Discovery through Innovation Manchester Institute of Discovery through Innovation Research at the Manchester Institute of Biotechnology

Contents Grand Challenge: Biomedical and Healthcare 43 12 Innovation in Action

45 Grand Challenge: Research Centres, Institutes and Facilities Industrial Biotechnology 48 18 Postgraduate and Training

51 Grand Challenge: Science and Society 22 Biofuels and Energy 53 Faculty Honours

57 Selected Publications Spotlight: 26 Centre for Office of the Director

Nigel Scrutton Director Spotlight: Lesley-Ann Miller Communications Manager Systems Biology Rosalind Le Feuvre Research and Planning Manager 31 Penny Johnson Research Strategy Co-ordinator (EU and Industry)

Janet England Support Services Manager Spotlight: Editor Lesley-Ann Miller 34 Text Mining Design & Production WeAreCreation.co.uk Spotlight:

www.mib.manchester.ac.uk Technologies [email protected] 37

3 Manchester Institute of Biotechnology Driving discovery through innovation

Fig. 1.0 Discovery through The Manchester Institute of Biotechnology inform and are informed by our research Grand Challenges and showcasing a Innovation Pipeline (MIB) is one of the leading biotechnology at the molecular, systems and design levels selected portfolio of projects that illustrate research institutes in the world. Focusing on as illustrated in our Discovery through the diversity, quality and dynamism of advanced quantitative approaches to specific Innovation Pipeline (fig 1.0). our research teams. Our reputation as an biotechnology challenges at the interface, international leader in the biotechnology We pursue and are actively engaged in the MIB enjoys a unique pluralistic and open field is evidenced with over 1400 Harnessing the synergy of interdisciplinarity challenging research projects that enable research culture that is realised through a publications, since 2009, in major journals us to make significant advances in science Focusing on specific challenges in biotechnology the co localisation of researchers from distinct coherent and integrated research concept and the impact of the Institute’s research is and engineering to benefit industry disciplines generates interdisciplinary teams with unique capabilities. and the establishment of a unique multi- and evident from a sustained commitment to the and society. Our track record in driving inter-disciplinary community of researchers successful translation of basic science into major interdisciplinary programmes in commercial success. committed to working across discipline Design promotes interaction biotechnology has attracted more than boundaries. The Manchester Institute of £90M in external funding since MIB’s As a leading industry-interfaced Reflecting the needs of interdisciplinary science, the MIB features open-plan, multifunctional Biotechnology is committed to inception in 2006 and our portfolio biotechnology institute we are proud to laboratories and extensive specialist research facilities. The MIB is based at the John Garside the pursuit of research excellence, continues to grow substantially primarily engage in technology transfers and have Building and houses over 500 research staff education, knowledge transfer through a ‘tightening’ of our focus in areas a number of strategic partnerships with and students from 52 research groups from Discovery through innovation and discovery through innovation of core strength (industrial biotechnology; companies from the chemical, biotechnology across The from Delivering internationally recognised programmes across all disciplines, with a strong emphasis whereby a coherent and integrated synthetic biology; catalysis science; systems- and biopharmaceutical sectors to translate the Faculties of Engineering and Physical on translational research, knowledge transfer and discovery through innovation. interdisciplinary research community based research; biomedical biotechnology; research council funding into products and Sciences, Life Sciences, and Medical and work towards developing new fuels and energy research), and supported services for the betterment of all people and Human Sciences. With a strong emphasis on that will find by strategic recruitment to new leadership the environment across the globe. Innovation in action translational research, knowledge transfer applications in areas such as human positions in the Institute. and discovery through innovation our Nigel Scrutton Advancing economic and societal development through knowledge generation and transfer. health, the energy economy, food philosophy has placed us in a strong position Our research strengths are showcased in Director Enabling companies of all sizes to benefit from our research technology and expertise. security, industrial transformations and to address a series of Grand Challenges that the ensuing pages defining our research Exploiting commercially significant innovation through licensing and the creation of spin-out/spin-ins. the environment.

4 5 The University of Manchester

Our goal, outlined in the Manchester 2020 quality of our research activity is unrivalled pioneering approaches to major global strategic plan, is to establish the University as in the UK. We have a distinguished history challenges in biotechnology it has evolved a major centre for interdisciplinary research. in research, innovation and enterprise into one of the leading biotechnology The large scale and quality of our activity at stretching back over 180 years with many of research institutes in the world. Manchester sets us apart. We are able to the major advances of the twentieth century We are committed to enhancing the lives combine disciplines and capabilities to meet having been discovered at the University. of all people, through knowledge transfer both the challenges of leading-edge research Our institutes carry responsibility for several and education and this commitment is and the external demands of society, of the University’s key research priorities, firmly embedded in the global challenges business and other stakeholders. working in areas where we have achieved that constitute the unique research vision The University of Manchester is one of or aspire to world-leading status. The of the MIB whose role is integral to the the world’s leading centres for biomedical Manchester Institute of Biotechnology was advancement of the research mission of the and biotechnology research that sits at the the first university-based, purpose-built University. forefront of new discoveries in science and interdisciplinary research institute of its kind Luke Georghiou engineering. Research is at the heart of the in the UK. Through the establishment of Vice President for Research University and the sheer scale, diversity and multi-skilled interdisciplinary teams applying

Expanding cross campus in spectroscopy through Professor Peter In a programme funded by the EPSRC the MIB collaboration Gardner. Our systems/modelling/text mining engaged in a suite of short-term speculative of modern cell sorters the relatively small on the design of these filter stages, and activities continue to assemble cross-faculty activities to consolidate the cross-disciplinary Stem cell fractionation using numbers obtained and the addition of use cutting edge science and technology We continue to develop collaborations across teams of researchers to deliver innovative culture within the Institute. In one project, interactions with artificial matrices labelling reagents mean that these methods to generate a completely new approach to the University campus with current research research at the forefront of medical Professor Peter Gardner in collaboration with There has been a recent explosion in interest are not suitable for widespread application of stem cell purification. Specialist techniques grant funding aligned with 83 research biotechnology. Professor Mark Dunne (FLS) differentiated four in and potential applications of stem cells. stem cell therapy. Stem cells have yet to find such as microfluidics, nanotechnology, rapid groups from all four Faculties. Recent separate cell lines in pancreatic stem cells using Their potential for therapeutic medical global application, because of their rarity. This microstructure prototyping will be combined funding successes and applications endorse FTIR cell population imaging technologies. applications is particularly exciting, with project proposes to change the current stem with the latest ideas in cell a closer alliance with other University of Cross-disciplinary feasibility the real prospect of growing replacement Manchester Institutes: Photon Science Following on from earlier work led by cell sorting methods from low throughput and cell biorecognition to fulfil the primary tissue and bone to overcome a wide variety Institute, Manchester Institute of Innovation There are numerous areas of research within Professor John Vickerman which utilised one-by-one techniques to very high objective of making it easier, cheaper and of disease conditions. Stem cells also have Research, and the Institute for Science, the biological and biomedical field that imaging for 2D and 3D throughput alternatives that will be capable faster to harvest useful stem cells. The benefit an important role in diagnostics, and have Ethics and Innovation. The development of require the ability to quantitatively analyse cellular characterisation in an Alzheimer’s of sorting millions of cells simultaneously. to society will be huge, making the possibility already shown promise in drug discovery our synthetic biology (SynBio) activity has single cells and large cell populations. study, Professor and Professor The key to this will be the design of a series of stem cell therapy a reality for everyone. research. To date, the key limitation to developed closer alliances with members of For example, metabolomic studies have Nick Lockyer will join a collaborative team of filters that behave as smart sieves. The the exploitation of stem cells has been This is an EPSRC funded project involving the Faculty of Humanities and broader, more the potential to yield understanding of of researchers from FLS led by Professor stem cells will be poured through new filters their scarcity. Furthermore, even when it is partners from across the University: comprehensive, links with the Faculty of complex disease processes, drug toxicity and Alan Dickson that will seek to describe and that will recognise the cells by their shape, possible to source stem cells, there is still the Professor Nick Goddard in collaboration Engineering and Physical Sciences and with cellular function whilst the development of understand the heterogeneity of stem cell size, flexibility and their chemical signature, formidable task of purification and sorting with Cathy Merry (Materials), the Faculty of Life Sciences. Our interactions innovative tools for accurate measurement populations at the molecular level. A stem without the addition of any extra reagents. of the usable cells from cells that have Cay Kielty (FLS), Tony Day (FLS), Chris Ward with the Faculty of Medicine and Human of transcripts and proteins necessitates novel cell model has been selected that has major A set of filters will be assembled; one on differentiated into unusable types. Presently, (Dentistry) from The University of Manchester Sciences have developed significantly sample handling, analyte amplification and significance in finding a potential cure for top of the other, to allow rapid screening of stem cells are labelled with markers and and Professors Steve Eichhorn from the through the appointment of Professor use of miniaturisation and microfluidics to diabetes, but which also serves as a model a mixture that contains both the valuable then sorted one-by-one using very expensive University of Exeter and Peter Fielden from Clare Mills, but also in the assist with high throughput measurements to for the general progression of stem cells wanted stem cells, alongside less useful instruments. Despite the very high speed Lancaster University. area through Professor Roy Goodacre and achieve sensitive detection. towards a specific functional fate. cells. This research programme will focus

6 7 and carbon dioxide to engine-ready and activity of open-source software. The determinants of common and rare fuels. In a separately funded project, Linked2Safety project (Advancing clinical skeletal diseases to gain a mechanistic a computational perspective is being practice and data security in clinical understanding of disease processes and undertaken by Professor Paul Popelier who research) brings together 11 partners to age-related changes. is developing innovative QSPR models and develop a secure framework to facilitate In March 2013, the world’s biggest expert systems for predicting toxicity of the efficient and homogenized access ever study of allergies was officially ionic liquids in the provision of safe green to shared distributed Electronical Health launched at the MIB led and coordinated solvents for the future. Records (EHRs) which would impact by Professor Clare Mills funded by the enormously across the healthcare sector. The Manchester Centre for Integrative European Commission under the 7th Systems Biology (MCISB) is involved The diversity of our research in the Framework Programme, iFAAM (Integrated in SYNPOL (Biopolymers from syngas biomedical and healthcare arena received Approaches to Food Allergen and fermentation) working alongside 13 an EU funding boost with GlycoBioM Allergy Risk Management), will develop partners across Europe. This project (Tools for the detecton of novel glycol- evidence-based approaches and tools for aims to develop a platform integrating biomarkers) bringing together Europe’s the management of allergens in food. biopolymer production through modern leading scientists to study glycosylation. The Manchester team will work with 38 Engaging with Europe processing technologies, with bacterial Hailing from Croatia (Genos), Denmark partners including, industrial stakeholders fermentation of SYNGAS, and the pyrolysis (UCPH), Germany (UKE and Galab), Ireland (represented by Unilever and Eurofins), and beyond of high complex bio waste enabling (NIBRT) and the UK (UNIMAN), the team is patient groups representing people at risk the treatment and recycling of complex identifying new biomarkers and tools for of severe allergic reactions from Germany, biological and chemical wastes and raw detection and diagnostic screening which UK and Ireland and a risk manager and materials in a single integrated process. could be used to develop personalised assessor group including the UK Food treatment for cancer and related diseases. Standards Agency. The project will work In contrast, the National Centre for Text Beyond The University of Manchester we with the aim of developing sustainable and industrial researchers looking to with the clinical community, working in Mining joins OSSMETER (Automated SYBIL (Systems biology for the functional have a strong portfolio of national and biological and chemical alternatives to develop enzymatic methods for green collaboration with the European Academy measurement and analysis of open source validation of genetic determinants of international collaborations and networks finite materials, such as precious metals, oxidation chemistry through the isolation, of Allergy and Clinical Immunology. software) working with 8 partners on skeletal diseases) will see Professor Roy with academics and industry. The diversity which are currently used as catalysts in redesign and application of cytochrome platform development that will support Goodacre and a consortium of world- Further details of our live portfolio can and quality of our research programmes is the manufacture of medicines. CHEM21 P450 that can be recruited decision makers in the process of class scientists, systems biologists, disease be found in the ensuing research pages. reflected in publications in major journals, will run initially for four years with for the clean, green chemical synthesis discovering, comparing, assessing and modellers, information technologists with over 500 publications with over 280 funding from the Innovative Medicines of important intermediates in the bulk monitoring the health, quality, impact and industrialists validate the genetic research institutes from over 65 countries. Initiative. BIONEXGEN (Developing chemical, pharmaceutical and agrochemical The impact of the Institute’s research is the next generation of biocatalysts for industries. evident from a sustained commitment to industrial chemical synthesis) is another Autumn 2014 will see the MIB and Photon the successful translation of fundamental flagship EU collaborative research project Science Institute (PSI) host 12 early stage science into commercial success. developing next generation biocatalysts researchers (ESR) as part of a €3.6 million for eco-efficient manufacturing processes Our EU portfolio continues to grow, with Innovative Doctoral Programme entitled in the chemical industry. This consortium current live awards in the region of “MAGnetic Innovation in Catalysis”, consists of 17 institutions from university £14 million, through collaborative research known as MAGIC. Manchester has research groups, small and medium sized programmes and major EU training partnered with six Universities (Tokyo, companies, to BASF, the world’s leading networks. Freiburg, Lund, Joseph Fourier in France, chemical company. Professor Nicholas Edinburgh and Copenhagen) and five A number of EU and RCUK funded Turner will also lead BIOOX (Developing companies (AZ, Bruker, TGK, Conformetrix, projects are tackling some of the key a validated technology platform for the and SarOMICS) with each ESR closely barriers to chemical manufacture in application of oxygen dependent enzymes linked to the international and industrial the 21st century. CHEM 21 (Chemical in synthesis and transformation of partners who will be actively involved in manufacturing methods for the 21st alcohols), a FP7 funded project involving their research projects. century pharmaceutical industries) is 11 partners from leading European a public-private partnership (PPP) that companies and universities to develop new, DirectFuel is another FP7 funded project was launched at the end of 2012, eco-efficient, and safer manufacturing involving four Universities from across led by Professor Nicholas Turner and processes for the chemical industry and Europe and the US, together with Chemtex GlaxoSmithKline. This is a €26.4 end-users. Italia and Photon Systems Instruments. million project that brings together six This exciting project aims to develop P4fifty is an FP7 funded European Marie pharmaceutical companies, 13 Universities photosynthetic microorganisms that Curie Training Network of academic and four SMEs from across Europe catalyse direct conversion of solar energy

8 9 10 virus to hijack the cellular machinery which virus tohijackthecellular machinerywhich among otherregulatory functions,helpsthe key multifunctionalprotein calledICP27,which During theinfection,HSVexpresses andusesa make asignificantbreakthrough. by thetherapiesoffuture, wouldtherefore ‘weak spot’intheHSV, whichcanbetargeted suppress viralreplication efficiently.a Finding antiviral treatment iscurrently available,which down itsprogress. Unfortunately, noeffective antiviral drugsmightbeeffective atslowing be ariskfactorinAlzheimer’s disease,andthat Professor RuthItzhakisuggestedthatHSV-1 can Recently, studieshere inManchesterledby encephalitis. lesions tomore seriousconditionssuchas range ofdiseases,from recurrent painfulskin Herpes simplexvirus1(HSV-1) causesawide hijacking thecell. interactions whichleadtotheherpesvirus mechanisms behindthecriticalprotein tojointlystudythemolecular California-Irvine Rozanne Sandri-GoldinattheUniversityof leading virology groups, ledbyProfessor exciting collaborationwithoneoftheworld’s of Manchesterhasestablishedanewand Dr AlexanderPGolovanovfrom TheUniversity MIB researcher secures NationalInstituteofHealthgrant Neil Dixon,twomembersofthedelegation, synergies. MIB’s DrChris Blanford andDr top universitiesinBraziltoexplore research Engineering andPhysicalSciencesvisitedthe the nineschoolsthatcompriseFacultyof In November2012,academicsrepresenting Brazil beginnings University ofDefenceTechnology inChina We havestrong linkswiththeNational relationships withChinesescientists. to partneranddeveloplongtermfruitful Academy ofSciences(CAS)andtheEPSRC co-funded bytheBBSRC,Chinese Synthetic BiologyChinaPartneringAward, have recently secured fundingthrough a Professors ErikoTakano andNigelScrutton Building linkswithChina collaborations International homologues. cancer asthesevirusesalsoencode ICP27 herpes virusessuchasKSHVwhichcauses helpful indevelopingdrugstargeted atother about ICP27mechanismofactionmaybe learn the MIBinDrGolovanov’s group. Whatwe NMR spectroscopy, willbeconductedhere in high-resolution structuralstudies,mainlyusing Irvine,inSandri-Goldin’sCalifornia group, while studies willbeconductedintheUniversityof complementary parts:virology andinvivo This collaborativeproject consistsoftwo this complexassemblyandHSVreplication. to designnewdrugs,whichwillinterfere with binding interfacesinthesecomplexesmayhelp viral replication. Theidentificationofcritical organised andregulated, ultimatelypromoting complexes betweenviralandcellularproteins is details ofhowtheassemblymulticomponent Institute ofHealth(NIH)willlookintofurther This five-yearproject fundedbytheNational between viralICP27andcellularmRNAfactor. first atomic-resolution structure ofthecomplex Pathog, 2011,7(1),e1001244)establishedthe performed intheMIB(Tunnicliffe etal,PLoS used toexportviralmRNA.EarlierNMRstudies nucleus tocytoplasm.Insteadthismachineryis normally exportsthecellularmRNAfrom the funding applicationsandpapersubmissions. bioenergy. Thishasledtoseveraljoint strengths inindustrialbiotechnologyand establish collaborationsbasedonmutual hosted areciprocal visitinMarch 2013to postdoctoral fellowstotheInstitute. a highproportion ofoverseasstudentsand and collaborations.We continuetowelcome encourage scientificandteachingexchanges Science &Technology andJilinUniversity)to Chinese Universities(HebeiUniversityof In additionwehavehostedeventswithtwo scientists andPhDstudents. and currently hostanumberoftheirvisiting

Pathog, 2011,7(1),e1001244).Linear stretch of viral protein ICP27hasadaptedtospecifically Image ofthefirstatomic-resolution structure Copyright: Golovanov APandTunnicliffe RB. of ICP27-REFcomplex(Tunnicliffe etal,PLoS bind tocellularmRNA exportfactorREF. Fig. 2.0

