Welsh School of Pharmacy Cardiff University Ysgol Fferylliaeth Cymru Prifysgol Cerdydd

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Welsh School of Pharmacy Cardiff University
Ysgol Fferylliaeth CymruPrifysgol Cerdydd
Professor / Yr Athro Stephen Denyer Head of
School / Pennaeth yr Ysgol
Dr K T Wann Director of Postgraduate Research
Studies
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Discoveries from the deepDarganfyddiadau or
eigion Dr Ken Wann (Wann_at_cardiff.ac.uk
)

• The Marine Laboratory experience
• The animal model systems
• The applied medical value

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The Worlds Marine Laboratories Labordai Môr y
Byd

• Plymouth, UK - home of the MBA
• Woods Hole, Cape Cod, USA - home of the MBL
• Bermuda Biological Station for Research

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Plymouth, UK Marine Biological Association
Cymdeithas Fiolegol y Môr y DU
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MBA School Visits Ymweliadau Ysgolion CFM
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Plymouth Cell Physiology Workshop (Sept each
year) Gweithdai Ffisioleg Celloedd yn Plymouth
(Medi bob blwyddyn)
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Woods Hole USA / UDA

• The MBL

• The heroes
• squid crab

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Bermuda Biological Station for ResearchGorsaf
Ymchwil Fiolegol Bermuda

• The laboratory

• A field course

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How does the brain work?
Sut maer ymennydd yn gweithio?
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• Brain cells in action
• electrical activity

• Celloedd yr ymennydd yn gweithio
• actifedd trydanol

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How do we see? / Sut ydyn nin gweld?
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Big questions in Neuroscience Cwestiynau mawr
mewn Niwrowyddoniaeth
What is consciousness? Beth yw ymwybod? What
are emotions? Beth yw emosiynau? What
is depression? Beth yw iselder ysbryd?
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The Worlds Marine Heroes and Heroines Arwyr ac
Arwresau Môr y Byd
They have helped us understand these questions
Maen nhw wedi ein helpu i ddeall y cwestiynau hyn
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Nobel Laureate in MedicineNobel Llawryfog mewn
Meddygaeth

• Squid - Loligo

• Hodgkin, Huxley 1963

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Nobel Laureate in Medicine Nobel Llawryfog
mewn Meddygaeth

• Crab - Limulus

• Hartline, 1967

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Nobel Laureate in Medicine Nobel Llawryfog
mewn Meddygaeth

• Sea hare -Aplysia

• Kandel, 2000

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Taming the nerve impulseDofi cynhyrfiad y nerf

• Largest animal cell (escape response)
• insert an electrode inside the cell interior
• measure the resting membrane potential
• measure the conducted action potential (the all
  or none message of the nervous system)

• The squid

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Nerves are specialised for conductionMae nerfau
wediu harbenigo ar gyfer dargludiad
Ask your GP about the squid giant axon? Ask the
anaesthetist about nerve conduction?
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The basis of Bioelectric PotentialsSylfaen
Posibliadau Biodrydanol

• How do neurones conduct?
• Gated movement of ions through ion channels
  control the process.
• Changes in ionic permeability occur.

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Defining the nerve cell messageDiffinio neges y
nerfgell
The action potential height depends on the
external Na ion concentration? Na ions move into
the cell causing depolarisation
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Conduction in non-myelinated (A) and myelinated
(B) nerve, by local circuit current flow, from an
active region to a resting area of membrane
A
B
The impulse skips from node to node Multiple
Sclerosis?
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Talking between nerve cells the synapseSiarad
rhwng nerfgelloedd y synaps

• Giant synapse in squid

• Electrical recording from both the pre- and post
  synaptic elements

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Memories are made of? Gwneir atgofion o?

• The sea hare

• 20,000 nerve cells (large)
• simple defensive reflexes which can be trained
  (gill withdrawal)
• measure directly strength of communication in a
  pathway during a simple learned response

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Seeing is believing?A wêl a grêd?

• Simple eye - a few photoreceptors
• large superficial optic nerve, 4 inches long
  making eavesdropping on electrical activity easy
• contrast is due to lateral inhibition

• Why Limulus?

