle and in different
cellular locations. We still have a lot to learn.
Genes are
important, but proteins are what do most of the work. Even so-called
"junk DNA" seems to have important regulatory functions.
More
terminology Proteomics
Proteomics
overviews & introductions
American Medical Association, Proteomics http://www.ama-assn.org/ama/pub/category/3668.html
ExPASy,
Human Proteomics http://expasy.org/sprot/hpi/
VIB, the Flanders Interuniversity Institute for
Biotechnology Research,
Proteomics Core Facility http://www.vib.be/Research/EN/Service+Facilities/Proteomics+-+Facility/Introduction/
Harvard Extension School,
Introduction to
Proteomics, 2004 http://www.extension.harvard.edu/2003-04/courses/12066.jsp
Information
resources Proteomics
Technologies
While genomics and proteomics are clearly part of the same
continuum (DNA makes RNA makes protein(s)) they are two different cultures
divided by instrumentation.
Biotech
Technologies overviews & introductions
BIO, Biotechnology tools in Research and
Development http://www.bio.org/er/biotechtools.asp
BIO
Biotechnology: A
Collection of Technologies http://www.bio.org/er/technology_collection.asp
Industry Canada,
Life Sciences Gateway http://strategis.ic.gc.ca/epic/internet/inlsg-pdsv.nsf/en/Home
National Research
Council, Canada, Biotechnology http://www.nrc-cnrc.gc.ca/randd/areas/biotechnology_e...l
Genomics has flourished with
PCR and automated
sequencing. Proteomics uses a variety of technologies.
Established technologies such as mass spectrometry and
NMR are more relevant to biology than ever before.
PCR
Terminology PCR
information resources
Proteomics
technologies
For a field so laden with razzmatazz
methods, it is striking that the number one need in proteomics may be new
technology. There are simply not enough assays that are sufficiently streamlined
to allow the automation necessary to perform them on a genome's worth of
proteins. Those currently available barely scratch the surface of the thousands
of specialized analyses biologists use every day on their favorite proteins.
What we need are experimental strategies that could be termed cell biological
genomics, biophysical genomics, physiological genomics, and so on, to provide
clues to function. In addition, a protein contains so many types of information
that each of its properties needs to be assayed on a proteome- wide scale,
ideally in a quantitative manner. Stanley Fields "Proteomics in Genomeland"
Science 291: 1221-1224 Feb. 16, 2001
Technologies
information resources
Microarrays
Roger Brent
compares microarrays, a technology still in its infancy to the
microscope and telescope because they "enable observation of the previous
unobservable" [transcripts expressed under different conditions in cells,
tissues, and organisms] Roger Brent, "Functional genomics: learning to
think about gene expression data" Current Biology 9: R338-R341, May
1999.
Microarrays,
with RNA begin to bridge the chasm between DNA and protein research.
Microarrays
definitions A microscopic, ordered array of nucleic acids, proteins, small molecules,
cells or other substances that enables parallel analysis of complex biochemical
samples. Mark Schena et al. "Quantitative monitoring of gene expression
patterns with a complementary DNA microarray" Science 270, 467-470 Oct. 20
1995
The term microarray
originally referred to spotted cDNA arrays, but now we and others use it
for any hybridization- based array. When the term microarray was first
introduced, the prefix micro served to distinguish this new generation of
arrays from their predecessors, which came to be called macroarrays.
Traditionally, microarrays differ from macroarrays based on the physical size of
the surface and the spots.
Numerous
types of microarrays are in common use today, but they can be categorized into
three main groups: spotted cDNA microarrays, spotted oligonucleotide
microarrays, and Affymetrix GeneChips, which are sufficiently unique
to warrant their own grouping. In the spotted- array categories, are both
traditional arrays produced using contact printing in the style of Pat Brown
(Stanford University), and ones produced using the newer ink- jet
technology pioneered in the laboratory of Lee Hood of the University of
Washington and developed to commercial fruition by Rosetta Inpharmatics and
Agilent Technologies.