GRAND CHALLENGES 11 New drug treatments for Alzheimer’s – inhibitors have been showing great promise in GlycoBioM bringing us one step adopting a drug repositioning strategy clinical trials for patients with breast, ovarian closer to understanding cancer and prostate cancers caused by mutations in Current drugs for Alzheimer’s can only delay genes called BRCA1 and BRCA2. They work A cure for cancer has become the Holy symptoms for about six months, so new by blocking the action of PARP – a protein Grail for many medical researchers but effective drugs are desperately needed. that chemically tags areas of DNA damage studying the changes that occur in cells to highlight them to the cell’s DNA repair and cell structure may bring us one step Several thousand chemicals safely exert a machinery. closer to understanding this elusive and change in the human biology and are currently complex disease. Keeping up with the in use for treating medical conditions. Professor cell changes associated with cancer is no Andrew Doig is adopting the strategy of drug easy task. A key cancer-related cell process repositioning to find new drug treatments by known as glycosylation could advance our testing to see whether any of these chemicals “Obtaining the crystal structure of PARG understanding significantly, leading to better are beneficial for Alzheimer’s disease. There is is a first and key step to guide and diagnosis and smarter drugs since all cell precedence for this approach: Viagra™ and illuminate future drug-design efforts surfaces, and more than half of the proteins Rogaine™ (a treatment for hair loss) were both aimed at treating certain cancers. in our bodies, are linked to sugar chains. found to have desirable side effects, though Knowing what this looks like, they were designed to treat other conditions. GlycoBioM (Tools for the detection of and having a good idea of how it BIOMEDICAL AND HEALTHCARE Old drugs that are effective in cellular models for novel glyco-biomarkers) is a FP7 funded operates, makes designing such drugs Alzheimer’s disease can be rapidly progressed project which brings together Europe’s less of a shot in the dark.” to clinical trials in humans, since many of the leading scientists to study glycosylation of New discoveries in biotechnology are applied to medical processes that can find applications in such areas as essential steps in drug development, such as David Leys biomolecules in cells, a process seen in many pharmacogenomics and drug production. The development of modern medicines requires an understanding of toxicity testing in animals and people, have Professor of Structural Biology cancers. The team, led by Professor Sabine already been done. Flitsch, is identifying new biomarkers and molecules and networks at the molecular and systems levels which involves imaging and spatial mapping of cell tools for detection and diagnostic screening A few hundred drugs have been tested so far responses in health and disease and in response to drug challenges. Our research ranges from structural and that could be used to develop personalised in cells and a promising hit called A-77636 has dynamic modelling of potential drug targets and their interactions including establishment of early phase drug treatment for cancer and related diseases. been found which was first discovered in the discovery pipelines through the challenges of systems mapping of the “virtual human”. In cancer cells, recognition between cells 1980s, as a possible treatment for Parkinson’s is disturbed, leading to invasive growth disease and cocaine addiction, by Abbott PARG removes these chemical tags after and dissemination of tumour cells. This Laboratories, but not tested for Alzheimer’s. the DNA damage has been repaired. So phenomenon is reflected in the glycans of Working with colleagues at the University of hope for developing drug therapies to target Abbott Laboratories showed that A-77636 can the researchers believe that, similar to PARP Degenerative disease researchers the cell coat, which is of particular interest to Leicester and the University of Lisbon in Portugal, neurodegenerative diseases such as Huntington’s, enter monkey brains when taken orally, a crucial inhibitors, drugs designed to block the action make breakthrough in bid to find researchers. treatment for Parkinson’s and researchers identified the molecular structure Alzheimer’s and Parkinson’s diseases.” requirement for an Alzheimer’s drug. A new of PARG could be effective in treating cancer. of the enzyme kynurenine 3-monooxygenase company, PharmaKure, founded by Professor Huntington’s Dr Flaviano Giorgini, the team’s neurogeneticist Lead author Dr Ivan Ahel, based at the Cancer (KMO), which is found in the human brain. It Andrew Doig and Dr Farid Khan launched from the , said: “This is Research UK Manchester Institute said: “For A significant breakthrough has been made took five years for the team to establish the in 2012 will take A-77636 forward and test a big move forward for the development of decades scientists have wanted to find out the by scientists at the MIB towards developing crystal structure of KMO – the first time it’s ever thousands of other known drugs. Hits found new KMO inhibiting drugs. It is hoped that such structure of PARG, but its large size makes it an effective treatment for neurodegenerative been done. The scientists then studied how the in cell culture will be examined to find out how compounds may ultimately be tested in clinical very hard to produce in the lab. By studying diseases such as Huntington’s, Alzheimer’s and compound UPF 648 binds incredibly tightly to they work and then tested in mouse models “Recombinant glycan receptors are used trials and prove beneficial for patients.” a smaller version of PARG found in bacteria, Parkinson’s. The work, published in the journal the enzyme to act as an inhibitor. Previous studies of Alzheimer’s and, if successful, ultimately in to identify tumour associated changes we’ve been able to create a ‘3D map’ that , was led by Nigel Scrutton, Professor with animal models of neurodegenerative disease human volunteers with Alzheimer’s. of the glycans in the cell coat of tumour Professor Sarah Tabrizi is the head of the researchers can use to understand more of Molecular Enzymology, and details how an have showed that switching off the enzyme cells. The recombinant receptors are Huntington’s disease research team at University about how PARG works. The next step will enzyme in the brain interacts with an exciting activity through drug binding should be effective used in different ways, such as for College London’s Institute for Neurology. be to investigate whether drugs that block its drug-like lead compound for Huntington’s in the treatment of brain disorders. Professor Bacteria to shed light on new identifying tumour associated changes Commenting on the research she says: activity might be an effective way of treating disease to inhibit its activity, demonstrating that Nigel Scrutton said: “UPF 648 works very well drug targets for inherited to carcinoma cells in tissue sections, “Unlocking the crystal structure of KMO is a cancers driven by faults in DNA repair genes.” it can be developed as an effective treatment for as an inhibitor of enzyme activity. However, in and recognising sub-populations of real boost to our efforts to find treatments for cancers BRCA1 and BRCA2 neurodegenerative diseases. its current form it does not pass into the brain leukaemia cells. The GlycoBioM team this devastating disease. It provides a solid basis from the blood. The search is now on for related Scientists at the MIB and the Cancer Research Handling of protein crystals for x-ray is also using the receptors to identify for the optimisation of inhibitor drugs like UPF compounds that can both inhibit the enzyme and UK Manchester Institute have succeeded in crystallography soluble glycobiomarkers in tumour 648 that are being developed by the global pass into the brain. Our research detailing the purifying a protein found in bacteria that patients’ blood samples”. Huntington’s disease research community. KMO molecular structure of the enzyme now enables could reveal new drug targets for inherited is one of our top drug targets, and the crystal Professor Christoph Wagener a search for new KMO inhibitors that are able to breast and ovarian cancers as well as other structure is a significant step along our roadmap University Medical Center Hamburg- cross the blood-brain barrier. This provides real cancers linked to DNA repair faults. to clinical trials of KMO inhibitors in patients.” Eppendorf (UKE), Germany The team are the first to decipher the structure of a protein called PARG, which A cartoon representation of Saccharomyces cerevisiae kynurenine 3-monooxygenase (KMO). Inhibition of KMO, an enzyme in the eukaryotic tryptophan catabolic pathway, leads to amelioration of Huntington’s-disease-relevant phenotypes. The figure shows a flavin plays an important role in DNA repair and adenine dinucleotide (FAD) highlighted in red (stick representation) with the cocrystallised inhibitor UPF-648 depicted as purple spheres. acts in the same pathway as PARP. PARP

12 13 In parallel, project members from The to visit hospital for lengthy infusions. The structural parameters governing their stability between high and low risk disease will direct virus from the bloodstream. Telaprevir™, A fragment based screening University of Manchester, in collaboration challenge for bioprocessing research is to in order to help solve this problem. In a research towards novel molecular markers which was launched in 2011 by Vertex, is approach to rationalizing M. with the , have been dissolve the dose of protein required in a related project, Dr Blanch is also working that may shed light on tumour progression currently the leading medicine in this area tuberculosis P450 molecular working on an analytical tool to capture and small volume to enable self-injection. This with Professor Andrew Doig to develop these as well as generating new molecular although in order to make it widely available selectivity characterise glycan binding proteins which challenging project will be led by Dr Xue- spectroscopic tools for detailed structural diagnostic markers for use in the clinic. at an affordable cost it is necessary to could eventually be used to pinpoint sugar Feng Yuan, Reader in Biochemical Physics in analysis of proteins and UCB Pharma are develop inexpensive manufacturing routes Expanding their work on cytochrome Professor Gardner is involved in a biomarkers in diseases such as cancer. collaboration with MIB colleagues Dr Robin now supporting this research. to the molecule. Professor Nicholas Turner, P450 enzymes Professors Andrew Munro corresponding study which brings together a Curtis and Dr Alexander Golovanov from in collaboration with Professor Romano Orru and David Leys together with Dr Kirsty This project has also progressed our critical mass of scientists from the Universities MIB and Dr Alistair Revell from the School of at the Free University of Amsterdam, has McLean will adopt a fragment based understanding of diabetes, in particular of Cardiff, Lancaster, Liverpool and Manchester Mechanical, Aerospace and Civil Engineering Towards disease diagnosis devised an efficient synthesis of Telaprevir™ screening approach (FBS) to rationalizing the discovery of a novel glycan biomarker and clinicians from the Christie, Lancaster (SMACE). through spectrochemical which combines with multi- Mycobacterium tuberculosis (Mtb) P450 related to the disease, and the team expects and Liverpool NHS Hospital Trusts with the imaging of tissue architecture component chemistry. molecular selectivity. to develop a system that will enable patients complementary experience and expertise to check for maturity-onset diabetes of the More than a quarter of a million people are to advance the understanding, diagnosis Initially an engineered biocatalyst Cytochrome P450 enzymes are a superfamily young (MODY), a form of diabetes that is diagnosed with cancer annually in the UK and treatment of cervical, oesophageal (monoamine amine oxidase), which has been of oxygenases that perform an array caused by mutations in a number of different and the four most common ones, breast, and prostate cancers. Cervical and prostate optimised by successive rounds of directed of physiologically important reactions genes. lung, bowel and prostate, make up over half cancers are very common and the incidence evolution, is used to convert a cheap achiral in organisms from bacteria through to of all these cases. Many, such as prostate of oesophageal is rising rapidly. There are starting material to an optically pure chiral man, including steroid and bioactive lipid The GlycoBioM project is truly a European cancer correlate strongly with age, with 77% cytology, biopsy and endoscopy techniques for building block. Thereafter this building block syntheses, and xenobiotic transformations. success story, with partners from opposite of cases being diagnosed in men over the extracting tissue from individuals who are at is used in a three-component Ugi reaction With increasing numbers of P450 (CYP) ends of Europe all contributing to ground- age of 55. There is a clear clinical need for risk of developing these diseases but there is resulting in a highly convergent synthesis genes identified from genome sequences, breaking results. When the Croatian team a robust and preferably automated system a national and international need to develop of Telaprevir™. The groups in Manchester it is apparent that there is a large untapped found that certain glycans can predict the which can not only facilitate the pathological more accurate diagnostics for these diseases. and Amsterdam have patented this route, resource of uncharacterized oxidase enzymes speed at which colon cancer will progress diagnosis but also to discriminate between in addition to publishing several papers, of unknown specificity. In M. tuberculosis (which could lead to tailored therapy – or Experiments will be conducted on specimens tumours of low risk, which require and have recently licensed the technology (Mtb) there are 20 P450s, with substrates ‘smart drugs’ – for individual patients), the from all three diseases using four different Funded by the BBSRC this project aims to surveillance or less aggressive treatment, to a pharmaceutical company who plan to definitively identified for six. This project Danish team took up the baton, developing infrared based techniques which have develop methods for use by industry to and those of high risk, which will progress exploit the technology for the manufacture will exploit and develop fragment based a new glycoprofiling method to reduce false- complementary strengths and weaknesses: screen protein formulations for viscosity and more rapidly and which need aggressive of Telaprevir™. screening (FBS) technology to identify small positive cancer diagnoses. This is expected hyperspectral imaging, Raman spectroscopy, other flow properties, using small quantities intervention to prevent morbidity and death. molecule ligands that bind to the active site to help women with ovarian cancer. Apart a new instrument to be developed by of protein. This will enable methods for We have shown previously in small scale of a panel of key Mtb P450 enzymes (using from having developed a new blood test combining atomic force microscopy with viscosity reduction to be developed. The studies that infra red spectral markers used Characterization of a superior X-ray crystallography to define the binding for ovarian cancer, the team has made infrared spectroscopy and a scanning near team will apply comprehensive rheological in conjunction with algorithmic models biocatalyst for pravastatin modes). It will then use a combination commendable progress in unravelling the field microscope recently installed on the free characterisation, RheoChip rheometry, and can be utilised not only to provide tumour production of chemical elaboration and ‘merging’ of complexities of breast cancer and it is hoped electron laser on the ALICE accelerator at advanced modelling as a platform, which grading data but also to provide staging and fragments binding at adjacent positions, to that these results lead to better stratification Daresbury. This combination of techniques Andrew Munro, Professor of Molecular can be used by industry to select the protein prognostic information. iteratively improve their efficiency of binding of patients regarding the choice of the will allow the team to probe the physical and and formulation for development of the Enzymology and Research Associate Dr and potency as inhibitors and as probes most appropriate therapy. This project chemical structure of these three cancers final dosage form, at an earlier stage than The attraction of infrared spectroscopy to Kirsty McLean, together with industrial of structural/catalytic features of targeted also featured in the Royal Society Summer with unprecedented accuracy revealing is possible today saving time and money aid clinical diagnosis is that it is a widely partner DSM, have used P450s. This will generate novel libraries Exhibition – see Science and Society section. important information about their character in the development of many new protein known technology which is readily available, and structural biology in order to redesign containing fragments representing both and the chemical processes that underly their medicines. The research will build on existing reliable, simple to use and relatively an enzyme catalyst (a cytochrome P450) in likely substrates classes for P450s (fatty acids, malignant behaviour. methods, which are already well established inexpensive. It also allows further post order to alter its substrate specificity and to steroids, polyketides) and unusual lipids Tackling the manufacture of for rheological characterisation of water scanning interrogation because it does enable it to convert a natural product into prevalent in and/or peculiar to Mtb, and then concentrated protein medicines soluble polymers and BSA solutions, and not destroy the tissue under investigation. the cholesterol-lowering drug Pravastatin™ exploit FBS with these libraries to generate/ adapt and apply them to the bioprocessing The aim of this EPSRC funded proposal Developing technologies in a single step. The synergistic efforts identify physiologically relevant substrate- Future trends in treating various chronic and injectability of high concentration is to adapt existing technologies and to produce inexpensive of industrial researchers at DSM, experts like molecules, with reference to active site diseases with recombinantly-produced protein biopharmaceutical solutions. protocols using spectroscopic analysis of pharmaceuticals in microbial fermentation and screening structure of the target P450s and knowledge therapeutic proteins (such as monoclonal cancer tissue to develop rapid and accurate techniques, together with the Munro of the metabolomics of Mtb. antibodies) require frequent and high Hepatitis C is a major global health problem Dr Ewan Blanch, Reader in , systems of analysis, which can be applied group, experts in enzymology and protein doses of an active protein ingredient in a that currently affects approximately 200 has been working on an EPSRC-funded to the identification and characterisation of crystallography, led P450 catalysts to This project exploits FBS, structural biology, small volume of liquid (e.g. >100mg/ml for million people worldwide. Many of the project with Dr Stavroula Balabani, a fluid biological tissues using prostate cancer as the perform the desired reaction with much synthetic chemistry and various spectroscopic subcutaneous (SC) injections using a prefilled infected people live in countries where access dynamics engineer at UCL, to investigate primary model. Using this system Professor greater stereoselectivity than other chemical methods to generate novel inhibitors for syringe or auto-injection device). There is a to modern expensive treatments is a major the destabilisation of a protein structure Peter Gardner, in collaboration with the or enzyme-based approaches. This new Mtb P450s involved in cholesterol oxidation need for underpinning research to support issue. Recently a new class of drugs has by shear force typically experienced by Cancer Research UK Manchester Institute, biotechnologically advanced method forms and secondary metabolite synthesis, to industrial development of novel protein been developed that are highly effective in protein therapeutics during bioformulation. will develop a model, which can distinguish the basis of a patented process for efficient identify substrates for ‘orphan’ P450s to therapeutics for more convenient delivery of tackling the infection and in the majority of The aggregation of protein therapeutics between low and high risk prostate cancers production of this blockbuster drug. enhance knowledge of the biochemistry of a products by subcutaneous injection. This is patients result in complete removal of the (biologics) is a major problem for the in samples that have been previously graded. biomedically important bacterium. an increasing priority for biopharmaceutical pharmaceutical sector and Dr Blanch and An added benefit of spectral screening is companies enabling patients to administer colleagues are developing Raman and that interrogation of the spectral differences medicines at home, rather than having infrared spectroscopies to understand the

14 15 Developing a technological of these materials. When used as structural platform for the design of novel materials, as in hydrogels, the quantity of biomaterials peptide required is significant.

