Schering-Plough Corporation (SP) is a research-based company engaged
in the discovery, development, manufacturing and marketing of pharmaceutical
products worldwide. SP is also one of the ten largest US based pharmaceutical
companies and in 2001 its annual revenue was about $ 9,800 million,
of which, more than 10% was invested in R&D activities ($ 1,200
million). Schering Plough's R&D operations are managed by the
scientific arm of the Corporation: the Schering-Plough Research
is located worldwide and it is involved in seven major therapeutic
areas: allergy, immunology, infectious diseases, oncology, central
nervous system, cardiovascular and gene therapy. The headquarters
are in Kenilworth, New Jersey. All of the therapeutic areas are
covered at this site and professional expertise range from initial
Drug Discovery to full clinical development. There are two additional
New Jersey sites which are closely linked to Kenilworth: one is
in Madison (Pharmacy) and the other in Lafayette (Pre-clinical development).
There are also additional US sites in California, one is in Palo
Alto near Stanford University (DNAX, focused on immunology, new
protein discovery, cell signalling and gene targeting technology)
and one in San Diego (Canji focused on gene therapy). European SPRI
sites are in France (Dardilly, near Lyon) specialised in immunology
research, Switzerland (Schachen, near Luzern) devoted to chemical
and biotechnological development and Milan focused on Neuroscience.
addition to the above, extensive support to the internal research
programs is given by strategic alliances with external centres of
excellence. These include Human Genome Sciences, Genome Therapeutics,
Incyte, Myriad Genetics, Transgène, Deltagene to name but
The Italian Research Centre
and its organisation
The Italian unit of the SPRI is located within the San Raffaele
Biomedical Science Park in Milan. The centre has a long-standing
reputation in neuroscience research as supported by publications
and patents in the area. In the past, activity was spread over different
disease areas such as Parkinson's, Alzheimer's, stroke and neuropathic
pain but in 2001, a significant operational reorganisation was undertaken
in order to optimise the chance of success.
first strategic change was to take responsibility of projects in
the neuropathic pain area only. This means that all our efforts
are focused on a single disease, with the aim of reaching a critical
mass. Three technology platforms have been created to develop the
technologies necessary to support the activities from target identification/validation,
through hit identification, and lead optimisation as required by
the new assignment. The technology platforms were identified based
on areas of expertise and the various phases of the process. These
include Neurobiology, Molecular Cell Biology and Neuropharmacology
the new organisation the Neurobiology section was designed to support
the early phases of target identification and validation. This role
was covered by developing expertise in the analysis of gene and
protein expression. Gene expression is studied using two complementary
techniques, real time PCR that allows a quantitative analysis of
expression and in-situ hybridization which permits transcripts to
be localized to the single cell level. Biochemical techniques such
as FACS, immunocytochemistry, histological staining and western
blotting are also routinely used to analyse the pattern of distribution
and the expression level of proteins.
The Molecular and Cell biology section is charged with supporting
the later stages of target validation, the hit/lead identification
and the lead optimisation phases in-vitro. This has been achieved
by developing cutting edge technologies to clone and transfect target
genes into appropriate cell systems (to obtain transient or stable
cell lines for functional and/or screening studies) and by gaining
expertise in the development of relevant cell based assays. With
regards to cell based assays, a major advancement has been the acquisition
of state-of-the-art instrumentation known as Flipr (Fluorometric
Imaging Plate Reader). This automated equipment can test up to 10,000
samples a day thus allowing a medium to high throughput capability
to run, full screening programs for new chemical entities entirely
The role of the Neuropharmacology section is to support the target
validation and the lead optimisation phases in-vivo. This is being
achieved by developing expertise in the identification, setting-up
and running of the relevant disease animal models to investigate
the pathophysiogy of neuropathic pain as well as to test new chemical
a key feature of the re-organisation of the Italian research centre
has been the full integration into the Schering-Plough drug discovery
strategy and process. To this aim interactions with SPRI headquarters
are implemented on a regular basis by teleconferences, videoconferences
and frequent exchanges of researchers between facilities.
area of interest: neuropathic pain
The Italian unit has been given the lead of neuropathic pain research.
In this disease current medications are not always fully effective
and since none of them has been specifically designed for chronic
pain, their use is often associated with significant side effects.
Therefore, the identification of relevant medicines for neuropathic
pain is a significant opportunity both scientifically and commercially.