Also known
as DNA chips, GeneChip TM is
an Affymetrix trademark.
Microarrays will be
regulated by the FDA as a medical device, but are being used now in clinical oncology
research. Analyte
specific reagents comes into this too somehow.
Protein
arrays Definitions
Can consist of proteins themselves
(e.g., for studies of protein/ protein interactions or protein/ small- molecule
binding) or of probes (often antibodies) for capturing proteins so
that protein levels in a sample can be gauged. Ciphergen has trademarked
ProteinChip™. Also called protein microarrays, antibody arrays,
etc.
Microarrays
Overviews & introductions
NCBI, Microarrays http://www.ncbi.nlm.nih.gov/About/primer/microarrays.html
Stanford University,
Pat Brown's Lab HomePage,
Dept of Biochemistry, http://cmgm.stanford.edu/pbrown/
Microarrays
information resources
Chemistry
Combichem
& chemogenomics
Combinatorial chemistry
Definition
Using a combinatorial process to prepare sets of
compounds from sets of building blocks. IUPAC Combinatorial
Chemistry
In the early 1990's it was believed
that combinatorial chemistry would revolutionize the drug discovery industry.
Ten years later the route from design and synthesis of compound libraries to
identification of lead structures is still long and costly. Synthesis of an
almost unlimited number of organic compounds covering as much of chemistry space
as possible is no longer the most cost effective and time saving approach to
hit identification. Creating libraries, using biological target
structure to inform chemical design, facilitated by quantum advances in structural
genomics and computational capabilities, is a smarter, more efficient way to
produce good initial leads. Considering solubility, permeability and
other drug- like properties early in library design and introducing both target
and lead structural constraints in lead development are further ways to
ensure more compounds make it to trial.
Note that there is not enough matter
in the universe to prepare all possible combinatorial variations
Chemical
genomics
Definition
Uses libraries of small molecules (natural compounds, aptamers or the products
of combinatorial chemistry) and high throughput screening to advance
understanding of biological pathways and to identify compounds that act as
positive or negative regulators of individual gene products, pathways or
cellular phenotypes. Francis C. Collins, Eric. D. Green et. al, A Vision for the
Future of Genomics Research, Nature (6934): 835- 847 April 24, 2003
Google =
"chemical genomics about 3,920 Dec. 11, 2003; about 62,500 Oct. 14, 2005
chemogenomics about
2,170 Dec. 11, 2003, about 35,100 Oct. 14, 2005
"chemical genetics" about 3,840 Dec 11, 2003, about 55,200 Oct. 14,
2005
More on
defining chemical genomics
Information
resources Combichem
& chemogenomics
Cheminformatics
Definitions and overviews
Information Resources
Drug Discovery and Development
New ways (both automated and human) of dealing with the tidal
waves of multi- disciplinary structured and unstructured data, integrating this
data into drug discovery, in response to the target glut are needed.
Pharmaceutical Research & Development
needs to focus on target
validation and moving better candidates more quickly into pre-clinical and clinical
development. Leveraging existing knowledge (text mining and other knowledge extraction
techniques) may offer hope for real competitive advantages – but pushes the envelope on
existing computational techniques and the interpersonal and soft people skills
needed to forge strategic partnerships and cross- departmental alliances.
Linear handoffs along the pipeline need to be replaced by
parallel processing and more integration. The proprietary cultures of industry
are slowly evolving (at varying rates and degrees of success) into ones which
encourage (and reward) information sharing.
A fair amount of today’s biopharmaceutical R&D is still at
the pre- competitive stage. But reaching agreement on what pre-
competitive really means (and agreeing on how best to protect future intellectual property
rights) is challenging, and much remains to be tested in the courtroom.
Big Pharmas cannot continue to spend more and
more on R&D to bring fewer truly new drugs into use.