In a project that will contribute significantly Dr Saiani is currently developing this to the field of healthcare technologies as technological platform by furthering our well as biomaterials and tissue engineering understanding of the self-assembly process research Dr Alberto Saiani, Reader in of these short peptides and designing novel Molecular Materials, has received an responsive and increasingly functional EPSRC Research Fellowship to develop a materials for a new field of applications. technological platform for the design of Through engagement with academic novel biomaterials that can be used across and industrial end-users throughout the a number of applications. The use of development process the team will ensure non-covalent self-assembly to construct that the materials designed will be relevant World’s biggest ever study of The Manchester team will work with 38 Dr Bert Popping, Eurofins Scientific Director, materials has become a prominent strategy whilst exploring new potential fields of partners including, industrial stakeholders said: “Eurofins is excited to be part of this in materials science offering practical routes food allergy gets underway application. (represented by Unilever and Eurofins), European Commission project. We are for the construction of increasingly functional Up to 20 million European citizens suffer patient groups representing people at risk of looking forward to sharing our newly- materials for a variety of applications ranging from food allergy, a disease that can be severe allergic reactions from Germany, UK developed multiple allergen detection from electronic to biotechnology. A variety MIMIT celebrates 4 years conquered, if critical steps are taken. However, and Ireland and a risk manager and assessor method and making a meaningful of molecular building blocks can be used management of both food allergy, by patients group including the UK Food Standards contribution to this crucial initiative.” for this purpose such as de-novo designed MIMIT (Manchester: Integrating Medicine and health practitioners, and allergens, by Agency. The project will work loosely peptides. With a library of 20 natural amino and Innovative Technology) has celebrated industry, is thwarted by lack of evidence to This research study featured in the BBC series with the clinical community, working in acids available it offers the ability to play its four year anniversary during which time either prevent food allergy developing or “Trust Me I’m A Doctor” presented by Dr collaboration with the European Academy of with the intrinsic properties of the peptide it has developed 27 projects, requiring protect adequately those who are already Michael Mosley. Allergy and Clinical Immunology. such as structure, hydrophobicity, charge and £1million initial investment (project and allergic. European Commission-sponsored This €9 million project builds on an earlier functionality allowing the design of materials infrastructure), based on 116 unmet clinical research, known as the Integrated Approaches This study involves 38 partners and is headed €14.3 million research study EuroPrevall also with a wide range of properties. needs. To date projects have leveraged to Food Allergen and Allergy Risk Management by MIB’s Clare Mills, Professor of Allergology, headed by Professor Mills which involved 62 £3million, 3 clinical research fellowships, (iFAAM), will set the stage for facilitating such from the Allergy and Respiratory Centre The main challenge facing scientists in this partners from 17 countries. numerous publications and patents. One of steps to be taken. This research will produce of The University of Manchester’s Institute field is being able to rationally design these the first developments reached the market a standardised management process for of Inflammation and Repair. Based in the peptides to gain control over the physical Professor Mills was recently elected to the place mid-2013 and resulted in 1 licence companies involved in food manufacturing. Manchester Institute of Biotechnology. properties of the resulting self-assembled International Academy of Food Science agreement with a SME, £5m VC funding It will develop evidence-based approaches Professor Mills said: “This is a massive materials. This requires not only an in depth and Technology, a distinguished group of and 1% estimated net returns of $250m and tools for the management of allergens research project that will have far reaching knowledge of the self-assembling processes outstanding scientists representing the per annum. Royalty returns will be shared in food and integrate knowledge derived consequences for consumers and food at all length scales, but also a detailed international community of food science between the NHS, academia and inventors. from their application and new knowledge producers. The evidence base and tools that understanding of the specific requirements and technology. The induction ceremony for Two other project have leveraged £2million from intervention studies into food allergy result from this will support more transparent of each application targeted. For example, new took place at the IUFoST* World VC and £5million Pharma investment management plans and dietary advice. The precautionary “may contain” labelling of injectable materials need to be developed Congress of Food Science and Technology between them and 9 projects have received resulting holistic strategies will reduce the allergens in foods which will make life easier for cell delivery while for drug delivery oral held in Iguassu Falls, Brazil. UMIP Proof of Principal investment to get burden of food allergies in Europe and beyond, for allergy sufferers as they try to avoid cavity sprayable systems could be required. *International Union of Food Science and Technology them ‘investor ready’. whilst enabling the European food industry to problem foods.” For cell culture and tissue engineering the compete in the global market place. issue of adaptability of material properties One of the early projects supported by MIMIT is even more critical as depending on cell Phagenesis won Bionow Healthcare Project type, origin and intended behaviour, cells of the year 2012. Congratulations also went have very different requirements in terms to Curtis Dobson, MIMIT Site Miner for the iFAAM kick-off meeting held in November 2013 at the MIB of the environment, (ie. material properties award of Biomedical Project of the Year 2012 and functionality) in which they are placed. to Microsensor, a novel infection sensing Finally, one other key element is the cost technology.

16 17 amines, oligosaccharides and renewable Biocatalytic tools for industry Directed evolution of polymer intermediates which are better in enantiocomplementary Professor Nicholas Turner will also lead terms of eco efficiency, economic potential, malonate decarboxylases complexity and /or specificity of the synthetic BIOOX (Developing a validated technology pathways than those currently employed. The platform for the application of oxygen This project is led by Professor Jason consortium consists of 17 institutions from dependent enzymes in synthesis and Micklefield, in collaboration with Professors university research groups, small and medium transformation of alcohols), a collaborative David Leys and Nicholas Turner, and is sized companies, to BASF, the world’s leading FP7 project involving 11 partners from funded by BBSRC and BASF through the chemical company. leading European companies and universities Industry Partnership Award (IPA) Scheme. to develop new, eco-efficient, and safer The MIB team used structure-guided The consortium have identified the key manufacturing processes for the chemical directed evolution to create new malonate technology fields of amine synthesis, polymers industry and end-users. This programme will decarboxylase enzymes that can produce from renewable resources, glycoscience and develop the tools for the implementation a wide range of carboxylic acids, which wider oxidase application as four key areas of biooxidation to synthesize and oxidize are particularly common intermediates where the next generation of biocatalysts alcohols for applications in flavourings and in the manufacture of pharmaceuticals, that will lead to improvements in both fragrances, and fine chemicals. The aerobic agrochemicals and other valuable products. economic and environmental performance biocatalytic oxidation reaction currently has The new decarboxylase enzymes are INDUSTRIAL BIOTECHNOLOGY of the chemical manufacturing industries. the potential for the biggest impact on the also attractive because the substrates This programme, funded under the EU 7th future uptake of industrial biotechnology (IB) can be generated from malonic acid, a Framework Programme, will enable industry in Europe. Bioprocesses have the potential natural precursor derived from renewable to use renewable resources with reduced to overcome the hazardous nature and sources (fermentation). The availability greenhouse gas production as compared high environmental impacts of current Industrial Biotechnology (IB) is a set of cross-disciplinary technologies that use biological resources, such as algae, of chiral carboxylic acids, which are to their fossil counterparts and deliver chemical oxidation processes. Biocatalysis for single enantiomers (one of two possible plants, marine organisms, fungi and micro-organisms, for the production and processing of chemicals, energy and biotechnological routes with reduced energy oxidative chemical manufacture processes stereoisomers that are non-superimposable materials. A multidisciplinary approach is essential to transform the traditional chemical and chemical-related sector consumption and less toxic wastes compared can deliver a major advantage to the mirror images) is of critical importance to a more sustainable and competitive one which draws on disciplines such as organic and synthetic chemistry, to conventional chemical processes. Routes to European chemical-using industries and the particularly for pharmaceutical production. specialised, high-value chemicals (e.g. chiral biochemistry, molecular biology, , genomics, proteomics, bio-informatics and bioprocessing. environment, and it is expected that this Fig. 3.0 chemical compounds) normally require long new technology platform will allow the rapid chemical synthetic routes involving complex development of bio-oxidations as a routine With major recent grant awards in Industrial Biotechnology and strategic participation in national and international reaction steps with toxic side products and technology for the IB industry and support Industrial chemicals of the forums over the past year, the widely recognised expertise in IB@MIB has seen major research programmes initiated. waste streams. This project will allow these the European knowledge based bioeconomy. monoterpenoid class realised methods to be replaced by clean biocatalysis The four-year, €7.4 million project will be through synthetic biology and routes. To broaden the range of fine and promoted by a dynamic public engagement pathway engineering speciality chemicals and intermediates and dissemination programme within the By essentially mimicking the process of Rapid evolution of enzymes and produced by biotechnological routes, research scientific community and the wider public, In partnership with GSK, Professors Nigel Darwinian evolution in the laboratory this synthetic micro-organisms for will address 1. the design and optimisation especially schoolchildren, to create extra Scrutton, John Gardiner, David Leys and Pedro interdisciplinary team will develop a new the development of industrial of enzymes to be used in synthetic chemistry; value for the European Union. Mendes have engineered bacterial strains to approach to engineering robust biocatalysts biocatalysts 2. the selection/development of modified produce flavours and fragrances that belong to that will enable the optimisation of enzymes microorganisms which are resistant to “This research will yield substantive the monoterpenoid family of compounds using In collaboration with GlaxoSmithKline, for industrial applications in a matter of weeks heat, pressure or low pH when used in the advantages to the scientific synthetic biology and enzyme engineering one of the world’s largest pharmaceutical rather than the months it currently takes, production of chemical entities and allow 3. community involved in industrial approaches. companies, this project seeks to develop an resulting in a much greener approach to the the integration of biotechnological steps into biotechnology. The Manchester accelerated laboratory evolution platform production of a wide variety of products. conventional chemical processes. Institute of Biotechnology is a for the rapid optimisation of biocatalysts recognised leader within this field This £5M project is funded under the BBSRC for industrial application in target molecule and represents a strong partner sLoLa initiative in partnership with GSK. synthesis. for the synthetic biochemistry team at GSK to develop new Expertise has been compiled from seven biotechnologies. Being able to diverse research groups based at the Developing next generation engineer bespoke biocatalysts more MIB under the leadership of Nicholas biocatalysts efficiently will result in a much Turner, Professor of Chemical Biology and wider application to our chemical Director of CoEBio3. Leading other work BIONEXGEN, led by Professor Nicholas manufacturing processes, and packages within this grant are Professors Turner, will develop the next generation support our research into new Sabine Flitsch (glycomics), Roy Goodacre of biocatalysts to be used for eco-efficient medicines.” (metabolomics), David Leys (crystallography), manufacturing processes in the chemical Jason Micklefield (synthetic biology and industry. It will also develop and integrate, Dr Joe Adams biocatalysis), Nigel Scrutton (enzymology) with chemical steps, the biotechnological Fig. 3.0 GlaxoSmithKline manufacturing routes for the synthesis and Dr Claire Eyers (mass spectrometry, Structure-guided directed evolution of of fine and speciality chemicals especially University of Liverpool). alkenyl and arylmalonate decarboxylases.

18 19 Bio- or ‘natural’ routes to the synthesis of pharmaceutical company GlaxoSmithKline. of biosynthetic gene clusters to discover Network in biocatalyst these compounds significantly enhance their The introduction of biotechnology to the novel natural products. Natural products are discovery, development and market value and this research will transform manufacturing processes for medicines will small molecules produced predominantly by scale-Up the industrial production of monoterpenoid limit the drain on the world’s resources and microorganisms and plants that have inspired synthesis by providing ‘natural’ routes to these have a lasting benefit on the environment. the development of many blockbuster drugs Professor Nicholas Turner, University of compounds, avoiding problems associated including anticancer and immunosuppressive Manchester and Professor John Ward CHEM21 brings together six pharmaceutical with classical chemical synthesis. Bio-routes will agents including most of the antibiotics in (University College London) companies, 13 Universities and four small “Improving the sustainability of our reduce the environmental impact associated clinical use today. Natural products are also This network aims to develop new tools to to medium enterprises from across Europe drug manufacturing processes through with classical synthesis and release industry used in agriculture as herbicides, pesticides accelerate biocatalyst research, discovery in a £21.2 million project with the aim collaborations such as CHEM21 will from the constraints of limited availability from and fungicides to increase crop yields. In and development. The network will provide of developing sustainable biological and not only reduce our industry’s carbon natural resources. This project is funded by addition, bioengineering methods and the framework and coordination to allow chemical alternatives to finite materials, such footprint, but will provide savings that the BBSRC as part of the Industrial Partnership synthetic biology tools will be developed research groups from industry and academe as precious metals, which are currently used can be reinvested in the development Award (IPA) Scheme. to enable rapid structural diversification to easily access and develop a truly broad as catalysts in the manufacture of medicines. of new medicines, increase access to and optimisation of the most promising range of biocatalyst panels and technologies medicines through cost reduction and natural product molecules for therapeutic, for screening whilst providing a pipeline CHEM21 will run initially for four years drive innovations that will simplify Pharmaceuticals and universities agrochemical and other applications. through to scale-up, manufacture and with funding from the Innovative Medicines and transform our manufacturing working together on multi commercial use of novel enzymes. Initiative. The project will establish a paradigm” million pound project European research hub to act as a source of up-to-date information on green chemistry. Dr John Baldoni Europe’s largest public-private partnership It will also develop training packages to GlaxoSmithKline (PPP) dedicated to the development of ensure that the principles of sustainable manufacturing sustainable pharmaceuticals manufacturing are embedded in the was launched at the end of 2012 and is education of future scientists. “These networks bring together led by Professor Nicholas Turner and the “The networks will drive new ideas a number of internationally to harness the potential of biological competitive, cross-disciplinary resources for producing and processing communities capable of materials, biopharmaceuticals, undertaking innovative research chemicals and energy. Each has a that will attract further investment Industry-academia networks in industrial biotechnology and bioenergy particular focus, such as: realising from the UK and abroad. They the potential of food waste and by- provide a new opportunity for products to produce chemicals and the research community to make The Biotechnology and Biological Sciences Research Council (BBSRC) announced in December 2012 an investment of biomaterials; unlocking the industrial significant contributions to the UK’s £18million in 13 unique collaborative ‘Networks in Industrial Biotechnology and Bioenergy’ (BBSRC NIBB) to boost interaction biotechnology potential of microalgae; bioeconomy: driving transformational between the academic research base and industry, promoting the translation of research into benefits for the UK. The producing high value chemicals from bioscience into industrial processes University of Manchester secured four networks, three of which will be led from MIB. These national networks pool skills plants; and making use of plant cell and products; creating wealth and from academia and business to develop research projects with the potential to overcome major challenges in the industrial walls (lignocellulosic biomass) to jobs; and delivering environmental produce chemicals and biofuels.” benefits, such as CO2 reduction.” biotechnology and bioenergy arena whilst allowing new members to come on board with skills that can benefit the group. David Willetts Dr Celia Caulcott IBCarb - Glycoscience tools for The analysis, synthesis and biosynthesis of polysaccharides) or energy (digesting the Minister for Universities and Science BBSRC Executive Director, Innovation biotechnology and bioenergy carbohydrates and their modification to indigestible). IBCarb is an interdisciplinary and Skills industrial products are, therefore, central network that will allow for exploitation of Professor Sabine Flitsch, University of challenges in both industrial biotechnology opportunities presented by Glycoscience. Manchester and Professor Rob Field, John and bioenergy. Innes Centre The last twenty years have seen a number of Carbohydrates constitute the largest source Natural Products Discovery fundamental changes in the glycosciences of biomass on Earth and their exploitation generating a technology push with respect and Bioengineering Network for novel applications in biomaterials, energy, to carbohydrate synthesis and modification, (NPRONET) food and health will be critical in moving enzymology and glycomic analysis. At the Professor Jason Micklefield, University of away from dependence on hydrocarbons Working closely with industry to advance the field of chemical biology same time, there is a technology pull - Manchester and Professor Barrie Wilkinson, to develop sustainable biotechnologies and great demand and opportunities in diverse John Innes Centre Funded by EPSRC, BBSRC and MRC and with commitments from its 10 industrial partners, the reduce GHG emissions, ensuring both energy areas such as biopharmaceuticals (8 out Manchester Chemical Biology Network brought together more than 50 research groups from and food security. Glycoscience is a broad Building on the UK’s established world- of 10 top selling drugs worldwide are a range of disciplines across The University of Manchester to share expertise with industrial term used for all research and technology leading expertise in natural product glycoproteins), foods (prebiotics designed for partners, including companies such as AstraZeneca, GSK and Pfizer. involving carbohydrates, ranging from cell chemistry, biosynthesis and microbiology the human gut microbiota), antimicrobials biology, human nutrition and medicine Professor Jason Micklefield and Professor This collaboration between research groups provides a more effective platform to tackle the major (targeting cell surface recognition and to carbohydrate-based materials and the Barrie Wilkinson will lead this network challenges associated with the discovery of new drugs and other products of importance to human biosynthesis), materials (from biorenewable conversion of carbohydrates to energy. devising methods to activate the expression health and wellbeing, using expertise ranging from synthetic chemistry through to cell biology.