Pain is a subjective and multidimensional experience comprising
several components: sensory (e.g. intensity, duration, location),
affective (e.g. unpleasantness, emotional, motivational) and cognitive
(e.g. awareness of the implications, fear, anxiety). In most cases,
the sensation of pain is produced either by stimuli which are intense
enough (noxious) to cause tissue damage, or by nerve injury. The
perception of pain can be influenced by many different factors that
can be, by themselves, major determinants of pain, e.g. psychological
factors. A formal definition of pain has been proposed by the International
Association for the Study of Pain subcommittee on taxonomy that
describes pain as "a highly subjective, unpleasant sensory
and emotional experience associated with actual or potential tissue
damage or described in terms of such damage". Chronic pain
is elicited by peripheral damage due to injury or to a disease and
it has more serious consequences than acute pain since damage overwhelms
the body's repair capabilities, as it is often associated with the
disruption of nerve endings. Chronic pain is a consequence of several
clinical disorders, it afflicts a large proportion of the population
and despite the remarkable advancement in understanding the disease
it still remains an area of highly unmet medical need.
commitment to excellence
SPRI firmly believes that a successful research group always needs
to be at the front edge of the discovery effort and has to keep
updated with technological evolution. To reach this objective the
confrontation with the external research environment is essential
and it takes place through participation at international scientific
meetings, collaboration with groups in academic institutions and
the organisation of seminars with leading scientists. In order to
enrich the research environment in the Milan group, foreign scientists
are encouraged to join the centre. One of the opportunities offered
to foreign scientists is the possibility to undertake post-doctoral
fellowships. These are granted to our centre by the European community
to help recruit young and talented researchers from other European
As in any company the experimental work is performed under strict
confidentiality rules. This is to prevent the possible premature
disclosure of information that could damage the competitive position
of Schering-Plough. However, publication of experimental results
obtained during the research effort is an important opportunity
to communicate to and interact with the scientific community as
well as to establish a solid, worldwide reputation in the disease
areas of interest. These aspects are fundamental to the development
of a successful research program not only in the academic environment
but also in the Pharmaceutical industry. Therefore, publication
of experimental results is encouraged to assure that the group has
the necessary visibility and integration into the international
scientific community. The fact that our research group has published
more than 40 articles in the last five years is a testament to this
ethos. We are however are also acutely aware of the commercial implications
of our research and to this end have contributed significantly to
the company patent portfolio by filing several patents.
of selected publication of the last three years
M, Sciorati C, Tarozzo G, and Beltramo M Flow cytometry analysis
of inflammatory cells in the ischemic rat brain. Stroke (2002) 33:586-592.
G, Campanella M, Ghiani M, Bulfone A, and Beltramo M Expression
of fractalkine and its receptor, CX3CR1, in response to ischaemia-reperfusion
brain injury in the rat. Eur. J. Neurosci (2002) 15:1-7.
MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R,
Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki
S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson
GA, George-Hyslop PS, and Westway D Early-onset amyloid deposition
and cognitive deficits in transgenic mice expressing a double mutant
form of amyloid precursor protein 695. J Biol Chem. (2001) 276(24):21562-70.
L, Briscini L, Ongini E, and Bertorelli R The putative OP(4) antagonist,
[Nphe(1)]nociceptin(1-13)NH(2), prevents the effects of nociceptin
in neuropathic rats. Brain Res. (2001) 905:127-33.
Yacoubi M, Ledent C, Parmentier M, Bertorelli R, Ongini E, Costentin
J, and Vaugeois JM Adenosine A2A receptor antagonists are potential
antidepressants: evidence based on pharmacology and A2A receptor
knockout mice. Br J Pharmacol. (2001) 134:68-77.
RI, Rabuffetti M, and Beltramo M Cannabinoids and neuroprotection.
Mol. Neurobiol. (2001) 24:(1-3):29-52.
R, Calo G, Ongini E, and Regoli D Nociceptin/orpanin FQ and its
receptor: a potential target for drug discovery. Trends Pharmacol
Sci. (2000) 21:233-4.
F, Corradini L, Smith RD, and Bertorelli R Nociceptin attenuates
opioid and gamma-aminobutyric acid (B) receptor-mediated analgesia
in the mouse tail-flick assay. Neurosci Lett. (2000) 292:83-6.
M, Diodato E, Lozza G, Brusa R, Casarini M, Uberti D, Rozmahel R,
Westaway D, St George-Hyslop P, Memo M, and Ongini E. Presenilin-1
regulates the neuronal threshold to excitotoxicity both physiologically
and pathologically. Proc Natl Acad Sci U S A. 2000 97(23):12822-7.
M, Sciorati C, Tarozzo G, Clementi E, Manfredi AA, and Beltramo
M Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-Chloromethyl
ketone induces long-lasting neuroprotection in cerebral ischemia
through apoptosis reduction and decrease of proinflammatory cytokines.
J. Neurosci. (2000) 12:4398-4404.
M, Barbieri I, Basudev H, Brusa R, Casati C, Lozza G, and Ongini
E Interleukin-10 modulates neuronal threshold of vulnerability to
ischaemic damage. Eur J Neurosci. (2000)12(7):2265-72.
M, and Memo M Possible role of NF-kappaB and p53 in the glutamate-induced
pro-apoptotic neuronal pathway. Cell Death Differ. (1999) 6(1):22-7.
R, Corradini L, Rafiq K, Tupper J, Calo G, and Ongini E Nociceptin
and the ORL-1 ligand [Phe1psi (CH2-NH)Gly2]nociceptin(1-13)NH2 exert
anti-opioid effects in the Freund's adjuvant-induced arthritic rat
model of chronic pain. Br J Pharmacol. (1999)128:1252-8.