Biotechnology and biopharmaceutical companies cannot survive indefinitely
without bringing products to market.
Capitalizing
on genomics, Phillips Kuhl, CHI Insights,
http://www.genomicsontarget.com/pdf-cog.asp
Target validation
While genomics has yielded a wealth of potential new targets, for
the vast majority of them very little is known about their function, role in
cellular pathways, or connection to disease. Target validation thus becomes the
central issue in the success or failure of large- scale drug discovery. With
steadily growing drug development costs, depleted pipelines, and no prospective
blockbusters on the horizon, many companies are relying on novel targets to
reach or maintain profitability. Researchers must find the means to choose the
best among these drug targets early in the process to reduce costly attrition
rates, underscoring the urgent need for target validation technologies that will
allow for more efficient drug discovery and development.
Lead optimization
Pharmaceutical companies are eager to assuage the innovation deficit by using
new approaches to drug discovery and development. Performing lead optimization
earlier, and paralleling lead optimization and target validation, are two key
goals. In vitro metabolic screens have a key role to play in early
attrition. Assays to reveal drugs that act by many pathways, as well as
drug -drug interactions, are gaining in popularity. Toxicity prediction is
an especially complex problem, and getting intense attention.
The emerging drug
discovery paradigm emphasizes in vitro and in silico
[virtual screening] methods to predict
in vivo
ADMET (administration/ dosage/ metabolism/ excretion/ toxicity parameters.
These methods are being applied as early as possible to enable early attrition
of compounds that will eventually fail.
Systems biology
is helping researchers to know
more about drug mechanisms and life sciences informatics is pushing the envelope
in computing. Demand for new algorithms, new methods of organizing and
interpreting data, new computing platforms (such as grid computing) and new
business models promise both opportunities -- and pitfalls -- for many. More
on systems biology
Clinical genomics
The linkage of clinical medical
information to molecular information represents one of the primary challenges
for bioinformatics in the next century. As the genome sequencing projects mature
and complete, we will have the genetic DNA sequences of both humans and a host
of human pathogens, and informatics tools will be necessary to deliver this
information in appropriate ways to medical decision makers. This information
will impact decisions about diagnosis, prognosis, treatment and epidemiology.
... [these] data sources are extremely valuable independently, but may contain
valuable information when properly combined. This becomes the challenge of what
some have termed "clinical genomics" or the marriage of clinical
investigation with genomic science. Russ Altman "Bioinformatics in support
of molecular medicine" American Medical Informatics Association Symposium
1998 www.amia.org/pubs/symposia/D005238.PDF
Clinical proteomics
Clinical proteomics aims to discovery
proteins with medical relevance said Alan Sachs, a director of R&D at Merck.
Such discoveries can be defined broadly as those that identify a potential
target for pharmaceutical development, a marker(s) for disease diagnosis or
staging and risk assessment, both for medical and environmental studies. (Note
that there is a difference between developing biological insight and identifying
clinically important diagnostic and prognostic protein- based assays.) Defining
the Mandate of Proteomics in the Post- Genomics Era, Board on International
Scientific Organizations, National Academy of Sciences, 2002 http://www.nap.edu/books/NI000479/html/R1.html
Medical
genomics: The mission of the Roche Centre for Medical
Genomics (RCMG) is to apply genetic and genomic knowledge to the understanding
of the molecular pathology of major human disease leading to the discovery of
new and more effective therapies. Research at the centre for medical genomics
will focus on: Genetics, as a basis for understanding gene functions and the
role of genes in disease; Bioinformatics and computer- aided biology, for
efficient use of new scientific data and findings; Functional genomics, as a
basis for developing medicines and diagnostic tests that are individually
tailored to patients' needs. Roche Centre for Medical Genomics, F.