20 21 and propane in photosynthetic cyanobacteria the environmental benefits and drawbacks targeting only non-toxic end-products that related to the concept. The knowledge have been demonstrated to function in generated through this innovative existing or minimally modified combustion biotechnological approach will not only engines. benefit the environmental management of terrestrial wastes, but also reduce As no natural biochemical pathways are the harmful environmental impact of known to exist for short-chain alkane petrochemical plastics. biosynthesis, it is necessary to identify Aquatic photobiology – cultures of potential gene candidates through In its first phase (funded to >£6M by photosynthesizing cyanobacteria which are informatics analysis and then tailor the the BBSRC and EPSRC) the Manchester the hosts for alkane production substrate specificities of the encoded Centre for Integrative Systems Biology enzymes by enzyme engineering. In order (MCISB) prepared a complete toolbox Photosynthetic organisms are able to to directly capture solar energy to drive fuel from computational analyses through utilize water, CO2 and sunlight to directly biosynthesis, the synthetic pathways are at experimental approaches to data handing synthesize fuel or chemical precursors - all in first assembled in the photosynthetic model and organisation. The results of this early one engineerable package capable of both organism Synechocystis sp. PCC 6803. To research can be found in a set of web BIOFUELS and ENERGY self-amplification and internal self-repair. deliver the energy reduction and metabolic resources and in the most recent issue of Terrestrial-grown plants however display poor precursors to the synthetic pathways with Methods in Enzymology devoted to Systems overall solar energy conversion efficiency. maximum metabolic flux it is essential Biology by the MCISB. to optimize the native host metabolism. The MCISB continues to be involved in two An alternative to land-based biomass Successful construction of the intended Biotechnology Research Industry Club (BRIC) During the next two decades the chemical industry will undergo a major transformation. As both oil and natural are aquatic photobiological organisms, strains will allow low-cost production projects funded by the BBSRC (on protein gas begin to run out, there will be a growing need to switch from oil based starting materials to those derived eukaryotic algae or cyanobacteria. These of transport fuel in a potentially neutral production in various microorganisms using from biomass. Biotechnology-based processes will need to be developed to efficiently convert inexpensive raw organisms display simple nutritional ‘greenhouse gas’ emitting process that does various feedstocks), as well as by a large materials to high-value products such as pharmaceutical drugs, cosmetics and fuels. From underpinning strategic requirements and are in some cases even not compete for agricultural land. cable of nitrogen fixation. number of other BBSRC and EU grants under research to the transfer of technology into the marketplace, The University of Manchester has a range of world- the leadership of Professors Hans Westerhoff, class activities supporting the need for solutions that can play their part in meeting the global energy challenge. The cultivation of eukaryotic algae or SYNPOL – Biopolymers from Pedro Mendes and Dr Jacob Snoep. cyanobacteria can be carried out on land that is not suitable for agriculture in constructed syngas fermentation (SYNPOL) enclosed systems that do not utilize soil. SYNPOL is an EU FP7 KBBE collaborative IONTOX Safe green solvents for By choosing aquatic instead of terrestrial Our contribution to the energy agenda components underpinning these processes project (Knowledge-Based Bio-Economy the future Bacteria making “oil” systems for harvesting sunlight it should be focuses in particular on the biological only recently identified. There is obvious (KBBE)) involving 14 European partners from possible to minimize the potential conflict In silico predictive chemometric models for aspects of energy including fuel cells, solar Solutions that seek to reduce our scope for application of these components, academia and industry. The basic idea of between food-producing agriculture and selected toxicity endpoints of ionic liquids energy and 2nd/3rd/4th generation biofuels. dependency on fossil oil are being tackled and engineered variants thereof, in the the SYNPOL project is the establishment photobiological fuel production. Aquatic by Professors David Leys, Andrew Munro of an integrated processing technology Research into alternative biofuels includes production of drop-in biofuels, provided Ionic liquids (ILs) are a modern addition to photobiological organisms are also capable and Nigel Scrutton who are working on for the efficient synthesis of cost-effective utilising biomass from both agricultural and high-levels of alkane production can be the world of chemical compounds, deployed of potentially greater solar energy conversion a BBSRC Industry Partnership Award with commercial new biopolymers using the marine sources to the development of novel achieved at competitive costs. in areas ranging from electrochemistry, over efficiency compared to terrestrial plants. Shell combining state-of-the-art enzymology products derived from fermentation of biocatalysts. organic synthesis, to cleaning, extraction and laboratory evolution techniques with An industrial award with Shell will challenge SYNGAS generated from very complex This EU FP7 collaborative project involves and separation technology. Their unique Fill your car with petrol or diesel today, and synthetic biology to make organisms produce this same research team with the scoping feedstocks. This revolutionary project will four Universities from across Europe and negligible vapor pressure, non-flammability, the fuel you buy will likely contain a small “oil”, bypassing the need to drastically adapt of natural variants as well as laboratory- see the establishment of a platform which the US, together with Chemtex Italia and enhanced thermal stability and outstanding (5%) proportion of biofuel. Could we use oil-dependent processes. The team will focus, evolution of the most promising variants integrates biopolymer production through Photon Systems Instruments with the aim of solvation potential make them green solvents more and limit our reliance on fossil fuels? in particular, on production of linear alpha- towards applicable alkane producing modern processing technologies, with developing photosynthetic microorganisms but their toxicity needs to be understood Almost certainly yes but current biofuels are olefins, a high value, and industrially crucial enzymes. bacterial fermentation of syngas, and the that catalyze direct conversion of solar and controlled. Reliable toxicity prediction not fully compatible with modern, mass- intermediate class of hydrocarbons that pyrolysis of highly complex biowaste (e.g., energy and carbon dioxide to engine-ready can only be achieved through computational market internal combustion engines. The are key chemical intermediates in a variety municipal, commercial, sludge, agricultural) fuels. means. Quantitative structure-property cost of modifying vehicles and fuel supply of applications. At present, no “green” Aquatic photobiology – enabling the treatment and recycling of relationships, known as QSPR, solve the infrastructure, to run on blends containing alpha-olefin production process is available, a Fuel production should not require complex biological and chemical wastes and exploring the potential problem created by stringent environmental 20% or more bioethanol or biodiesel is the situation which this project seeks to change. destructive extraction and further chemical raw materials in a single integrated process. regulations and costly and time consuming Biological fuel production is already a major limiting factor. The grand challenge conversion to generate directly useable experimental determination. commercial reality with biology expected to R&D activities will be focused on the is to produce a biodiesel with the same transport fuels. The DirectFuel consortium, contribute further towards fuel-production integration of innovative physico-chemical, chemical structure as conventional diesel fuel Alkane producing enzymes represented by Professors Nigel Scrutton This EU International Incoming Fellowship in both intermediate and future energy biochemical, downstream and synthetic in commercial volumes. Biofuels with these and David Leys from Manchester, chose to will see Professor Paul Popelier develop systems, particularly with the advancement technologies to produce a wide range of characteristics are being termed ‘drop-ins’. The production of alkanes in nature has develop an exclusively biological production ecotoxicological models for ILs in silico, in technologies that enhance economic new biopolymers, based on a number of been documented for a limited set of process for the volatile end-products obeying OECD principles, based on available sustainability. novel and mutually synergistic production organisms, with many of the molecular ethylene and short-chain n-alkanes ethane toxicity data against various endpoints. methods, and including an assessment on

22 23 24 multicopper oxidasestocreate miniature fellowship workfocusedonexploiting Dr ChristopherBlanford’s recent EPSRC elements suchasiron, nickelandcopper. catalysts andusesmallamountsofabundant functions asefficientlytheprecious metal and multicopperoxidasescarryoutthesame containing enzymessuchashydrogenases energy conversionprocess. Somemetal- platinum-group metalstospeedupthe These devicesfrequently rely onexpensive and oxygenfedfrom outsidethecell. battery buthavethereactants likehydrogen electrical energy. Thesefunctionlikea directly convertchemicalenergyinto Fuel cellsare electrochemical devicesthat Enzymes forenergyconversion ILs, ready forEuropean regulatory purposes. and expertsystemsforpredicting toxicityof models deliveringinnovativeQSPR for experimentalvalidationofthedeveloped toxicologists atTheUniversityofManchester establish collaborationwithexperimental chemometrics. Professor Popelieraimsto rooted inquantumchemistryandrigorous expertise inphysicochemicalparameters ILs. Thisproject combinescomplementary advantageous indesigningthedesired truly predictive QSPRmodelswillbehighly Considering theevergrowing interest inILs, potential. mitigated bylimitingtheelectrode’s output found thatthesedestructiveeffects canbe diminish theirlifetimetominutes.Thegroup current extractedfrom theelectrodes could output isrequired, rapidlyvaryingtheelectric remain viablefordayswhenaconstant of fuelcellelectrodes. Whiletheenzymes world usageconditionsaffects thelongevity crystal microbalance (EQCM) to testhowreal- The group alsouseanelectrochemical quartz E. coli. enzymes incommonexpression systemslike adapted toproduce more efficientfuel-cell unique copperconfigurationthatcouldbe surface modification,theydiscovered a group’s research intorationalelectrode their activityformonths.Aspartofthe efficient electron transportwhilepreserving partners toorientthemacromolecules for essentially usingtheenzyme’s natural numerous biomimeticsurfacemodifications, Dr Blanford andhisgroup havediscovered immobilised enzymes. and maximisingthelongevityofthese of reactants, products andelectrons, to havethemostefficientpossibletransport inorganic onesare immobilisingtheenzymes to adaptingbiologicalcatalystsreplace mobile phones.Two ofthekeychallenges be usedtopowerconsumerdeviceslike components forportablefuelcellsthatcould

RESEARCH SPOTLIGHTS 25 Industry stakeholders-partners Our research computational and systems modelling of prototypical pathways in engineered chassis; We have an established track record of We have a strong portfolio of current research pathway/biocatalyst control (e.g. orthogonal CENTRE FOR leadership in industry and stakeholder grants in the region of £42M and state-of- regulatory circuits, riboswitches); chassis collaborations in the chemicals/natural products the-art-facilities underpinning our research engineering (e.g. yeast, bacterial) for robust RESEARCH sectors including: in synthetic biology with world leading and high yield industrial producers; informatics Spotlight Synthetic programmes in biocatalysis (CoEBio3), systems and genomics/metagenomics to facilitate ACIB, AstraZeneca, BASF, Bayer, Bruker, CatSci, biology (MCISB) and protein redesign, structure building block discovery; enzyme engineering Charnwood Consulting, Codexis, Dr Reddy’s, and mechanism (MCBC) as well as leading and evolution to generate new biocatalytic Evolva Biotech, GlaxoSmithKline, Janssen, science technology programmes embedded in module libraries; robotics for accelerated host Biology Orion, Lonza, Merck, Pfizer, Reaxa, Synthace, the wider MIB/UoM research portfolio. These optimization and refactoring; metabolomics/ Syngenta, Shell, Solvay, Unilever and more OF SUSTAINABLE CHEMICALS projects are already providing SynBio solutions analytical science supporting chassis AND NATURAL PRODUCTS to the green manufacture of fine chemicals, optimization and intermediate/product analysis; therapeutic small molecules and new routes to pathway refactoring/assembly comprising EU science and training biofuels. assembly of building locks/modules, pathways programmes in synbio and regulatory components. The Centre of SYNBIOSCHEM integrates We enjoy ‘hub status’ for major EU science and expertise across several knowledge themes These technology platforms are integrated In the wake of the human genome project, microbiology is currently undergoing a major training programmes in this sector, including including: biosynthesis pathway refactoring; through iterative (n) cycles of (circuit design— transition: we are now capable of obtaining a comprehensive molecular view of the entire the innovative medicines initiative award CHEM systems modelling and primary metabolic computational modelling—experiment—data 21 (€25M), EU training networks (MAGIC, cellular circuitry of our microbes of interest, followed by an equally comprehensive re- pathway engineering, chassis (host) and end- analysis— modelling—redesign). These cycles P4FIFTY) and EU FP7 consortium awards engineering of their cellular functions, called Synthetic Biology. Synthetic Biology aims at product yield optimization. These activities will be implemented at different levels, within (DIRECTFUEL; BIONEXGEN; AMBIOCAS; the rational design of biological systems and living organisms using engineering principles, are supported by cutting-edge Technology individual platforms as well as between BIOINTENSE; SUPRABIO). Platforms that are integrated to deliver to achieve new useful functions in a modular, reliable and predictable way. It has the platforms, to establish a semi-automated and outcomes in these knowledge themes and potential to drive a new industrial revolution in biotechnology, with applications in many integrated pipeline for the discovery and re- ultimately assembled to deliver new sustainable engineering of biocatalysts building blocks and sectors, including healthcare, sustainable energy, green chemistry, pharmaceuticals, novel Networks production prototypes for chemicals and engineered pathways/cells. materials and bioremediation. It requires cutting-edge research at the interface of biology, natural product synthesis. BBSRC Natural Products Discovery and engineering, chemistry and computing science. The Manchester Institute of Biotechnology Bioengineering Network (NPRONET) led by The technology platforms support integrated has assembled one of the strongest interdisciplinary teams with world-class expertise in all Jason Micklefield (MIB, UoM) and Barrie work programmes involving (but not these areas in a single state-of-the-art facility. Wilkinson (John Innes Centre) exclusively) the following discipline areas:

SynBio@MIB - Synthetic with a number of SMEs as well as large global MIB-based synthetic biology Biology advancing synthetic companies through regular Industry Days researchers Pipeline to discovery biotechnology hosted at the MIB bringing together academia and industry in focused groups to explore Rainer Breitling, Robin Curtis, Philip Day, Neil Through active collaborations with a large future perspectives in synthetic biology. In Dixon, Sabine Flitsch, Roy Goodacre, Sam variety of industry partners the Centre for addition we have links with international Hay, Finbarr Hayes, Douglas Kell, Ross King, Synthetic Biology of Sustainable Chemicals and Centres of Excellence including the Austrian David Leys, Pedro Mendes, Jason Micklefield, Natural Products (SYNBIOSCHEM) at the MIB Centre for Industrial Biotechnology (ACIB), Aline Miller, Clare Mills, Andrew Munro, Nigel is harnessing the power of synthetic biology to CSIRO biofuels cluster in Australia, SynBerc in Scrutton, Eriko Takano, Nicholas Turner, Simon propel chemicals/natural products production the US (multi-university SynBio Centre), Beijing Webb, Jim Warwicker, Lu Shin Wong. towards ‘green’ and more sustainable Genomics Institute and the Chinese Academy Technology Platforms manufacturing processes, and boost UK of Sciences as well as several SynBio centres research capacity by stimulating innovation across Europe. Associated researchers TP1 Rapid identification of components and with industry and other key stakeholders in the accelerated directed evolution for SynBio Andrew Balmer, School of Sociology chemicals/natural products sectors. Emerging societal, ethical, and regulatory challenges associated with this rapidly Sarah Chan, Faculty of Life Sciences TP2 Bioengineering technologies and Major EU funded projects in synthetic biology advancing new technology are addressed Phillip Shapira, MIIR chassis design include BIONEXGEN, BIOINTENSE and BIOOX in close interaction with social scientists We actively link across campus with network TP3 Metabolomics, analytical science and focused on developing the next generation of and economists across The University of partners as part of a wider synthetic biology metabolic engineering platforms biocatalysts for industrial chemical process. Manchester. strategy. Strategic links in this field have been developed TP4 Computational systems biology, bioinformatics and genomics

26 27 Exploiting natural product assembly Additionally, these co-expression technologies a major global threat. New antibiotics are quantity. In collaboration with Croda, a large STREPSYNTH: Rewiring the to genetic intervention. In setting up SNIP the line genomics and synthetic biology will be used to optimise a number of urgently needed to combat the emerging chemicals company with established routes Streptomyces cell factory for consortium chose two classes of biomolecules for discovery and optimisation of multivariate co-expression challenges, helping critical problem of bacteria resistance. The to market. The team will fully unlock the cost-effective production of with obvious immediate industrial value and novel agrochemicals to guide metabolic engineering efforts leading European Centre for Disease Prevention and potential of this promising broad-spectrum biomolecules application: heterologous proteins (industrial to improved bioprocessing efficiencies, with Control has estimated that antimicrobial antibiotic using synthetic biology approaches. enzymes, biopharmaceuticals, biofuel enzymes, Harnessing world leading expertise in natural the potential to reduce both drug development resistance costs the EU about 1.5 billion Professor Roy Goodacre is bringing his diagnostics) and small molecules (lantipeptides Bioinformatics and biosynthetic gene product synthesis this project brings together times and manufacturing costs. euros in healthcare each year. The UK expertise to bear on STREPSYNTH, an EU FP7 and indolocarbozoles) useful for multiple cluster refactoring will be used for optimum Jason Micklefield, Professor of Chemical government has made clear actions into funded project involving 16 partners and led by industrial purposes (biopharmaceuticals, Dr Dixon has also been awarded a Technology expression and for introducing additional Biology with Professors Greg Challis (Warwick), fighting antimicrobial resistance with a 5 Professor Anastassios Economou (Katholieke additives, food technology, bioenergy). Science Board (TSB) feasibility grant entitled diversity of the chemical structure. The Peter Leadlay (Cambridge) and Russell Cox year Antimicrobial Resistance Strategy Report Universiteit Leuven, Belgium). ‘Rapid Engineering of Cellular Factories’ optimized biosynthetic machinery will then It is envisioned that SNIP is a modular platform (Bristol) to develop a platform technology that published in September 2013. working alongside collaborators from UCL and be introduced into Demuris’s optimised STREPSYNTH aims to establish a Streptomyces- that can be repurposed for diverse future can exploit the potential of microbes for the Synthace to advance the industrial application Despite this, the majority of antimicrobial production host for maximum yield required based new industrial production platform applications. Professor Goodacre is very excited production of useful compounds for use in of synthetic biology. This is a collaborative agents used today belong to old classes for commercialisation. In addition, the methods (SNIP) for high value added biomolecules. to be involved in this novel synthetic biology. agriculture and medicine. R&D project, with the goal of demonstrating of antibiotics discovered before 1970. established in this work will be utilised for Streptomyces lividans was chosen as a bacterial His role is to develop a metabolomics and Many microorganisms produce beneficial the rapid creation of bacterial cellular factories, In partnership with GSK, Professors the activation of novel silent gene clusters host cell because it has already shown itself to fluxomics toolbox which aims to establish compounds, such as penicillin made by a for fine chemical production that is both Jason Micklefield, David Leys and Eriko identified from the genome sequence of be highly efficient in extracellular production standard operation procedures for robust fungus with most microbes having the capacity economically and environmentally sustainable, Takano will investigate the biosynthesis the broad-spectrum antibiotic producer and of a number of heterologous molecules that metabolomics and for 13C- and 15N-based to produce many more compounds than based on industrial biotechnology, and and bioengineering of lipoglycopeptide the products identified and characterised for vary chemically, has a robust tradition of fluxomics in Streptomyces lividans TK24. are actually observed. If their full potential advanced synthetic biology and bioprocesses. antibiotics of the ramoplanin and potential industrial applications. industrial fermentation and is fully accessible can be activated then it could provide new enduracidin family. The lipoglycopeptides compounds for the testing of medicines and are highly potent antibiotics which have agricultural chemicals. Engineered compartments for considerable clinical potential, with monoterpenoid production using ramoplanin having entered phase III clinical This grant funds an ambitious programme China Partnering Award synthetic biology trials. The team will develop alternative to rapidly sequence the genomes of 40 biosynthetic engineering approaches to Professors Eriko Takano and Nigel Scrutton “Synthetic biology is an exciting new field with enormous potential to bring microorganisms with the known ability to TERPENOSOME is led by Professor Eriko enable the rapid structural diversification of have secured funding through a Synthetic benefits to people around the world in all sorts of ways, for example producing produce potential compounds that benefit Takano, and together with Professor Nigel this class of antibiotics, providing access to Biology China Partnering Award, co-funded better antibiotics or manufacturing low carbon fuels. Co-funded initiatives such agriculture. The team will work with partners Scrutton and partners across Europe, it will use large numbers of lipoglycopeptide variants by the Biotechnology and Biological Research as this scheme will see British and Chinese scientists learning from each other’s in the international agrochemical company synthetic biology to engineer novel organelles with potentially improved antimicrobial Council (BBSRC), the Chinese Academy of expertise and benefiting from the globalisation of excellent science.” Syngenta to develop these as new herbicides, for the overproduction of monoterpenoids activities, for subsequent development with Sciences (CAS) and the Engineering and insecticides and fungicides, while partners at in microbial hosts. The project aims to Professor Douglas Kell, Chief Executive of BBSRC industrial partners. Physical Sciences Research Council (EPSRC) the biotechnology company Biotica will focus generate a portfolio of generic methods for to partner and develop long term fruitful on compounds with use in human medicine. the compartmentalization of biosynthetic The new biosynthetic insights will be used relationships with Chinese scientists. The pathways for bioactive molecules; improve the to guide the development of bioengineering This £5M project is funded under the BBSRC funding is provided for up to four years and biosynthetic enzyme systems for more efficient strategies aimed at altering the glycosylation, SLoLa initiative in partnership with Syngenta it is anticipated that the partnerships will bioprocessing and overproduce industrially halogenation and lipidation patterns, as and Biotica. lead to new joint grant applications and high relevant terpenoids, for commercialization by well as the amino acid sequence of the impact research. one of the partners. lipoglycopeptides. The bioengineering “We at CAS attach great importance to international collaboration. The idea of methodologies developed here will be used Professors Eriko Takano and Nigel Scrutton Development and application of The generic compartmentalisation this programme is to put the best minds together. Together our scientists and to engineer a wide range of derivatives for will collaborate with Professor Lixin Zhang at next generation synthetic methodology will be exploited by industrial these from the UK can advance this field more efficiently. In the progress of their other promising classes of antibiotics as the Chinese Academy of Sciences Institute of partner, Life Technologies, in synthetic biology cooperation, I hope they will further strengthen their linkages and collaboration, biology Tools well as other natural product variants for Microbiology to establish cooperative research projects on a wide range of biotechnologically and tackle bigger challenges for the needs of mankind.” alternative therapeutic and agrochemical on the use of synthetic biology approaches for Dr Dixon seeks to develop novel protein relevant high-value compounds. The second applications. production of high-value fine chemicals. production and metabolic engineering tools, Cao Jinghua, industry partner, ACS International, will exploit and demonstrate the applications of these Deputy Director-General of Bureau of International Cooperation of CAS the improved production strains for the widely In a complementary project, funded by novel synthetic biology tools in the context used precursor material limonene, as well as the TSB, Professor Eriko Takano aims to of the bioprocessing industry. Although the two high-value compounds that are the use synthetic biology as a key technology biopharmaceuticals offer many health major target molecules of TERPENOSOME. to discover and develop new antibiotics benefits along with substantial commercial overcoming common problems associated opportunities, their production remains a with antibiotic discovery from natural significant technical challenge. Dr Dixon will Delivering next generation sources, such as poor understanding develop and demonstrate four important “EPSRC is pleased to be part of this joint international call which demonstrates the antibiotics of the antibiotic producer, poor growth flavours of a novel gene co-expression characteristics, reproducibility, poor yield wide scope for synthetic biology to create impact in many academic fields. It has technology, to allow multimeric protein One of the major challenges in healthcare is and lengthy delays to market. Demuris Ltd, the potential to create new solutions to address pressing global challenges, such products to be produced more effectively, the provision of new antimicrobial agents that an SME with expertise in natural products as the need for new fuels, better waste management and new medicines.” along with the potential to provide a simpler can combat antibiotic-resistant pathogens discovery has identified a promising broad- Professor David Delpy, Chief Executive of EPSRC and more efficient manufacturing process. (superbugs), which are widely recognised as spectrum antibiotic but it is produced in low