Ask your optician about crab vision
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Natures chemical experiments -learning from the
master (mistress) Arbrofion cemegol byd natur
dysgu or meistr (or feistres)

• Toxins - tetrodotoxin / conotoxins / brevetoxin
• Statins - bryostatin, dolastatin, spongistatin
• Photoproteins - aequorin / pholasin
• Polymers - chitin (drug formulation / delivery)
• Adhesives - polyphenolic proteins

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Na channel modulatorsModylyddion Na channel

• Puffer fish - TTX

• Specific Na channel blocker
• Local anaesthetic / analgesic (nerve)
• anti-convulsant (brain)
• anti-stroke (brain)
• anti-arrhythmiac (heart)
• anti-metastatic (cancer)

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Harmful Phytoplankton Toxic(Red Brown
Tides)Ffytoplancton Niweidiol Gwenwynig
(Llanw Coch a Brown)
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Pain killers from marine snails Poenladdwyr o
falwod môr

• Cone snail

• deadly venom of conotoxins
• arsenal of 50-150 small peptides
• potent non-addictive pain killer (ACV1)
• Neurex - phase II / III clinical trials
  (intractable pain)

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Cancer cures from the deep?Triniaethau cancr or
eigion?

• Arizona State University

• Marine organisms dont get cancer ?

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Marine treasure chest of statins Cist
trysoraur môr o statinau

• Bryostatin 1 (ship fouling barnacle) - Phase II
  clinical trials
• dolastatin 10 (sea hare) - Phase I
  clinical trials
• spongistatin (sponge) -
  Preclinical development

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What about medicinal products from local marine
organisms? / Beth am gynnyrch meddyginiaethol
o organeddau lleol y môr?

• Marine organisms produce a variety of secondary
  metabolites with medicinal properties.
• Compounds with therapeutic potential in cancer,
  pain relief, inflammation, Alzheimers and asthma
  have been reported.
• Currently, 16 marine natural products are under
  evaluation in clinical trials as anti-cancer
  agents1

Spongo-thymidine
Hymenialdisine (Preclinical)
Cytarabine Current Clinical Use
Bryostatin 1 (Phase 2)

• The chemical diversity of natural products is a
  good source of lead compounds for medicinal
  chemistry.

1 Newman, D.J. Cragg, G.M. Curr. Med. Chem.
(2004), 11, 1693-1713.
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Gower Collection / Casgliad Gwyr

• British marine organisms are largely unexplored
  a preliminary study to investigate the potential
  for discovery of anti-cancer compounds from local
  sources has been commenced now.
• Sponges are common to the west coast of the UK
  an orange encrusting sponge (Hymeniacidon sp.)
  was collected from the Gower Peninsula.

• The organism is common in small quantities in
  rock pools and at the low tide line.

• AIM
• Conduct a bioassay-guided fractionation of
  sponge extracts and determine if they possess
  anti-cancer activity. Ultimate aim is the
  isolation and characterization of any active
  components.

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The future looks promising
Y dyfodol yn edrych yn
obeithiol

• Excellent anti-proliferative activity has been
  discovered in crude extracts from a UK sponge 96
  growth inhibition observed in both lung and
  breast cancer cell lines.
• The activity seems to residue in the polar
  fractions.
• CFUX3 and CFUX9 could contain the same active
  component both displayed similar activity
  against both cell lines, and have similar TLC
  Rfs (baseline)

• These compounds may provide a unique natural
  product or suggest leads for further study.

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Algae and spongesAlgâu a sbyngau

• dinoflagellate
• poriferans

• Sources of okadaic acid (PP inhibitor)
• endocrine disrupter / tumour promoting

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A master
Chitosan
Hormone patches ?
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Drug delivery / formulationCyflenwi /
fformiwleiddiad cyffuriau

• blue crab
• chitin / chitosan

• Control the release of drugs - orally / nasally
  / transdermally
• ingredient of tablets
• aids wound formation, reduces fat absorption and
  serum cholesterol

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Drug delivery making barriers leaky
Cyflenwi cyffuriau gwneud rhwystrau yn ridyllog
Artursson P, Lindmark T, et al. Pharm Res
1994,11(9)1358-61
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Bioluminescence Bywoleuni
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Bioluminescence Bywoleuni

• Light produced by a chemical reaction within an
  organism
• mostly a marine phenomenon (prime light source in
  deep sea)
• in the deep ocean 80 of life glows

• luminescent jellyfish
• photoprotein aequorin

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Marine molluscs glow too Mae
molysgiaid môr hefyd yn disgleirio

• pholus dactylus

• photoprotein - pholasin
• emits light in response to reactive oxygen
  species, very sensitive to free radicals
• signals oxidative stress (inflammatory disease,
  vascular surgery, sports medicine)

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Lessons from the master how to make glue
Gwersi or
meistr sut i wneud glud

• Mytilus edulis
• mussels foot scrubs, spins a new byssal thread
  and varnishes to protect

• Cell-Tak mimics mussel glue (polyphenolic
  proteins)
• repair corneas / retinas
• dental fillings

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A Pembrokeshire database species , genes, gene
products
Marine Pharmacy ?
The End and thank you Y Diwedd a diolch yn fawr