Hoffman LaRoche, Ltd. 1996- 2005 http://www.roche.com/home/science/sci_gengen/sci_gengen_med.htm
Medical proteomics
Proteomic technologies will play an
important role in drug discovery, diagnostics and molecular medicine because is
the link between genes, proteins and disease. As researchers study defective
proteins that cause particular diseases, their findings will help develop new
drugs that either alter the shape of a defective protein or mimic a missing one.
Already, many of the best-selling drugs today either act by targeting proteins
or are proteins themselves. Advances in proteomics may help scientists
eventually create medications that are "personalized" for different
individuals to be more effective and have fewer side effects. Current research
is looking at protein families linked to diseases including cancer, diabetes and
heart disease. American Medical Association, "Proteomics" How can
proteomics be applied to medicine? http://www.ama-assn.org/ama/pub/category/3668.html#2
Drug discovery and development Overviews
& introductions
About Pharmacology, American Society for Pharmacology and
Experimental Therapeutics http://www.aspet.org/public/pharmacology/about_pharmacology.html
Molecules
to Medicine http://www.nigms.nih.gov/medbydesign/molecules/
part of Medicines by Design, NIGMS http://www.nigms.nih.gov/medbydesign/
Information
resources Drug discovery & development
Pharmacogenomics, pharmacogenetics,
personalized/ individualized medicine
The Human Genome will need to be sequenced only once, but it
will be resequenced thousands of times … Eric Lander, Whitehead Institute
"The New Genomics" Science 274: 536, 25 Oct. 1996
Definitions
Pharmacogenomics
Can be construed as the study of the
entire complement of pharmacologically relevant genes, how they manifest their
variations, how these variations interact to produce phenotypes, and how
these phenotypes affect drug response. A key element of pharmacogenomics is, not
surprisingly, the large- scale and high throughput collection of data, including
DNA sequence variations, mRNA expression analysis, enzyme kinetic assays,
and cellular localization experiments. Russ Altman "Challenges for
Biomedical Informatics and Pharmacogenomics, Stanford Medical Informatics,
c.2001
http://www-smi.stanford.edu/pubs/SMI_Reports/SMI-2001-0898.pdf
More than 100,000 people die each year from adverse responses to
medications that are beneficial to others. Another 2.2 million experience
serious reactions, while others fail to respond at all. ... Genomic data and
technologies also are expected to make drug development faster, cheaper, and
more effective. Most drugs today are based on about 500 molecular targets;
genomic knowledge of the genes involved in diseases, disease pathways, and drug-
response sites will lead to the discovery of thousands of new targets. New
drugs, aimed at specific sites in the body and at particular biochemical events
leading to disease, probably will cause fewer side effects than many current
medicines. Ideally, the new genomic drugs could be given earlier in the disease
process. As knowledge becomes available to select patients most likely to
benefit from a potential drug, pharmacogenomics will speed the design of
clinical trials to bring the drugs to market sooner. Medicine and the New
Genetics: Genomic and its impact on Medicine and Society, A 2001 primer, Oak
Ridge National Lab, US http://www.ornl.gov/hgmis/publicat/primer2001/6.html
Genomics is beginning to offer the possibility of more precise patient
stratification and segmentation, as well as the opportunity to revive some
failed candidates, as appropriate patients can be identified and adverse reactors
can be screened out. While pharmacogenomics has always threatened to further
fragment an already fragmented pharmaceutical industry, the possibility of real
savings by more selective use of expensive therapies and identification of non-
responders is quite real.
Disease related tissues, which now seem
very indistinguishable (even to pathologists) may be quite identifiable at the
molecular level. Technologies for measuring differential gene and protein expression
levels in healthy and diseased cells and tissue are emerging and interpretation
of the results is beginning to move into clinical research work.
Researchers at the National Cancer Institute (US) and elsewhere are
working on obtaining more reproducible results and interpreting very noisy
biological data. Discussions on standards are evolving, higher throughput,
more automation and expense are among the challenges.
Greater knowledge of population genetics and population genomics
should also be useful.
From pharmacology + genomics.