28 29 RESEARCH Systems Spotlight Biology understanding the dynamics of biological systems

After a century of studying nature in greater and greater detail, generating the “parts list” of the molecular components within the cell, the biological sciences have undergone iGEM Team (l-r): Marco Pinheiro, Jessica Birt; Matthew Birt; Elsa Axelsdottir; Ralf Wenz; Lorna Hepworth, Tim Curd; Divita Kulshrestha; Tan Vun a paradigm shift in the last decade, moving towards putting together these individual Hiang; Eriko Takano (Team Leader) and Rainer Breitling molecular pieces to understand their interactions in a holistic context. Systems biology brings together a wide range of information about cells, genes and proteins, as well as the small molecules that act on and within these biological structures. In the service of its application areas, such as drug discovery and industrial biotechnology, it gives a holistic perspective aiming to track and eventually simulate the entire functioning of biological systems. MIB iGEM team take Best Biological Parts. The teams use these parts “We are very proud of what the team has Undergraduate Human together with new parts of their own design achieved – the Manchester iGEM team is Practices Award at the World to build biological systems and operate them the only first-time undergraduate team in living cells. Championships Jamboree to win this award without the benefit of Manchester Centre for Integrative system require stable and unique identifiers. Along with 60 other teams from across building on the experience of earlier teams For the first time in history an undergraduate Systems Biology (MCISB) These identifiers are assigned to entities Europe the Manchester iGEM team from the same university. This makes team from The University of Manchester such as genes, proteins or small molecules presented their project at the regional iGEM their achievement all the more amazing. competed in the International Genetically The Manchester Centre for Integrative by standardisation bodies and database Jamboree held in Lyon on 11 – 13 October The team involves first-year to last-year Engineered Machine competition (iGEM), Systems Biology (MCISB) at The University providers, and effectively allow the molecular ChEBI provides for the bioscientific 2013 gaining gold medal status and Best students working very closely together”. the world’s premiere UG Synthetic Biology of Manchester was founded in 2006 parts list to be catalogued. In addition to this, community semantic, biological Undergraduate Human Practices Award competition. Student teams are given a having been awarded £6.4M by the BBSRC further relevant information such as names, Professor Eriko Takano and chemical information as which they went on to win at the World kit of biological parts at the beginning of and EPSRC to pioneer the development chemical formulae, structures, relationships and Team Leader iGEM well as stable identifiers for small Championship Jamboree in Boston. the summer from the Registry of Standard of new experimental and computational properties are also associated with the various chemical compounds relevant in technologies in Systems Biology, and their entities in the databases, providing resources biology enabling the integration of exploitation. that are useable by both software tools and metabolomics and systems biology. researchers themselves. The database Chemical Expanding upon the approaches developed Entities of Biological Interest (ChEBI) acts as by the MCISB, members of the centre are a resource for such information and provides now applying these techniques to a range of stable identifiers in the area of small molecules applications, from biotechnology through to of biological interest. systems medicine. COPASI (COmplex PAthway 2012-13 saw the expansion of our research strengths in SynBio with the arrival of Professors Eriko Takano and Rainer Professor Pedro Mendes, together with Dr Simulator) Breitling. The Takano group is focused on the use of synthetic biology for the large-scale genome-based re-engineering Chris Steinbeck from the EMBL - European Bioscience research is becoming increasingly of antibiotic production, awakening “sleeping” antibiotic biosynthesis gene clusters discovered in newly sequenced Chemical Entities of Biological Bioinformatics Institute at EMBL and Dr Neil dependent on construction and simulation microbial genomes. This approach will aid in the combat against antibiotic resistant bacteria, which is an emerging Interest (ChEBI) Swainston of MCISB will further develop of computational models as the technical public health threat worldwide. They will also be applying the synthetic biology tools developed in the group to design the ChEBI resource and create surrounding In order to build up holistic models from such aspects of modelling and simulation are and produce not only antibiotics, but a wide range of bioactive molecules, including anticancer agents. Using and tools towards comprehensively addressing a vast collection of diverse data, integration often overwhelming to a large number of redesigning the enzymes and microbes found in nature they aim at expanding chemical diversity and biotechnological the chemical informatics (software and data) of individual units of information from many biomedical researchers. COPASI provides the efficiency, while avoiding the negative environmental impact of classical organic chemistry at the industrial scale. This needs of the systems biology and metabolic diverse databases needs to be performed. This appropriate numerical algorithms shielded synthetic biology approach brings together expertise from molecular microbiology and many other disciplines, reaching modelling communities, enabling them to integration of such a high volume of data can by a user interface to assist the researcher out towards chemistry, computing science, and engineering. In contrast, the Breitling group explores the application of create comprehensive and reusable models only feasibly be performed computationally. in conducting the required simulations. This bioinformatics and systems biology techniques to the engineering of “designer microbes”, and using metabolomics and to facilitate whole-systems research into To facilitate smooth integration, individual project aims to extend the capabilities of transcriptomics in the diagnosis and debugging of the organisms created by synthetic biology approaches. pressing public health and energy challenges. molecular components within the cellular COPASI by adding the means to simulate

30 31 models with explicit time delays; providing a “This research is the second, important SYBIL provides insight into Perfecting drug combinations achieve as people are often unaware they Sorting and testing 50 drug combinations mechanism for easy calculation of summaries stage of our understanding of the human skeletal diseases to combat severe diseases and are having a stroke – and even then do not at a time using robotics in the laboratory, of entire simulations and groups of genome. If the sequencing of the human conditions completely solve the problem, often leaving the scientists were able to find effective simulations and incorporating a new feature genome provided us with a list of the SYBIL (Systems biology for the functional sufferers with serious disabilities. combinations and then refine them as that will allow researchers, for the first time, biological parts then our study explains validation of genetic determinants of skeletal A multidisciplinary team of researchers, led many times as necessary to find ideal However, using ideal drug combinations to be able to navigate the entire history of how these parts operate within different diseases) is a large scale collaborative project by Professor Douglas Kell, have found a combinations. Ultimately, they hope this will the researchers suggest they can block a model, such that the reasons for changes individuals. It provides a network mapping that brings together a complementary group way of identifying ideal drug combinations lead to the development of tailored therapies inflammation and therefore greatly reduce that took place are formally identified, as all the small molecule transactions that of world-class scientists, disease modellers, from billions of others which would prevent for treating inflammation. the damage caused by non-communicable well as decisions on the model structure. define what goes on with these so-called information technologists and industrialists. inflammation from occurring. The findings, diseases such as stroke. Although the Another advantage of choosing ideal drug The project will also improve and extend metabolites in human biochemistry. The The overall concept of this project is to published in Nature Chemical Biology, could researchers have initially concentrated combinations is that it allows patients to the software’s interoperability and standards results provide a framework that will functionally validate genetic determinants be the first step in the development of new on stroke, they believe the process can take smaller doses, which reduces potential compliance to allow bioscience researchers lead to a better understanding of how of common and rare skeletal diseases to drug combinations to combat severe diseases be applied to all drugs and for a huge toxicology concerns. to freely exchange data and models. an individual’s lifestyle, such as diet, or a gain a mechanistic understanding of disease and conditions. variety of diseases. The team developed particular drug they may require is likely processes and age-related changes, and COPASI (COmplex PAthway Simulator) is Most non-infectious disease, such as cancer, an evolutionary computer program which to affect them according to their specific to deliver new and validated therapeutic based on the GEPASI simulation software stroke and Alzheimer’s are worsened by rapidly sifted through nine billion different genetic characteristics. The model takes us targets. (General Pathway Simulator) that was inflammation, which is the body’s natural combinations of potential drugs. an important step closer to what is termed developed in the early 1990s by Professor Rare skeletal diseases (RSDs) are an extremely defence mechanism. Inflammation has ‘personalised medicine’, where treatments Pedro Mendes. It is the result of an diverse and complex group of diseases that evolved to help fight infection but can also are tailored according to the patient’s genetic international collaboration between The primarily affect the development skeleton. be very damaging in long term disease, information.” University of Manchester (UK), the University There are more than 450 unique and well- prolonging suffering and ultimately risking of Heidelberg (Germany), and the Virginia Douglas Kell, Professor of Bioanalytical characterised phenotypes that range in premature death. After a stroke, the body Bioinformatics Institute (USA). The initial Science at the MIB said: “To understand severity from relatively mild to severe and reacts to the injury as if it were an infection, development of COPASI was funded by the behaviour of a system one must have lethal forms. Although individually rare, as a causing further damage. By blocking the the Virginia Bioinformatics Institute, the a model of it. By converting our biological group of related orphan diseases, RSDs have inflammation, the chances of survival or Klaus Tschira Foundation, the BBSRC and knowledge into a mathematical model an overall prevalence of at least 1 per 4,000 higher quality of life following a stroke are EPSRC. Professor Pedro Mendes has received format, this work provides a freely accessible children, which extrapolates to a minimum of thus greatly enhanced. This can be achieved additional follow on funding from the BBSRC tool that will offer an in-depth understanding 225,000 people in the 27 member states and by quickly and effectively identifying to maintain and develop this important of human metabolism and its key role candidate countries of the EU. combinations of drugs which can be used resource. in many major human diseases. It offers together. Dr Jean-Marc Schwartz will lead one of the the most complete model of the human work packages and, alongside Professor Existing ‘clot-busting’ stroke drugs are only metabolic network available to date to Roy Goodacre, provide the core qualitative effective if administered within three hours Study maps human metabolism help analyse and test predictions about the systems biology analyses for the consortium. after the stroke – often very difficult to in health and disease physiological and biochemical properties Roy has over 18 years experience in mass of human cells. Pharmaceutical drugs get spectrometry (MS), advanced data analysis Scientists from the MIB working with into cells by ‘hitchhiking’ on the transporter applied to spectroscopic, mass spectrometric researchers from Cambridge, Edinburgh, proteins that normally serve to move small and metabolomic data and over 11 years in Berlin, Reykjavik and San Diego among molecules around. An area of particular vibrational spectroscopy. He has published Erythrocyte and fibrin imaging for others have produced an instruction manual interest is thus the incorporation into our over 180 peer-reviewed papers and has disease diagnosis for the human genome that provides metabolic network map of knowledge of a framework to better understand the co-edited books on metabolic profiling and pharmaceutical drug transport.” In a separate study, Professor Douglas Kell has relationship between an individual’s genetic systems biology. He is the Editor-in-chief shown that unliganded iron is responsible for a make-up and their lifestyle. The team have Dr Nicolas Le Novère, from the Babraham of the journal Metabolomics and on the large number of degenerative and inflammatory mapped 65 different human cell types and Institute in Cambridge (UK), said: editorial board of the Journal of Analytical diseases. In collaboration with Prof Resia Pretorius half of the 2,600 enzymes that are known and Applied Physics. Finally, he is a founding “This is a model that links the smallest (University of Pretoria, South Africa), he has now drug targets in order to produce the network director of the Metabolomics Society and molecular scale to the full cellular level. It shown that this manifests in highly aberrant model, providing the most comprehensive director of the Metabolic Profiling Forum. contains more than 8,000 molecular species morphologies of fibrin - the protein responsible model yet to explain why individuals react and 7,000 chemical reactions – no single for blood clotting - and or red blood cells. Work differently to environmental factors such researcher could have built this alone. Having is in progress to use these kinds of measurements as diet or medication. Pedro Mendes, large collaborations like these, using open for the rapid, cheap, and minimally invasive Professor of Computational Systems Biology standards and data-sharing resources, is diagnosis of the severity of such diseases and the commented: crucial for systems biology.” effectiveness of their treatment.

Aberrant morphologies of red blood cells in the genetic disorder hereditary haemochromatosis Picture courtesy Prof E. Pretorius

32 33 Europe PubMed Central An MRC funded project between Supporting evidence-based Manchester (Ananiadou, McNaught), NICE public health interventions using Europe PMC forms a European version of the and the University of Liverpool will address text mining PubMed Central repository, in collaboration these limitations by exploring new research with the National Institutes of Health (NIH) in methods, which combine text mining and Funded by the Medical Research Council RESEARCH Text the United States. NaCTeM collaborates with machine learning to produce novel search (MRC) this project will address current Spotlight the European Bioinformatics Institute (EBI), while screening tools for public health limitations in Evidence-based public health MIMAS and the British Library. NaCTeM’s reviews. Text mining methods will discover (EBPH) interventions by exploring new Mining contribution to this major project is in the automatically knowledge from unstructured research methods which combine text provision of advanced semantic search data and machine learning will support the mining and machine learning to produce facilitating the discovery, extraction and over full papers, involving massive analysis prioritisation and ranking of the extracted novel “search while screening” tools for at the level of individual facts (some 83m information into meaningful topics. The public health. This is a collaborative project structure of knowledge sentences have been analysed so far for our combination of text mining and machine with NICE and the University of Liverpool. EvidenceFinder application). learning methods will reduce the burden of producing public health reviews which will The objectives are to deliver content from be completed more quickly, thus meeting Mining the history of medicine annotated documents, such as concepts, policy and practice timescales and increasing e.g. anatomical entities, genes, chemical Funded by the Arts and Humanities Research their cost efficiency. They also allow more compounds, links to databases, and relations Council (AHRC) this cross-disciplinary Text mining software facilitates the discovery, extraction and structuring of relevant timely and reliable reviews, thus improving amongst concepts, through a sophisticated collaboration between the National Centre knowledge from unstructured text. The output of text mining systems can enrich decision making across the health sector. search facility. EvidenceFinder presents the for Text Mining (NaCTeM) and the Centre documents with semantic information, which can in turn be used to develop search user with a list of questions relating to his for the History of Science, Technology systems that allow users to locate information of interest more quickly and efficiently query, where these questions are derived Text mining interoperable and Medicine (CHSTM) at The University than is possible using traditional search methods. from the abovementioned analysed and of Manchester, seeks to demonstrate the software platforms indexed facts, thus are known to have potential of text mining in medical history. answers. For example, given the query “IL- Interoperability, text mining processing, Initially an asset will be created out of two 2”, EvidenceFinder will present questions and annotation are supported by Argo, a very large, long-running digital sources, the such as “What inhibits IL-2 receptor?”, Web application for analysing (primarily British Medical Journal (BMJ) (1840 - present) “What binds to IL-2 receptor?”, etc., for the annotating) textual data. The workbench and the London-area Medical Officer of user to click on. This allows information to The National Centre for Text scientific publications. Using conventional This project was led by Professor Sophia supports the combination of elementary Health (MOH) reports (1848-1972), by be located that might otherwise be missed, Mining (NaCTeM) provides means, Pathway model reconstruction and Ananiadou in collaboration with Professor text-processing components developed by applying text mining techniques to enrich and to quickly establish which articles do and text mining systems and maintenance is a manual and expensive Jun’ichi Tsujii, Professor Douglas Kell, and the centre to form comprehensive processing these data with semantic annotations. The do not contain information being sought. infrastructure at large scale curation process due to new discoveries. Professor Hiroaki Kitano (Systems Biology workflows. It provides functionality to project plans to extend its impact to the EUPMC funders led by Wellcome Trust. However, PathText links pathway models with Institute, Japan). It was funded by BBSRC. manually intervene in the otherwise following sectors: public health, public policy, NaCTeM has developed text mining tools, textual evidence by combining and ranking Event extraction in collaboration with automatic process of annotation by publishing, media and libraries, with a view resources and services to support the relevant information from the literature using AstraZeneca. correcting or creating new annotations, and to ensuring sustainability and wider uptake automatic extraction of information and text mining methods. http://www.nactem.ac.uk/pathtext2/ Text mining supporting public facilitates user collaboration by providing of methods and technologies. knowledge from the growing amount of http://www.nactem.ac.uk/facta/ health sharing capabilities for user-owned resources. PathText integrates and ranks the evidence literature in an efficient, manageable and from text using a number of text mining Evidence-based public health (EBPH) reviews comprehensive manner at large scale. The workbench builds upon a previous, Open Source Software receives tools and services including the identification play a central role in public health policy, Applications areas include: drug discovery, NaCTeM receives three first place standalone application (U-Compare) that funding boost of reactions, genes, proteins and metabolites practice and guidance. Their development chemistry, systems biology, clinical trials, rankings at Biocreative IV currently hosts over 100 text-processing in their semantic context, from text currently involves first searching, then public health, medical historical archives, components. This EU FP7 funded project will see NaCTeM automatically. NaCTeM’s interoperable text screening and synthesizing evidence from the newswire analysis, pathway reconstruction NaCTeM’s text mining tools were recently working with 8 partners across Europe on mining infrastructure links the text analysis vast amount of literature. Unlike systematic Argo benefits users such as text analysts by and advanced search systems. NaCTeM, led ranked highest in three separate tasks to OSSMETER which aims to extend the field components and text mining workflows reviews, EBPH reviews require dynamic providing an integrated environment for by Professor Sophia Ananiadou and Dr John develop software that can identify important of automated analysis and measurement with an annotation environment to further and multidimensional views of relevant the development of processing workflows; McNaught, is a fully sustainable text mining information in chemical text. In particular, of Open Source Software, and develop a support curators in their task. information from the literature, without annotators/curators by providing manual centre. It has been funded by JISC, BBSRC, NaCTeM was ranked first out of 12 groups platform that will support decision makers relying on a priori research questions. annotation functionalities supported MRC, AHRC, Wellcome Trust, NIH and in the recognition of chemicals, and the in the process of discovering, comparing, PathText currently links CellDesigner with by automatic pre-processing and post- industrial partners. recognition of genes, and first out of 23 assessing and monitoring the health, quality, NaCTeM’s text mining services FACTA+ As a result, EBPH reviewing is a time processing; and developers by providing a teams in a task involving the recognition of impact and activity of open-source software. (mining direct and indirect associations consuming and resource intensive process workbench for testing and evaluating their chemical names. To achieve this, OSSMETER will compute between concepts and bioprocesses), KLEIO that can take more than a year to complete. automatic text analytics. trustworthy quality indicators by performing PathText: reconstructing (advanced semantic facetted search based Since crucial information can be difficult BioCreative IV is the latest in a series of text advanced analysis and integration of pathways with evidence from on bio-entities) and MEDIE (semantic search to locate, and indeed understand given These platforms have been funded by the EC in mining challenges in which teams from both information from diverse sources including text based on bioprocesses). Novel methods such the complex nature of EBPH problems, the the framework of META-NET and by the BBSRC. academia and industry apply their technology the project metadata, source code as automatic event and biological process multiple causes and interrelations between http://argo.nactem.ac.uk to extract a range of types of information repositories, communication channels To understand complex biological http://nactem.ac.uk/ucompare/ recognition from texts have facilitated this from text. interventions, diseases, populations and systems in detail we need to incorporate and bug tracking systems of Open Source task. outcomes can remain hidden. knowledge scattered over millions of

