Current Opinion in Investigational Drugs

14
Editorial overview
The genome: Five years on
Michael Williams
Address
Department of Molecular Pharmacology and Biological Chemistry
Feinberg School of Medicine
Northwestern University
Chicago
IL 60611
USA
Email: mazarine1643@comcast.net
Current Opinion in Investigational Drugs 2006 7(1):14-17
© The Thomson Corporation ISSN 1472-4472
In 2001, one of the major milestones in the history of
biomedical research was achieved, namely the publication of
draft maps of the human genome [1,2], an activity that was
reportedly completed in 2003 [3]. This was inevitably
accompanied by various predictions that the discrete
molecular source of all human diseases would soon be
known [4-6] and, as a consequence, that the path to the
discovery of novel, more efficacious and safer drugs, based
on as yet unknown and unproven targets resident in the
genome, would be exponentially more facile, more
productive, faster and cheaper, owing to the unique diseaseassociation
of the targets. The then US President, Bill
Clinton, predicted that 'with this new found knowledge,
humankind is on the verge of gaining immense new power
to heal' [7]. Conversely, recent research by Accenture/CMR
International notes that 'only 3% of projects aimed at new
targets will enter preclinical development compared with
17% for projects on established targets' [8].
Almost five years later, an informal survey of 500 scientists
involved in the drug discovery process found that 67% were
unconvinced that the genome maps had 'even moderate
effects on drug research' [9]. Similarly, biotechnology
industry observers and genomic scientists cautioned that the
promised 'fruits of genomics' [10] are unlikely to emerge in
the near future, with a 10 to 20 year timeframe being
considered more likely [11].
Additionally, in following the theme of using novel
approaches to finding new drugs, in this same group of 500
scientists, 64% 'considered that their organization, at best,
only supported innovation to a moderate extent' [9], echoing
similar comments made by Drews [12] and Vagelos [13].
This finding indicated a disconnect between the concept of
innovation−'the act of introducing something new'−that is
religiously cited as the driver for drug discovery [8,14], and
the rampant technology acquisition and implementation in
the biotech and pharmaceutical industries over the past
decade. Clearly, the acquisition of enabling technologies is
very distinct from their effective use and subsequent ability
to impact the way things are done. In reflecting on the
contributions of the late Paul Janssen to the pharmaceutical
industry, Black noted that successful drug discovery should
avoid 'wishful thinking' and superficiality, and focus instead
on conception, concentration, commitment and creativity
[15]. In this context, the strategic management of the
drug-discovery process appears critical to support the
process of innovation and entrepreneurship [16] to ensure
that the enabling technologies actually contribute to, rather
than diffuse, the focus.
As with many of the new technologies in biomedical
research, the expectations for genome-based information
have far outweighed their fledgling status with 'overhyping'
being a frequently expressed concern [17-20]. Genetics was
described as a 'science of exceptions' by Jones in 2000, with
human life expectancy far more dependent on the
environment (epigenetics) than the genome (genetics) [17].
Jones also noted that geneticists have made promises
regarding the deliverables in genetics for decades,
controversially suggesting that four letters of the genetic
code might more reasonably be H, Y, P and E.
However, hype related to new technology introductions is not
unique to either the genome or biomedical research and has
been formalized in Fenn's 'hype cycle' (Figure 1) [21]. Initially
used in 1995, the concept has been more broadly extended to
the maturity and adoption rates of a wide range of emerging
technologies in different industries. The question for the
genome-based, biomedical research enterprise in 2006 is where
genome-based drug discovery currently lies on the maturity
scale. One may argue that the thought leaders in genomics are
still operating in the 'peak of inflated expectations', while those
reducing the genome to practice (by fiat or choice) in pharma
and biotech are operating in the 'trough of disillusionment'
(Figure 1) [9]. The sceptics are at least ahead of the pundits on
the hype cycle abscissa of maturity.
While many heritable disorders have already been identified in
which a mutation in a single gene is necessary and sufficient to
produce a disease, critics of genome-based drug discovery have
pointed out that the genetic associations for Huntington's
disease [22], sickle cell anemia [23] and cystic fibrosis [24] were
known before the mapping of the genome and, despite the
identification of discrete molecular lesions involving these
associations, have yet to yield effective treatments. Similarly, in
the Alzheimer's disease (AD) field, the two key mechanisms
thought to contribute to disease progression and neuronal
death−amyloid β deposition and tau hyperphosphorylation
[25]−together with the genetic association of AD with
apolipoprotein E alleles [26], have been active research targets
for many years with, again, little progress having been made in
either understanding the origin and contribution of the
molecular lesion to disease etiology or how this knowledge can
be used to find effective treatments. Of additional concern in
the area of AD therapeutics is that the National Institute for
Health and Clinical Excellence in the UK has recently
recommended that the drugs currently approved for use in the
treatment of AD (eg, donezepil) are no longer prescribed,
because their benefit to the patient does not justify their cost
[27]; the implications of this recommendation represent part of
a much broader debate [28].