Pharmacogenomics overviews & introductions
American Medical Association, Pharmacogenomics http://www.ama-assn.org/ama/pub/category/2306.html
Dept. of Energy, Oak
Ridge National Lab, Pharmacogenomics, 2003 http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml
Promise of
pharmacogenomics http://www.ncbi.nlm.nih.gov/About/primer/pharm.html
National Center for
Biotechnology Information, US, 2001.
Part of NCBI's Science Primer
Public Health
Genetics Unit, UK, 2003 'My Very Own Medicine:
What Must I Know? Information Policy for Pharmacogenetics',
http://www.phgu.org.uk/about_phgu/pharmacogenetics.html
Funded by the Wellcome Trust
Redefining
Genetics
Clearly defined terminology should form the basis for
informative discussions so that the word ‘genetics’ is not demonized. For
example, tests that are specific to disease genes can help diagnose disease,
determine the carrier status of an individual or predict the occurrence of
disease. These are quite distinct from profiles ... which provide information on
how a medicine will be metabolized in an individual. … Language needs to be
more precise so that there can be clarity, especially for public policy debates.
Allen D. Roses "Pharmacogenetics and the practice of medicine" Nature
405: 857- 865 June 15 2000
Biomarkers
The key role of diagnostic, efficacy, and toxicity
biomarkers in drug development is clearly accepted. Biomarkers provide the basis
for developing new diagnostic products, accelerating clinical trials, predicting
disease progression, and enhancing the drug safety profiles by assessing
toxicity and efficacy at the pre- clinical stage.
Pharmacoproteomics
Once you have identified a number of
proteins secreted in sera or urine, you can segregate the proteins by which are
linked to early disease, the onset of metastasis, who does and does not tolerate
treatment, toxic effects, and who is prone to resistance or relapse."
Fundamentally, you establish a pharmacoproteomic profile of an individual. Like
pharmacogenomics, which allows researchers and clinicians to predict the
response of an individual to drug treatment on the basis of his or her genetic
profile, the evolving field of pharmacoproteomics allows drug developers and
clinicians to further subdivide the treated population. Randall C. Willis,
":The Matching Game" Modern Drug Discovery, 5(5): 26-35, May 2002 http://pubs.acs.org/subscribe/journals/mdd/v05/i05/html/05willis.html
Information
resources Pharmacogenomics
Toxicogenomics
Definitions
The study of the structure and output of the genome as it responds to adverse
xenobiotic exposure. Ulrich RG. The
toxicogenomics of nuclear receptor agonists. Current Opinion in Chemical
Biology 7(4) 505- 510, August 2003 [and personal communication]
An emerging discipline that combines expertise in toxicology, genetics,
molecular biology, and environmental health to elucidate the response of living
organisms to stressful environments. Of particular interest to scientists in the
field is the advancement of high- throughput and computational methodologies to
study gene and protein expression at all levels, and the application of this
knowledge to enhance our understanding and therapeutic management of human
illnesses. The promise of toxicogenomics will become a reality as we begin to
fully understand how subtle variations in the environment give rise to altered
phenotypes that compromise organ and system functions. NIEHS, EHP
Toxicogenomics, Jan. 2003 http://ehp.niehs.nih.gov/txg/docs/2003/111-1T/eds/eds.html
Both legal departments and funding sources see the
possibilities of reduced costs as patients susceptible to toxic side effects may
be screened out before receiving a drug and patients now being unnecessarily
over- treated can offset some of the costs of more expensive new drugs.
Toxicogenomics Overviews & introductions
Concept Statement, National Center for Toxicogenomics,
NIEHS http://www.niehs.nih.gov/nct/concept.htm
Toxicoproteomics
The use of global protein expression technologies to better understand
environmental and genetic factors, both in episodes of acute exposure to
toxicants and in the long-term development of disease. Integrating transcript,
protein, and toxicology data is a major objective of the field of
toxicogenomics. KB Tomer, DB Merrick, Toxicoproteomics:
a parallel approach to identifying biomarkers Environmental Health
Perspectives 2003 Aug;111(11): A578- 579.