34 35 Software projects. OSSMETER does not aim Tackling early cognitive decline – at building another OSS forge but instead a text mining perspective at providing a meta-platform for analysing existing Open Source Software projects Critically only 50% of people with dementia that are developed in existing Open Source ever receive a diagnosis that could lead to Software forges and foundations such as them receiving medical care and support. RESEARCH SourceForge, Google Code, GitHub, Eclipse, Professor John Keane is collaborating with Spotlight Mozilla and Apache. Professor Alistair Burns and Dr Iracema Leroi from FMHS as part of a joint programme, Technologies NaCTeM leads work package 4, which with Lancaster University and King’s College, concerns the extraction of quality metrics London to look at novel ways in which related to the communication channels, data and text-mining techniques, combined defining the past, informing the present, and bug tracking facilities of Open Source with adaptive user interfaces, may enable driving our future Software projects using Natural Language Linked2Safety : advancing sufferers’ new opportunities for self-referral. Processing and text mining techniques. clinical practice and data security Funded by the EPSRC, the project is entitled NaCTeM will utilise supervised text mining in clinical research SAMS: Software Architecture for Mental techniques to automatically identify Health Self-Management. Understanding how life works and using this knowledge to our advantage is the basis of our questions and answers in threads and Electronic Health Records (EHRs) contain an success as an intelligent species. A sustainable society is achieved through advances in basic analyse types of threads (e.g. problems, increasing wealth of medical information. By exploiting novel data and text mining solutions, complaints) based on the extracted They have the potential to support clinical techniques, combined with adaptive user knowledge and technology. The science of biology is evolving at an unprecedented pace. questions and answers in threads. Opinion and medical research, improve health interfaces, SAMS will validate thresholds Biological systems are quantitative and heterogeneous and these realisations have far reaching mining techniques will be adopted, for the policies, ensure and empower patients’ by non-intrusively examining changes in consequences for their measurement and modelling. This involves expanding our traditional performance in people with established classification of sentiment, in threads will safety and improve the overall quality of understanding of the single organism to the molecular basis of life as well as the workings of be based on a combination of supervised cognitive dysfunction and mild Alzheimer’s healthcare. The Linked2Safety project is the entire biosphere. In order to achieve this we are developing powerful novel technologies methods using statistical, linguistic and funded through the EU 7th Framework disease and begin to explore the potential based on mass spectrometry and spectroscopy that provide detailed chemical information on pragmatic features, and resources such as Programme and involves ten partners from for technology-enhanced detection of early Wordnet and Wiktionary. Text mining analysis eight EU countries including MIB researchers cognitive dysfunction. Patterns of computer the cellular make up of cells and can do this both as a function of time and space. of online threads at several levels will result Professor John Keane and Dr. Goran Nenadic use and content analysis of e-mails, such as in rich multi-layer, feature-based annotations together with colleagues from the School of forgetting topics, expressions of concern, over the input texts, enabling indexing, Computer Science. emotion, etc., will be analysed and coupled flexible interrogation, manipulation and to feedback mechanisms to enhance users’ re-use in subsequent OSSMETER processes. The project aims to advance clinical practice cognitive self-awareness, enabling them Mass Spectrometry@MIB and peptides at the molecular level and Barran formed a team with Professors OSSMETER website: http://ossmeter.eu and accelerate medical research by providing to self-refer themselves for expert medical have developed IM-MS (ion mobility-MS) Ted Hupp and Kathryn Ball (Edinburgh/ healthcare professionals, pharmaceutical advice. Gas-phase ion chemistry research provides instrumentation, in collaboration with CRUK) and Dr Penka Nicolova (KCL) to companies and patients with a secure an enhanced understanding of the analytical Waters, to investigate changes in protein investigate the flexibility of the protein p53 This project is supported by the EPSRC, framework facilitating the efficient and techniques that underpin proteomics, conformation to understand biological using mass spectrometry and IM-MS. This Dementias Neurodegen Network (DeNDRoN), homogenized access to shared distributed metabolomics and the investigation of systems using MS-based techniques which work has been extended to examine other The Alzheimer’s Society, Microsoft Research, Electronic Health Records (EHRs). other molecules of biological significance. have widespread application. The Barran intrinsically disordered proteins of the Cancer the University of British Columbia and Johns New developments in quantitative mass group is currently developing two new ion Genome, including c-MYC, and MDM2 and Linked2Safety facilitates the use of EHRs in Hopkins University School of Medicine. spectrometry provide much needed mobility instruments, one to provide higher has attracted further collaborations with clinical research to support early detection of information for modelling of biological resolution cross section measurements and Professor Richard Kriwacki (Tennessee) and potential patient safety issues based on the networks, while techniques are being one to also allow for photo-interaction. Professors Giovana Zinzalla and Gunner genetic data analysis and the extraction of developed for the analysis and quantification Larson (Karolinska Institute). They have the bio-markers associated with an identified An extremely successful area of multidisciplinary of a variety of post-translational other on-going collaborations with groups type of an adverse event. It also aims to investigation is the structure activity relationship modifications. in UCL, Bristol and Birmingham, Innsbruk support sound decision making and effective of a group of anti-microbial peptides known as and EPL (Switzerland). Since building their organization and execution of clinical trials. In September 2013 we were delighted to -defensins, where Barran led a platform grant β IM-MS instrument they have also been welcome Professor Perdita Barran to the (EPSRC) funded team comprising 7 academic The underlying architecture will be based on sought by several groups in the UK as well MIB as Chair of Mass Spectrometry and groups. Research in this area continues to be a common shared semantic infrastructure as in the USA and Brazil, to provide accurate Director of the Michael Barber Centre for fruitful, and has recently been extended to including linked data, ontologies, common calibration for their mobility data obtained Collaborative Mass Spectrometry. The Barran examine other chemokines in collaboration with medical vocabularies and state-of-the-art with commercial IM-MS instruments. group have developed and maintained Professor Brian Volkman (Wisconsin, USA) and clinical data analytics techniques. many successful collaborations within chemokine GAG interactions with Professor academia and industry in developing and Rob Woods (Georgia USA). Barran is currently applying gas phase methods to problems of collaborating with Professor Cait MacPhee biological and medical relevance. Through and Dr Tilo Kunath (Edinburgh) and Professor the adoption of solvent free methodologies David Allsopp (Lancaster) to look at pre-fibrular they are able to provide an understanding of amyloid aggregates of neurodegenerative structure function relationships of proteins proteins.

36 37 Professor Perdita Barran joins MIB

Perdita graduated from The University of Manchester with a degree in Chemistry with Industrial Experience in 1994. She went on to obtain a PhD in Chemical Physics in 1998 from Sussex University under the supervision of Professors Tony Stace and Sir . Following postdoctoral appointments in the UK and USA she was awarded an EPSRC Advanced Research Fellowship to study “The Structure and Energetics of Peptides and Small Proteins” which she took up at the where she helped to establish a Centre of Proteomics (SIRCAMS).

Since 2009 she has published 38 papers with five currently in review. She has a total publication list of 70 peer reviewed papers (over 900 citations, H factor 23). This impressive The High Arctic camel on Ellesmere Island during the Pliocene warm period, about three-and-a-half million years ago. The camels lived in a boreal-type output spans work on the fundamentals of Ion Mobility Mass Spectrometry, including forest. The habitat includes larch trees and the depiction is based on records of plant fossils found at nearby fossil deposits. instrument development all the way to its application to biomedical problems. Barran CREDIT: Dr. Julius T. Csotonyi, scientific illustrator (csotonyi.com) has communicated 2 book Chapters, and an entry for the European Encyclopaedia of Biophysics (2012). Perdita was awarded The Desty Memorial Prize for ‘Innovation in Professor Perdita Barran Separation Science in 2005, and the Joseph Black award from the Royal Society of Chemistry Chair of Mass Spectrometry and 2009 for her ‘significant developments in the fields of mass spectrometry and separation Director of the Michael Barber Forensics and archaeology Palaeobiodiversity and science, especially ion mobility techniques’ Recently she was appointed as an Editor of the Centre for Collaborative Mass vertebrate evolution ZooMS - short for ZooArchaeology by International Journal of Mass Spectroscopy. Spectrometry. Mass Spectrometry – is a pioneering new Recently, Dr Mike Buckley was approached by Dr “This is the first time that collagen has technique called “collagen fingerprinting” Natalia Rybczynski, a vertebrate paleontologist been extracted and used to identify which uses the persistence and slow with the Canadian Museum of Nature to a species from such ancient bone evolution of collagen as a molecular identify bone fragments dating from three- fragments. The fact the protein was able barcode to read the identity of bones. The and-a-half million years ago. By extracting to survive for three and a half million method, developed by Dr Mike Buckley minute amounts of collagen, the dominant approaches to studying carbohydrate years is due to the frozen nature of Adopting a combined during his PhD, uses a well-established protein found in bone, from the fossils and structure. the Arctic. This has been an exciting experimental-computational approach, peptide mass fingerprinting, using chemical markers for the peptides that project to work on and unlocks the huge approach allied to high throughput Time of Flight make up the collagen, a collagen profile for the Paul Popelier, Professor of Chemical Theory potential collagen fingerprinting has to Mass Spectrometry. Bones are identified by fossil bones was developed. Dr Buckley then Many advances in medicine, biology, and Computation has joined forces with Dr better identify extinct species from our differences in the mass of the peptides which compared the profile to 37 modern mammal chemistry and materials science of the last Ewan Blanch, Reader in Biophysics and a preciously finite supply of fossil material.” arise as a result of sequence differences species, as well as that of a fossil camel found in few decades owes much to the structural Raman spectroscopist on an EPSRC funded between species. the Yukon. The collagen information, combined Dr Mike Buckley information that has been obtained project to develop a combined computer with the anatomical data, demonstrated that Royal Society University Research for proteins and nucleic acids by X-ray modelling and spectroscopic lab-based the bone fragments belonged to a giant camel crystallography and NMR spectroscopy, and approach to characterising the structures as the bone is roughly 30% larger than the which has revolutionised our view of how of carbohydrates, from simple sugars to Secondary Ion Mass same bone in a living camel species. key carbohydrate polymers known to be Spectrometry (SIMS) life works. Unfortunately, these techniques are far more difficult to apply to the main involved in regulating biological functions SIMS is developed and used for the analysis class of biomolecules - carbohydrates. generating a uniquely incisive new tool for and imaging of chemical and biological Despite carbohydrates constituting over half glycobiology. The team will be combining systems, including advanced materials, of the biomass of our planet and performing high level quantum chemistry calculations, Discovery of detailed genotype adolescent buried sometime between 1840 are particularly interested in linking strain single cells and biological tissue. The aims an almost limitless number of roles in living molecular dynamics simulations and highly of a historic strain of M. and 1911 in a crypt in Leeds, England variations to changes in TB virulence during involve novel insights into the chemical and systems, we don’t really understand how detailed Raman spectra to develop and tuberculosis through the use of pioneering new methods the medieval period, when Britain became spatial organisation and function of these they work in the same way that we do for validate novel computer modelling tools based on next generation sequencing. increasingly urbanised. They are also The study of ancient DNA enables the systems at the molecular level. proteins and DNA. The lack of definitive that will provide new insights into many comparing strain data for TB in Europe with prevalence of diseases in past populations to M. tuberculosis is the second deadliest data means there is still considerable debate other areas of research, such as protein- similar results from the Americas, the latter Nick Lockyer and Professor John Vickerman be determined by analysis of skeletons for infectious agent worldwide, yet little is as to how we even define structure in ligand interactions and DNA-drug molecule helping us to understand why many native are developing applications of SIMS in the presence of pathogen DNA. In a recent known about the bacterium’s historic genetic carbohydrate polymers. In order to best binding. Americans died of TB after first contact with areas involving the characterisation and study of Mycobacterium tuberculosis (MTB) variations and how such historic strains capitalise on the immense potential of Europeans even though strains of TB had classification of cells and tissue at the Although the resulting development of published in PNAS, Terry Brown, Professor have evolved over time. The genotyping carbohydrates in both science and industry been endemic in the New World for many molecular level. They are also working new computational tools will be focused of Biomolecular Archeology, together with of historic strains of M. tuberculosis could we have to understand in more detail years prior to contact. The Brown group closely with industry to develop new on the structures and behaviour of researchers from York and Durham, have enable comparisons between strains from the molecular principles that govern their have worked on several diseases, including instrumentation and analytical protocols to carbohydrates, the end product will also be obtained the detailed genotype of a historic different geographic locations and time assembly, organisation and interactions with malaria and syphilis, and most recently on advance SIMS applications in biosciences. widely applicable to all other biomolecules, strain of M. tuberculosis from a female periods, and may yield clues about the other molecules which requires alternative tuberculosis and leprosy. particularly proteins and nucleic acids. pathogen’s evolutionary history. The group

38 39 Raman spectroscopy and cells: Fingerprinting food lighting up sub-cellular research MIB researchers using MALD-TOF-MS and Raman spectroscopy is a physicochemical chemometric approaches have found new method based on the interaction of light applications as a fast and accurate viable with matter. In Raman scattering a molecular bacterial detection and quantification vibration yields light of a different wavelength. method for routine use in the milk and This enables a very powerful and non-invasive meat industry. Major food adulteration and analysis of the chemical and structural contamination events seem to occur with information of a sample; indeed one can some regularity, such as the widely publicised use this to measure protein structure and adulteration of milk products with melamine Bruker & MIB – investing in the posttranslational modifications. Moreover, and the recent microbial contamination of future of NMR Spectroscopy vegetables across Europe for example; and Terry Brown, Professor of Biomolecular Archaeology it is highly sensitive and when coupled with atomic force microscopy (AFM) has exquisite more recently the horsemeat scandal, which Nuclear Magnetic Resonance (NMR) “This project will provide I became fascinated with the natural world when I was very young. I began my research spatial resolution (<20 nm). In the MIB we has rocked consumer confidence in the spectroscopy is an essential platform career studying the effects of metal pollution on microorganisms and the tolerance that a new dimension to our are developing Raman to analyse cells and food supply chain. With globalisation and technology for research in the life and some plants display to high concentrations of toxic metals. I then became excited by understanding of early their components and this has recently been rapid distribution systems, these can have chemical sciences and currently makes a major DNA and worked on mitochondrial genes in fungi in order to learn the new (in those European agriculture facilitated via three new approaches: (i) optical international impacts with far-reaching and contribution to UK research priorities such as days) techniques for gene cloning and DNA sequencing. I contributed to the discovery of and also inform work on trapping of eukaryotic cells using Raman sometimes lethal consequences. These events, ageing and infectious disease characterizing though potentially global in the modern mitochondrial Group 1 introns and to work that described the base-paired structure of the impact that future tweezers; (ii) coupling in situ cell growth biomolecular structure, function and dynamics. these introns. I then became interested in ancient DNA and was one of the first people facilities within the instrument so that drugs era, are in fact far from contemporary, and Our capabilities in NMR have expanded rapidly environmental change internationally to carry out DNA extractions with bones and preserved plant remains. and metabolites can be mapped within cells; deliberate adulteration of food products is with the purchase of an 800 MHz instrument This work has required close collaboration with archaeologists, both in Manchester could have on the (iii) the very recent acquisition of an AFM- probably as old as the food processing and from Bruker. This addition to our facility, which and elsewhere, and has led to my current interests in the origins of agriculture, genetic sustainability of modern Raman system which shall be developed for production systems themselves. Professor currently houses 400 MHz, 500 MHz and 600 profiling of archaeological skeletons, and the evolution of disease. cereal cultivation.” tip enhanced Raman spectroscopy (TERS) Roy Goodacre’s critical review “Fingerprinting MHz instruments, will open up a substantial imaging, following on from our pioneering food: current technologies for the detection number of new research programmes focusing work in bacterial surface enhanced Raman of food adulteration and contamination” on the structures and dynamics of complex scattering (SERS). features on the inside cover of the September macromolecular systems. Our commitment to 2012 edition of Chem Soc Rev. This developing methods and technologies in the ADAPT – Life in a cold climate: Combining genome sequencing and adaptation to the new environments into review first introduces some background area of magnetic resonance spectroscopy is the adaptation of cereals to transcriptome profiling with ecological which they were being taken. The Brown into these practices, both historically and shared by Bruker UK Ltd who has committed 4 new environments and the niche modelling of a large collection of group will also compare with demographic contemporary, before introducing a range fully funded studentships to the MIB. establishment of agriculture in historic varieties of barley and wheat data on early farming communities, which of the technologies currently available for the detection of food adulteration and Europe landraces collected from different parts of suggest that in some regions an initial Europe this project aims to identify regions increase in population size was followed by contamination. These methods include the Professor Terry Brown has recently secured of Europe where early crops underwent rapid decline, possibly indicating that further vibrational spectroscopies: near-infrared, significant funding from the European evolutionary adaptation in response to genetic adaptation was needed before crops mid-infrared, Raman; NMR spectroscopy, as “Bruker has long maintained an Research Council to explore the concept of local environmental conditions. These data became productive enough to support long well as a range of mass spectrometry (MS) interest in structural biology with active agricultural spread as analogous to enforced will then be compared with archaeological term population growth. techniques, amongst others. This subject area collaborations in various research climate change and asks how cereals information on the rate at which agriculture is particularly relevant at this time, as it not projects into method development adapted to the new environments to which spread through different parts of Europe, only concerns the continuous engagement and applications across an array of they were exposed when agriculture was in order to understand whether pauses in with food adulterers, but also more recent technology including the development introduced into Europe during the period the advance of agriculture were caused issues such as food security, bioterrorism of the National EPR Centre. Our 7000–4000 BC. by the need for crops to undergo genetic and climate change. It is hoped that this company ethos and commitment to introductory overview acts as a springboard knowledge advancement is shared by for researchers in science, technology, the MIB and we are very excited to be engineering, and industry, in this era of directly involved in the training of young systems-level thinking and interdisciplinary scientists through our sponsorship of approaches to new and contemporary four MIB-Bruker studentships aimed at problems. developing a strong strategic partnership with MIB that will ultimately generate new discoveries and innovations.”

Jeremy Lea Bruker UK Ltd Ribs from the female adolescent skeleton 4006 from St. George’s Crypt, Leeds. Bone formation possibly indicative of pulmonary 1cm TB is visible on the surface of the ribs within the area indicated by the boxes.

40 41 Manchester Centre for through temporal analysis of dynamic to large pharmaceutical companies (ie. Biophysics and Catalysis (MCBC) transitions relevant to biological function and Shell, AstraZeneca, DSM, TgK) on a range of catalysis from the femtosecond to second projects. MCBC also works with instrument MCBC is a state-of-the-art cross disciplinary timescale. developers to generate next generation platform technology centre integrating biophysical instruments, for example specialised MCBC is home to a number of platform biophysical, structural, and computational applications in laser/infra red spectroscopy, technologies in the biophysical and catalysis methods to address contemporary problems high pressure NMR spectroscopy and high areas. At Manchester we emphasize the in catalysis and the dynamical properties pressure optical spectroscopy. State-of-the-art integration of these technologies to address of biological macromolecules. The MIB facilities in the MIB include: anaerobic facilities, major biological challenges at the molecular has recently emerged as a world-leader in bioengineering and evolution, chemical level. This molecular insight is crucial in integrated biophysics and catalysis, with biology and synthesis, computation and theory, developing larger scale understanding of capabilities spanning all aspects of biological electron microscopy, electron paramagnetic biology at the systems level. We also place structure determination, magnetic resonance resonance, laser facilities, microfabrication and emphasis on developing new technologies spectroscopies, time resolved and single nanotechnology, nuclear magnetic resonance, and the translation of molecular-based molecule spectroscopy and biological/ single molecule approaches, structural research. MCBC develops programmes chemical computation. By going beyond biology, time resolved spectroscopy and x-ray with external partners in most areas of simple structure determination of biological crystallography facilities. molecules MCBC is driving the new research expertise and works with a number ‘dynamics determines function’ paradigm of industrial partners ranging from SMEs Innovation in Action

Robots are already part of the pharma industry’s development process, but could they ever The MIB pursues and is engaged in challenging research projects that enable us to make significant advances in take over completely? science to benefit industry and society. Through innovative research, we can help you advance your business, “…the motivation for our work is partly philosophical and there is a strong view solve technical problems, improve your processes, develop new products and build the technical capabilities of Ross King, Professor of Machine Intelligence, that holds that we do not fully understand a phenomenon unless we can replicate and his colleagues have spent a decade it: “What I cannot create, I do not understand” [Richard Feynman from The Universe your staff. We understand the importance of adapting the approach to meet the needs of the project. developing Robot Scientists – machines in a Nutshell]. Automating science is an excellent test bed for AI as it involves designed to automate the discovery of formal reasoning with interaction with the real-world. However the most important There are a number of ways for commercial businesses to benefit from the academic expertise fostered in the scientific knowledge. motivation is that we wish to make scientific research cheaper and more cost- MIB. We run a successful programme of networking events with industrial partners and other stakeholders effective”. that focus on developing practical strategies to create short-term, mid-term and long-term relationships for The King group built two Robot Scientists. “Adam” was designed to understand how Ross King mutual benefit. Our partnerships range from collaborative research programmes to joint studentships and the components of cells work together Professor of Machine Intelligence instrumentation-technologies development across the chemical, biotechnology and biopharmaceutical sectors. (functional genomics) and is the first machine to have discovered some novel scientific knowledge. New Robot Scientist “Eve” is designed to automate drug screening and Collaborations Benefits of collaborative research with MIB include: design. Eve has been applied to the discovery We actively engage with a wide range of companies from large • the cost effective trialling and testing of products, drugs and of leads for neglected tropical diseases such pharmaceutical to smaller SMEs. Existing partnerships include compounds using University facilities and expertise as malaria, African sleeping sickness, Chagas companies from the Chemical, Biotechnology and Biopharmaceutical disease etc. • the development of close long-term relationships with academic sectors as outlined in our research portfolio including Bruker, BASF, staff to build a relevant and comprehensive portfolio of research GSK, Novartis, Shell, Siemens, Solvay, Syngenta and Unilever. and expertise needed to meet your company’s specific needs. We offer an unrivalled environment that presents opportunities for • the transfer of innovative techniques and practices from the placements in industry across a variety of research disciplines. Our laboratory to the manufacturing process portfolio of industrially sponsored postgraduate studentships includes Bruker Ltd, Lonza, Unilever, AstraZeneca, TgK, Chirotech, Shell and • the direct licensing of innovative technologies and processes GlaxoSmithKline. • the accessing of government and European Union funds for We also host European biotechnology training networks in Industrial academic research that would be out of reach for purely Biotechnology including P4fifty and BIOTRAINS, for the support commercial projects for the chemical manufacturing industries and MAGIC (MAGnetic Innovation in Catalysis).

42 43 Technology Transfer Spin-out companies PeptiGelDesign was founded in 2013 by Drs Aline Miller and Alberto Saiani. A The University of Manchester Intellectual C4X, known as Conformetrix, founded technological platform has been developed Property Limited (UMIP) assists in the by DrAndrew Almond, is focused on based on the fundamental understanding commercialisation of any innovative the optimisation of drug discovery and of the self-assembly of oligo-peptides technologies and processes that may be design using NMR-based technology to across the length scales. This allows the derived from collaborative research. UMIP accurately solve bioactive three-dimensional design of bespoke biocompatible and has over a 20 year history of Intellectual molecular structures. Conformetrix Ltd and biodegradable hydrogels with tailored Property (IP) commercialisation and works AstraZeneca signed a research collaboration mechanical properties and functionality for closely with MIB to ensure that any IP is fully agreement under which Conformetrix’s a range of biotechnological applications. developed to maximise technology transfer. proprietary NMR-based technology will be These hydrogels are composed of an applied across AstraZeneca’s pre-clinical entangled network of elongated fibres that In the FY2012-13 the MIB has secured over therapeutic pipeline to enhance lead mimic the structure of extra cellular matrix. 31 invention disclosures which represents discovery and hit identification. Their mechanical strength can be tailored a 48% increase from the previous year and to span those of a large range of human filed 1 priority patent and 2 new licences. PharmaKure, founded by Professor Andrew tissues. Moreover the hydrogels can be Doig and Dr Farid Khan, launched in 2012 to functionalised with multiple biologics and explore new Alzheimer treatments through pharmaceuticals. These novel materials For further details of collaboration and the screening of existing drugs. Pharmakure are therefore suitable and proven as drug is a new drug discovery company focused Research Centres, partnership opportunities please contact: delivery vehicles, scaffolds for cell based on Alzheimer’s disease through the discovery therapies and assays as well as tissue Dr Ros Le Feuvre of new uses for old drugs, offering great Institutes and Facilities engineering, thereby enabling the next E: [email protected] promise for delivering new therapeutic generation of therapeutic treatments. This Embedded within the Institute are a number of internationally renowned research centres. T: +44(0)161 306 5184 options to patient care. research is now being commercialised through the spin out PeptigelDesign Ltd. Dr Penny Johnson E: [email protected] T: +44(0)161 306 4474 Research Centres Michael Barber Centre for Collaborative Manchester Centre for Integrative Mass Spectrometry Systems Biology (MCISB) Centre of Excellence in Biocatalysis, Biotechnology YES 2012 - MIB The competition was hosted by The University bioscience postgraduate and postdoctoral Biotransformations and Biocatalytic The Michael Barber Centre for Collaborative The MCISB provides a hub for cutting-edge team triumphs in National of Manchester’s Innovation Centre (UMIC) researchers develop hypothetical business plans Manufacture (CoEBio3) Mass Spectrometry is a leading research centre systems biology research pioneering the competition to be the and organised jointly by the BBSRC and for plausible biotechnology companies. They devoted to developing mass spectrometry development of new experimental and Development of new biocatalyst-based biotechnology stars of the future the University of Nottingham’s Institute for receive help and advice from speakers, mentors based technologies and their application to computational technologies and skills necessary processes to meet the changing needs of Enterprise and Innovation (UNIEI). Biotechnology and judges in areas such as intellectual property, biological problems. Professor Perdita Barran, for the development of quantitative Systems industry in the next 10-20 years. CoEBio3 Members of Jason Micklefield’s research Yes is in its 17th year and aims to help financial planning and marketing. Waters Chair in Mass Spectrometry has recently Biology, and their exploitation. will train graduate and postdoctoral scientists group secured a place in the final of such that they possess the necessary taken up the post of Director. www.mcisb.org a national competition to find the combination of skills in chemistry, biology entrepreneurial bioscientists of the future. Enzomax and engineering needed to support these Matthew Styles, Anna-Winona Struck, Sarah (l-r): Brian Law, Anna-winona Struck, Matthew Styles, Sarah Shepherd, James Leigh changes. Manchester Centre for Biophysics and Manchester: Integrating Medicine and Shepherd, Brian Law and James Leigh formed www.coebio3.org Catalysis (MCBC) Innovative Technology (MIMIT™) team Enzomax and beat off stiff competition MIMIT™ uses its unique Innovation from 377 competitors across 82 teams in MCBC is a state-of-the-art cross disciplinary Development Process™ to scope five regional workshops held in October platform technology centre integrating National Centre for Text Mining unmet healthcare needs and accelerate and November in the Biotechnology Young biophysical, structural, and computational (NaCTeM) the development of new healthcare Entrepreneurs Scheme (Biotechnology YES) methods to address contemporary problems technologies; thereby enabling new 2012 competition. The team flew the flag in catalysis and the dynamical properties of The National Centre for Text Mining technologies to reach patients faster and for Manchester in December at the UK finals biological macromolecules. By going beyond (NaCTeM) is the first publicly-funded text more effectively. held in London. Although the team did not simple structure determination of biological mining centre in the world. The Centre www.mimit.org.uk scoop the top prize, which went to Calvitium provides text mining services in response molecules MCBC is driving the new Solutions, they won the category for “Best to the requirements of the UK academic ‘dynamics determines function’ paradigm consideration of IP strategy” sponsored by community leveraging the UK e-Science through temporal analysis of dynamic Potter Clarkson. framework, grid technology, relevant transitions relevant to biological function and standards and OMII-UK middleware. catalysis from the femtosecond to second Enzomax have a proprietary platform www.nactem.ac.uk timescale. technology, known as Enzomax SHIELD™, www.mcbc.ls.manchester.ac.uk which they use to deliver cost-effective solutions for maximising the performance of enzymes in industrial biotechnology.

44 45 Research Institutes Biophysics ÄKTAxpress Protein Purification systems; Nuclear Magnetic Resonance (NMR) Mass Spectrometry Bionanotechnology and Imaging Biomek FXp liquid handling robot; Syngene The University has established a number Enquiries: Dr Derren Heyes Enquiries: Dr Matthew Cliff Enquiries: Reynard Spiess Enquiries: Dr Steven Marsden chemiluminiscence imaging system and a 10 of prestigious interdisciplinary Research [email protected] [email protected] [email protected] [email protected] litre wavebag (GE Healthcare) for insect cell Institutes in addition to existing specialist Tel: +44(0)161 306 5159 Tel: +44 (0)161 306 4229 Tel: +44(0)161 306 5157 Tel: +44 (0)61 306 5186 scale up. research centres and groups. Research The Biophysics Facility is one of the largest, Nuclear Magnetic Resonance (NMR) Gas-phase ion chemistry research provides This facility includes instrumentation for institutes incorporate the acknowledged The facility collaborates extensively across academic ‘Kinetics and Spectroscopy’ spectroscopy is one of the principal an enhanced understanding of the analytical the imaging, manipulation or measurement research strengths across the University into departments in the University that includes: facilities for bioscience research in the techniques used to obtain physical, chemical, techniques that underpin proteomics, of single biomolecules or single molecule core research priorities. Researchers in the Michael Smith building, AV Hill, Stopford world and consists of over £1.5 million of electronic and structural information about metabolomics and the investigation of biochemical reactions. Recent AFM projects MIB have strong links with the following Building, St Mary’s Hospital, Patterson state-of-the-art instrumentation. We offer molecules. It is a powerful technique that other molecules of biological significance. include imaging of graphene on silicon institutes: Institute and MIB. External collaborators have cutting-edge biophysical equipment, which can provide atomic resolution information New developments in quantitative mass oxide in air, fixed xenopus embryos in PBS, been growing over the last two years now Photon Science Institute can be used to study many different chemical on the topology, dynamics and three- spectrometry provide much needed protein fibrils, mucins, gold nanoparticles, and some examples are Sheffield University, www.manchester.ac.uk/psi and biological processes over a range of dimensional structure of molecules in information for modeling of biological etched troughs and pits in silico, end to end Abcam, Syngenta, Takeda & Heptares. timescales and temperatures. The facility is solution and the solid state. The breadth networks, while techniques are being protein stretching and a selection of cell and Institute for Science Ethics and actively involved in a wide range of research The protein expression team have recently and quality of information attainable from developed for the analysis and quantification surface indentation experiments on the JPK Innovation topics and has contributed to a number of been named on two successful grants NMR measurements makes it unique among of a variety of post-translational modifications. CellHesion AFM. www.isei.manchester.ac.uk publications in a broad range of high impact (£250,000 ‘EURenOmics EU FP7 collaborative spectroscopic tools. Additional capabilities include: Mass The facility offers a range of microscopes journals. project & £157,000 from Kidney Research Cancer Research UK Manchester Institute In March 2012 the MIB took delivery of a Spectrometry (including Secondary Ion Mass for routine fixed specimen imaging and UK) with Professor Paul Brenchley at St www.cruk.manchester.ac.uk The facility has developed the use of new 800 MHz Bruker NMR spectrometer, Spectrometry (SIMS) and Fourier Transform specialised microscopes including multimode- Mary’s Hospital to study the role of the advanced spectroscopic tools to study along with upgrades to existing 600 and 500 Ion Cyclotron Resonance (FT-ICR)), Electron picoforce atomic force microscope (AFM); protein PLA2R in the disease membranous catalytic, binding, structural and dynamical MHz spectrometers. These new additions to Paramagnetic Resonance (EPR), Infrared JPK cellhesion AFM; Total Internal Reflection nephropathy. Research Facilities processes in biological macromolecules our facility will open up a substantial number and Raman Spectroscopy, Fluorescence Fluourescence Microscope (TIRFM); Raman including advanced fluorescence techniques; of new research programmes focusing on Spectroscopy (including anisotropy decay). Laser Tweezers; Fluorescence Correlation We have an impressive range of specialist Circular Dichroism (CD) spectroscopy; the structures and dynamics of complex Spectrometer (FCS); Typhoon Trio+ Variable research facilities in the MIB which are Manchester Protein Structure Facility electrochemical approaches to probe redox macromolecular systems. Mode Imaging System for scanning maintained by dedicated experimental properties of biological molecules using fluorescent and radiolabelled gels and an Enquiries Dr Colin Levy Secondary Ion Mass Spectrometry (SIMS) officers offering flexible and tailored use of We have close links with Bruker who potentiometry apparatus; Fourier Transform Olympus BX51 upright fluorescence snapshot [email protected] our facilities, ranging from walk-in service have contributed four 4-year fully funded Infra-Red (FTIR) spectroscopy; Isothermal Enquiries: Dr Nick Lockyer microscope with colour and monochrome Tel: +44 (0)161 306 5185 to formal collaborations. Services and industrial PhD studentships. titration calorimetry (ITC) and surface [email protected] cameras. equipment are available to University of plasmon resonance (SPR). X-Ray crystallography utilises X-ray diffraction Tel: +44(0)161 306 4479 MIB has both state-of-the-art very high Manchester researchers and external users In addition a large selection of widefield, by single protein crystals to elucidate three magnetic field strength instruments, and from academia and industry. Complementary spectroscopic techniques SIMS is developed and used for the analysis confocal and specialist microscopes are dimensional structures at atomic resolution. more economical lower field instruments. are available in MIB in EPR spectroscopy and imaging of chemical and biological available in the Michael Smith Building The technique plays a pivotal role in (Steve Rigby) and Raman spectroscopy (Ewan systems, including advanced materials, single Bioimaging Facility. understanding how individual amino acids Blanch/Roy Goodacre/Peter Gardner). cells and biological tissue. The aims involve Protein Science – an integrated approach interact with small molecule ligands and Computational Chemistry novel insights into the chemical and spacial cofactors. In addition to the above we offer a number The Protein Science Facility at the MIB organisation and function of these systems of kinetic instruments to study biological and Enquiries: Linus Johannissen provides protein production services and The Facility provides a complete service at the molecular level. chemical reactions on the fs – sec timescale. [email protected] access to the state-of-the-art instrumentation pipeline, taking you from purified protein Tel: +44 (0)161 306 4559 Nick Lockyer and John Vickerman are for the analyses of protein structure, to crystal structure. Meeting the often rate developing applications of SIMS in dynamics and function. Supported by a suite limiting challenge of crystallogenesis are two Simulating protein function and dynamics areas involving the characterisation and of anaerobic facilities all experiments can be Manchester Protein Expression Facility complimentary high throughput nanolitre using computational methodologies classification of cells and tissue at the carried out in O2-free environment. dispensing robots (Mosquito & Phoenix) including protein dynamics & conformational Enquiries Dr Eddie McKenzie molecular level. They are also working allowing rapid screening and optimisation. change (MD simulations); free energy Maintained by a team of dedicated [email protected] closely with industry to develop new The facility also houses two rotating calculations (umbrella sampling, experimental officers we offer flexible and Tel: +44 (0)61 306 4170 instrumentation and analytical protocols to anode X-ray generators and associated metadynamics); ligand binding (docking, tailored service, ranging from walk-in to advance SIMS applications in biosciences. data collection equipment. These in-house The facility provides a comprehensive metadynamics) and catalytic mechanisms formal collaborations. The facility is open facilities are further supplemented with resource for the high level expression (QM & QM/MM calculations). to researchers and students from across the regular synchrotron access. and scale-up production of recombinant University, other educational institutions, and MassSpec@Manchester proteins. Currently we offer a choice of industry scientists. four expression systems: bacteria, pichia, Mass spectrometric research has a long and insect and mammalian cells. Depending rich history at The University of Manchester. on particular needs we are able to provide In this network we attempt to bring together either small scale production facilities the experience and expertise of these for biochemical analysis and antibody researchers under one umbrella. production or larger scale production for structural studies. Equipment includes