Identification of patients likely to incur adverse and toxic
reactions is a more complicated situation. Certainly earlier identification of
and knowledge about toxicities will ultimately be useful. But in the short run,
when information will be incomplete it seems less valued.
Information
resources Toxicogenomics
Clinical Trials
Redefining
diseases
The human genome sequence will
dramatically alter how we define, prevent, and treat disease. As more and more
genetic variations among individuals are discovered, there will be a rush to
label many of these variations as disease- associated. We need to define the
term disease so that it incorporates our expanding genetic knowledge, taking
into account the possible risks and adverse consequences associated with certain
genetic variations, while acknowledging that a definition of disease cannot be
based solely on one genetic abnormality. Disease is a fluid concept influenced
by societal and cultural attitudes that change with time and in response to new
scientific and medical discoveries. Historically, doctors defined a disease
according to a cluster of symptoms. As their clinical descriptions became more
sophisticated, they started to classify diseases into separate groups, and from
this medical taxonomy came new insights into disease etiology. K Larissa et. al.
"Defining Disease in the Genomics Era" Science 293 (5531): 807- 808,
Aug. 3, 2001 http://www.sciencemag.org/cgi/content/full/293/5531/807
See
also Redefining diagnosis
Molecular
Medicine
Definitions Molecular Medicine
Recent advances in molecular and cell
biology have enormous potential for medical research and practice. Initially
they were most successfully exploited for determining the causes of genetic
diseases and how to control them. However, it is now clear that recombinant DNA
technology is finding applications in almost every branch of medical practice.
It is revolutionising cancer research, offers new approaches to vaccines, has
spawned a biotechnology industry that is already producing a wide range of
diagnostic and therapeutic agents and, in the longer term, promises to play a
major role in clarifying the causes of some of the unsolved mysteries of modern
medicine: heart disease, hypertension, major psychiatric illness, rheumatic
disease and many others. It should also help us gain insights into broader
aspects of human biology, including development, ageing and evolution. Wetherall
Institute of Molecular Medicine, Univ. of Oxford, UK http://www.imm.ox.ac.uk/pages/about.htm
More
molecular
medicine terminology
Molecular Medicine Introductions & overviews
AMA, Genetics 101, http://www.ama-assn.org/ama/pub/category/4646.html
DOE Dept. of
Energy, Oak Ridge National Lab, Medicine and the
New Genetics http://www.ornl.gov/TechResources/Human_Genome/medicine/medicine.html
NCBI National Center for
Biotechnology Information, Genes and
Disease http://www.ncbi.nlm.nih.gov/disease/
NHGRI National
Human Genome Research Institute, Exploring our Molecular
Selves http://www.nhgri.nih.gov/educationkit/
NIGMS National
Institute of General Medical Sciences, From Molecules to
Medicine http://www.nigms.nih.gov/moleculestomeds/
Sanger Centre, UK
Your Genome.org Beginner
http://www.yourgenome.org/primer/
Molecular
medicine information resources
Emerging medical genomics
specialties
Genomics
and public health
Genomics will cut across virtually all areas of public health. Public health
activities traditionally associated with genetics include newborn screening,
reproductive health, and genetic services. As genomics advances, related public
health activities will include chronic diseases, infectious diseases,
environmental health, and epidemiology. http://www.genomicstoolkit.org/moxie/integrating/whyintegration.shtml
Public
health information resources
Molecular
Diagnostics
Molecular diagnostics definitions
The scope note of the Journal of Molecular Diagnostics
mentions "translation and validation of molecular discoveries in medicine
into the clinical diagnostic setting, and the description and application of
technological advances in the field of molecular diagnostic medicine. The
editors welcome for review articles that contain: novel discoveries with direct
application to clinical diagnostics or clinicopathologic correlations including
studies in oncology, infectious diseases, inherited diseases, predisposition
to disease, or the description of polymorphisms linked to disease states or
normal variations; the application of diagnostic methodologies in clinical
trials; or the development of new or improved molecular methods for diagnosis or
monitoring of disease predisposition." Journal of Molecular
Diagnostics, Association for Molecular Pathology http://jmd.amjpathol.org/misc/ifora.shtml
"The
term molecular diagnostics has a relatively narrow clinical definition, namely,
the use of nucleic acids as analytes in assays designed to investigate given
disease states." Review by Charles P. Cartwright of Molecular Diagnosis
of Infectious Diseases by U. Reischl, Humana Press, 1998, American Journal
of Clinical Pathology Archive. Is this changing?
Molecular Diagnostics Overviews &
introductions
Understanding Gene Testing, National Cancer Institute, US, 2001 http://newscenter.cancer.gov/sciencebehind/genetesting/genetesting01.htm
Our Genes, Our
Choices,
PBS http://www.pbs.org/fredfriendly/ourgenes/
Your genes, your
choices: Exploring the choices raised by genetic research,
Catherine
Baker, part of the AAAS Science + Literacy for Health Project http://ehrweb.aaas.org/ehr/books/index.html
Redefining
"diagnosis"
Allen Roses, worldwide director of
genetics for Glaxo Wellcome [now Glaxo SmithKline] notes that "precise
diagnoses leading to universal specific treatments are, for many illnesses,
myths... for many diseases there is no accurate, single diagnostic test" .
A.D. Roses "Pharmacogenetics and future drug development and delivery"
Lancet 355 (9212):1358-61 Apr 15, 2000
See
also Redefining diseases
Traditionally, diagnostics has been quite distinct from therapeutic
development. Molecular medicine is changing that paradigm, as molecular markers
become increasingly important for understanding disease biology, selecting and
validating targets, and assessing the efficacy and safety of compounds under
development. Such molecular diagnostics have a much greater role, only one of
which involves commercialization and use in patient care. Pharmaceutical
companies are making use of molecular diagnostics within the drug development
process. Strategic Implications of Therapeutically Specific Molecular
Diagnostics, CHI report, 2003
Molecular diagnostic technologies
are likely to have a strong impact on the drug treatment of many major
illnesses. The first molecular diagnostic products to reach the market included
tests for detection for viral RNA or DNA, genetic tests, and tests to determine
risk for developing certain cancers, such as breast or colon cancer. Now, a
wealth of genomic data is enabling researchers to predict a patient's response
to therapy based on the genetic make- up of a tumor (in the case of cancer), or the
viral genotype..
HIV genotyping is an early example of how
treatment decisions are made based on the genotype of the virus. Genetic
polymorphisms of certain cytochrome P450 enzymes can affect how a patient
metabolizes certain drugs, and thus can affect effectiveness or toxicity of
these drugs in certain patients. Potential applications for emerging molecular
diagnostics tests include viral genotyping for drug resistance, cancer diagnosis
and prognosis, disease susceptibility and prediction, diagnosis of inherited
genetic disorders, prediction of drug response, and identity/forensic testing.
Molecular pathology
The collection and analysis of tissue samples is a long- established
technique in pathology. What is new in "molecular pathology" is the
emphasis on assessing gene expression in addition to morphology, and the
use of gene expression analysis to validate large numbers of targets. (However,
histochemistry and immunohistochemistry have been used, for specific
proteins, since before the advent of genomics.) Corporate genomic researchers
are increasingly seeking access to human tissue samples via collaborations with
pathology departments at clinical research institutions
Genomics related diagnostics are apt to precede therapeutics for
some time to come. A trickle of approved drugs
(mostly for fairly rare conditions) has begun. Look for progress to be difficult to
predict and nonlinear for some time -- but physicians and patients are apt to be
surprised by the speed with which medical decisions are affected. That doesn't
mean the decisions will necessarily be easy. They will almost certainly involve
balancing various tradeoffs.
Genetic and Genomic testing
Extensive media coverage of genomic discoveries has fueled the public
appetite for personalized medicine and a rush to develop and market new genomic
tests,
often without the necessary intervening research. Public health sciences have an
important role in evaluating the validity and utility of genomic tests, which
include not only DNA- based tests for single gene variants, but complex
genotypes, tests for acquired mutations, and measures of gene expression, from
RNA microarrays to biochemical assays. Before a genomic test can be used for
epidemiologic research or clinical practice, laboratory comparison with a gold
standard must demonstrate analytic validity. Epidemiologic studies are needed to
establish clinical validity (sensitivity, specificity, and predictive value).
Research Priorities for Public Health Sciences in the Post- Genomic Era, Marta
Gwinn and Muin J. Khoury, Centers for Disease Control, US Genetics in
Medicine 4(6): 410- 411, 2002 http://www.cdc.gov/genomics/info/reports/research/priorities.htm
Molecular
diagnostics information resources
What do
we know now?
Weather may be a good metaphor for what we can hope to do with genomics,
proteomics and
informatics. We can predict and track hurricanes a lot better than we could 100
(and even 25) years ago. Modern building codes have reduced property damage
and mortality rates. But we are still far from being able to stop storms (or
earthquakes) or prevent them.
Are we really post-genomic yet?
We know something about monogenic
diseases, with high penetrance. Do we really know anything about polygenic
diseases with varying penetrance?
We are just starting to learn about
genetic trade-offs (such as heterozygotes for sickle cell trait being more
resistant to malaria).
We are post-Mendelian.
The more
we know, the more we realize we still have to understand.
Nobody can be experts in all the disciplines
relevant to
biopharmaceuticals today. We need people who are good at
communicating across information silos. Artificial intelligence has been
struggling to agree on unambiguous, mutually exclusive, disjoint definitions for
medical terms for 30 years. A combination of automation and human interventions seems
likely to produce the best results.
Multi-disciplinary
and inter-disciplinary challenges
Genomic success stories (still being written)
Herceptin
Gleevec
Antimicrobials:
MD DeBacker , P Van Dijck, Progress in functional genomics approaches to
antifungal drug target discovery, Johnson & Johnson Pharmaceuticals Group,
Trends in Microbiology 11(10): 470-478, Oct. 2003
As traditional drug screening on existing targets is not delivering the long-
awaited potent antifungals, efforts to use novel genetics and genomics- based
strategies to aid in the discovery of novel drug targets are gaining increased
importance. The current paradigm in antifungal drug target discovery focuses on
basically two main classes of targets to evaluate: genes essential for viability
and virulence or pathogenicity factors. Here we report on recent advances in
genetics and genomics- based technologies that will allow us not only to
identify and validate novel fungal drug targets, but hopefully in the longer run
also to discover potent novel therapeutic agents. Fungal pathogens have
typically presented significant obstacles when subjected to genetics, but the
creativity of scientists in the anti- infectives field and the cross- talk with
scientists in other areas is now yielding exciting new tools and technologies to
tackle the problem of finding potent, specific and non- toxic antifungal
therapeutics.
There are
exciting signs of progress -- but only for a limited number of patients and
conditions right
now.
As Cohen
wrote in Science, use of the term "new paradigm" has
grown exponentially. How many changes are truly new is
questionable. But mixed in with incremental changes are the truly new and
profoundly different approaches. J Cohen "The March of Paradigms" Science 283 :
1998-1999 Mar 26, 1999
Information resources
Genomics Proteomics
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discovery & development Chemical
genomics Pharmacogenomics
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Technologies
Molecular
Medicine Business
What are genomics
and proteomics chemical
genomics pharmacogenomics toxicogenomics bioinformatics
cheminformatics