46 47 “MAGIC” brings Marie Curie involved in their research projects. success to Manchester The concept of team-based activity is well The MIB and Photon Science Institute (PSI) founded across research groups in MIB- have secured a Marie Curie FP7 IDP training PSI and will enrich the training experience “Our aim is to train the future network grant worth 3.4 million euros. bringing multiple skills embedded in these generation of leading investigators of The four year grant entitled “MAGnetic teams to MAGIC programmes. These novel biological catalysis/enzymology with Innovation in Catalaysis”, known as MAGIC, methods will transform current experimental a view to developing new enabling will see the MIB and PSI host 12 Early Stage capabilities and will be applied to a range technologies that can advance physical Researchers (ESR’s) who will be appointed of important biological catalysts to probe understanding of catalysis and to three-year PhD training programmes. the mechanistic importance of coupled mechanism. Collaborative research Hosted at the MIB and PSI this project will motions and quantum physico-chemical projects will explore the mechanistic see Manchester partner with six Universities effects. Innovative physical sciences magnetic details of enzyme systems by adopting (Tokyo, Freiburg, Lund, Joseph Fourier resonance techniques (NMR and EPR) will be innovative, versatile and unique in France, Edinburgh and Copenhagen) developed and implemented in a life sciences experimental techniques to probe the and five companies (AZ, Bruker, TGK, context to transform studies of enzyme contributions of motions across multiple Conformetrix, and SarOMICS) with each mechanisms and catalysis, and ultimately spatial and temporal timescales and Postgraduate and ESR closely linked to the international and rational design. quantum chemical effects. In turn industrial partners who will be actively these novel methods will transform current experimental capabilities and Training will be applied to a range of important biological catalysts to probe the mechanistic importance of coupled motions and quantum physico-chemical effects.” The MIB offers a unique environment to carry out multidisciplinary research with open-plan laboratory and write-up areas designed to promote open communication between researchers from diverse and hybrid Professor Nigel Scrutton scientific backgrounds. Home to over 250 PhD students and 80 MSc students we endow our interdisciplinary Director investigators with the key skills to enable them to work successfully across the disciplinary interfaces at the forefront of biotechnology.

In addition to the traditional UK doctoral chemistry through the isolation, redesign and In the search for new enzymes and training programmes we host a number application of cytochrome P450 enzymes. As biocatalysts, high-throughput screening of EU training networks (P4fifty, Biotrains part of the P4FIFTY network, research groups methods for catalysis have a key role and they and MAGIC). Students join a vibrant at ten European institutions will collaborate are necessary for screening libraries generated and dynamic international community of on trying to address some of these limitations, either from sampling the biosphere or from researchers and students from across the including the following areas: Gene discovery diverse generation methods. The technique “The MIB has a reputation for pushing the boundaries in technology development and EU and around the world including China, for new P450 activity from microbes and suitable for HTS must be rapid and cost innovation. I was delighted to join the MIB as it promotes interdisciplinary, challenge Egypt, Saudia Arabia, India, Pakistan, USA, plants; Enabling P450 application through effective and reflecting the desired functions. oriented science that is supported by an outstanding structural biology infrastructure.” Mexico, Chile and amongst others. fusion protein technology; The MIB team has successfully developed new using strategies informed by X-ray structure Claudio Santos We offer an unrivalled environment that fluorescence based HTS methods for several and bioinformatics; Process technology for the Ph.D Biochemistry, 2nd Year Bruker Studentship presents opportunities for placements biocatalytic reactions. This HTS method will be scale-up of P450-catalysed reactions. in industry across a variety of research used to screen bacterial, plant, fungal (and their disciplines with a growing number of Cytochromes P450 (P450s or CYPs) are mutants) P450 libraries for hydroxylation activity research students industrially funded heme-containing oxygenase enzymes that against a set of standard compounds which through Bruker UK Ltd, Lonza, Cypex, catalyse crucial reactions in physiology, have to give specific reaction with human Unilever, UCB Pharma, AZ, TgK, biosynthesis and biodegradation. The power P450s. Another aspect of MIB efforts will be Medimmune, Chirotech and Shell. of P450s can be recruited for the clean, green to develop P450s active in both conventional “The MIB is an exhilarating environment in which to carry out research. I enjoy chemical synthesis of important intermediates organic solvents and also alternative ones (such associating with peers from around the world, and the up-to-date facilities mean the in the bulk chemical, pharmaceutical and as fluorinated solvents) providing engineering research undertaken here is of the highest quality. I also believe that the integration P4FIFTY in the search for new agrochemical Industries. However, their solutions for large scale application to be of different experimental approaches provides a key advantage over other competing enzymes and biocatalysts application is frustrated by natural limitations investigated. The adaptation of existing HTS groups and institutions.” such as low activity, insoluble gene expression methods is associated with synthesis and testing Alex Geddes P4FIFTY is an FP7 funded European Marie and the dependence on auxiliary electron new potential substrates. Ph.D Biochemistry, 2nd Year Bruker Studentship Curie Training Network of academic and transport proteins for full activity, each of industrial researchers looking to develop which militate against the scale-up of P450- enzymatic methods for green oxidation catalysed reactions.

48 49 BIOTRAINS – leading the green the Centre of Excellence for Biocatalysis, alternative energy and biomaterials and chemical training push Biotransformations and Biocatalytic has the potential to enable economies to Manufacture (CoEBio3: www.coebio3.org), become less dependent on fossil fuels by The ‘European biotechnology training this four-year project involves eleven partners employing the power of natural biocatalysts Science and Society network for the support of the chemical from academia and industry who will recruit and modern manufacturing techniques manufacturing industries’ (BIOTRAINS) and train research fellows and another to deliver safer and less-environmentally programme brings together microbiologists, six industrial partners who are offering damaging industrial methods. It is a term Informing... consulting... collaborating enzymologists, chemists, engineers and placement training that is expected to make used mainly in Europe for the application of process development experts involved in the a major contribution to efforts to replace nature’s catalysts, such as enzymes and cells, training of the next generation of scientists traditional chemical manufacturing – reliant in biotechnology for industrial purposes. who will develop green manufacturing on highly toxic chemicals and solvents – with The use of the word ‘white’ distinguishes The University of Manchester is committed to the discovery and dissemination of knowledge and seeks to lead methods for the chemical industry. Led so-called ‘white biotechnology’. The term it from other biotechnologies such as ‘red’ by Professor Nicholas Turner, Director of covers the manufacturing of chemicals, (medicinal) and ‘green’ (plant) biotechnology. on public engagement in all forms, providing expertise in public discourse and policy development, listening to the wider community, and involving the public in its work.

We work closely with the University Public students developed a number of laboratory Interactive stands included: Protein Science Engagement team, Manchester Museum and demonstrations that covered topics as | Genomics (RNA/DNA) | Protein Structural the Museum of Science and Industry (MOSI) diverse as NMR, protein expression and Biology | Enzyme Reactions | Spectroscopy/ to deliver events and activities including the robotics. A variety of interactive stands Spectrometry | Systems and Computational Manchester Science Festival and National showcased the rich array of MIB research Biology | Microfluidics/nanoscale devices Science and Engineering week. from the developing enabling technologies | Biofuels and Energy | Microbiology | (including micro fluidics, nanotechnology and Glycobiology and . We continue to host students as part of the spectrometry/spectroscopy), protein science Nuffield Bursary Placement Scheme enabling Tour demonstrations included: Protein and genomics through to systems and students to work alongside professional Structure | Mass spectrometry | NMR | Protein computational biology. scientists, technologists, engineers and Expression | Robotics | Enzyme reactions. mathematicians. In particular the scheme encourages from schools in difficult social circumstances, and students who do not have a family background of higher education or STEM professions.

On Friday 9 November 2013 the MIB “... a distinctive feature of the opened its doors to 200 A-A/S students University is its commitment to a social from 12 schools/colleges from across the responsibility agenda. This ethos is North of England providing them with a embedded in our outreach activity unique opportunity to visit a world class at the MIB and we are committed to interdisciplinary research institute. Students engaging with our wider community witnessed and participated in a number with the aim of increasing awareness, of activities throughout the day including interest, and understanding of science interactive research stands followed by and hopefully inspiring the next guided tours of the research laboratories generation of scientific leaders”. with an opportunity to talk with researchers about their work. MIB postdocs and research Dr Rosalind Le Feuvre MIB’s Research and Planning Manager

50 51 HIGHLIGHT : Royal Society The stand demonstrated how the study of has since had over 700 views. They were Summer Exhibition carbohydrates such as sucrose, starch, pectin also successful in the Royal Society Games and alginate can help improve many aspects Jam competition with their game, ‘Cell of our lives from producing renewable Invaders’, which was voted the best game energy and materials to generating new at the exhibition and won £2,000 worth medicines. How cell sugars interact with of development and is now available to foreign molecules have applications in a download on PC and iPad. variety of areas, including improving human fertilisation therapies, developing anti flu medicines and diagnostic tools, and creating new anti-cancer treatments. Identifying the difference in glycocalyx between cells can help scientists distinguish between pandemic, seasonal and bird flu and develop the correct therapies for flu outbreaks. As the “It was very exciting to be selected to glycocalyx also differs between individuals, it exhibit at the Royal Society and we provides a method for producing advanced very much enjoyed interacting with the In summer 2013 Professor Sabine Flitsch diagnostic tools for personalised medicines. students. Our exhibit demonstrated FACULTY HONOURS hosted an exhibition stand entitled ‘The One of the main exhibition activities was how the study of these sugars can FACULTY Complex Life of Sugars’ at the prestigious focused on cell surface sugars and visitors help improve many aspects of our lives Royal Society Summer Exhibition alongside The Institute is home to approximately 52 Research groups with over 500 staff and students from across were encouraged to build a cell surface sugar from producing renewable energy and collaborators from Imperial College London, the Faculties of Engineering and Physical Sciences, Life Sciences and Medical and Human Sciences. and explore its interaction with cell invaders materials to generating new medicines. University of Liverpool, John Innes Centre both on a cell surface and also a gold Understanding the glycocalyx and its and the University of Leeds. The exhibition glycan array. This activity was very popular interaction with other molecules will was visited by over 12,500 people including Faculty of Life Sciences and designed to highlight and directly provide a wide range of opportunities students, teachers, public, scientists, media, promote the GlycoBioM work. As part of for the development of new foods, potential donors/key decision makers and the exhibition the team also commissioned medicines and healthcare treatments” ALMOND, Andrew - 3D-structure DOIG, Andrew - protein structure, PRINCE, Steve - structural biophysics of celebrities. This stand was part of the EU a three minute animation which provided and function of biologically important bioinformatics, amyloidosis. membrane proteins and protein-protein funded GlycoBioM project featured in the an introduction and overview of the whole Sabine Flitsch oligosaccharides and polysaccharides. interactions. GOLOVANOV, Alexander - biology: structure, Biomedical and Healthcare section. area of carbohydrate science. This video Professor of Chemical Biology BELLA, Jordi - extracellular matrix proteins: mechanism and engineering of new properties. RIGBY, Stephen - biological electron structure, design possibilities and biomaterial paramagnetic resonance (EPR) spectroscopy HAY, Sam - quantum and theoretical applications. and related techniques. biophysics. BLANCH, Ewan - biostructural analysis using SCRUTTON, Nigel - enzyme biophysics, HAYES, Finbarr - molecular engineering of a Raman spectroscopies. structure and mechanism, quantum DNA trafficking nanomachine. enzymology, enzyme engineering, BREITLING, Rainer - metabolomic systems LEYS, David - structural biology to look biocatalysis, biofuels. biology and postgenomic data analysis at new metabolic pathways/novel enzymes TAKANO, Eriko - synthetic biology of BROWN, Terry - biomolecular archaeology – systems; structural insights guide rational bioactive molecules/antibiotics. using DNA to study the past. engineering/synthetic biology applications. WALTHO, Jon - NMR investigations of BUCKLEY, Mike - determination of species- LU, Hui - redox regulation and biogenesis of protein structure and dynamics. Binding of the egg and sperm using cell surface sugars Nature’s Catalyst stand specific biomarkers in bone for studying mitochondrial proteins. © The University of Manchester as part of National Science and Engineering Week vertebrate palaeobiodiversity. WARWICKER, Jim - models for structural MUNRO, Andrew - structure and cell biology. DIXON, Neil - RNA as a tool, RNA as a target; enzymology of biotechnologically and small-molecule inducible gene expression control. biomedically relevant redox enzymes.

Faculty of Medical and Human Sciences

Institute of Information and Repair

BAYAT, Ardeshir - wound healing, tissue repair & regeneration, bio- MILLS, Clare - why are some proteins allergens and not others; what surgical engineering. makes certain types of foods or pollens more allergenic; why do only some people become allergic?

Institute of Population Health

DAY, Philip - single cell analyses within heterogeneous populations of cancer cells

52 53 Faculty of Engineering and Physical Sciences Royal Society Wolfson Research Merit Award

Currently three members of our faculty hold prestigious Royal Society Wolfson Research Merit Awards for their exceptional contribution to their School of Chemical Engineering and Analytical Science given research fields. Jointly funded by the Wolfson Foundation, the Royal Society Wolfson Research Merit Award recognises talented scientists of outstanding achievement and potential. CURTIS, Robin - weak protein-protein GODDARD, Nick - microfluidics; sensors SUTCLIFFE, Mike - computational interactions, protein aggregation, (electrochemical/optical); high throughput enzymology & protein modelling. Professor Sabine Flitsch Professor Nicholas Turner Professor Nigel Scrutton bioprocessing, biomolecular platforms; microseparations (electrokinetic); WESTERHOFF, Hans - integrative systems Glycoarrays for studying carbohydrate- New Biocatalysts by Design and Evolution Catalysis by enzymes - beyond the transition thermodynamics. mutiphase microfluidics; micro- and nano- biology. protein interaction state theory paradigm fabrication. De VISSER, Sam - computational studies of YUAN, Xue-Feng - rheology of complex fluids/ enzyme mechanism and function. MILLER, Aline – application of physical soft matter such as biofluids and biomaterials principles to mimic, manipulate and improve GARDNER, Peter - vibrational spectroscopy in living system: quantitative rheological and biomolecular self-assembly to create of bio and biomedical systems. structural characterisation under physiological Philip Leverhulme Award materials for regenerative medicine. conditions, integrated multiple scale modelling.

Dr Aline Miller has been awarded a Philip Leverhulme Award for her work on “engineering the self-assembly of biomolecules for regenerative medicine”. The prize recognises rising stars of research, whose work has already made an international impression. School of Chemistry

BARRAN, Perdita – mass spectrometry; KEANE, John – development of clinical POPELIER, Paul - predictive modelling of instrument development and IM-MS decision support systems (DSS) and analytics structure and dynamics from first principles; fundamentals. of multi-modal (structured, semi-structured, drug design; chemical insight from modern Fellows unstructured, image) data for bio-health wave functions. FLITSCH, Sabine - glycosciences and applications. biocatalysis. TURNER, Nicholas - discovery and directed Dr Chris Blanford Dr Dr Alberto Saiani KELL, Douglas - development and evolution of tailored biocatalysts: applications EPSRC Career Acceleration Fellowship BBSRC David Phillips Fellowship EPSRC Research Fellow GARDINER, John - carbohydrate chemistry/ application of novel analytical methods at the in industrial biotechnology including fine Three-dimensional laccase electrodes for Linking experiment to theory: Quantum Developing a technological platform based chemical biology, biocatalysis, dendrimer interface between postgenomic biological chemicals, pharmaceuticals and biofuels. miniaturised fuel cell power sources entanglement during on the fundamental understanding of synthesis and heterocyclic bioorganic systems, quantitative bioanalytical science and peptide self-assembly for the design of novel chemistry. WEBB, Simon - supramolecular chemistry, machine learning, with a special emphasis on Dr Mike Buckley Professor Paul Popelier biomaterials biomimetics, understanding biomembrane evolutionary computing and systems biology. GOODACRE, Roy - integrative ’omic Royal Society University Research Fellowship EPSRC Established Career Fellowship behaviour, biosensor design. analyses and vibrational spectroscopy for Molecular timers Reliable computational prediction of Professor Nigel Scrutton LOCKYER, Nick - Imaging Mass Spectrometry understanding biological systems. WONG, Lu-Shin - combining chemical molecular assembly EPSRC Established Career Fellowship in (SIMS), instrument development. biology and nanotechnology applications in Dr Neil Dixon Catalysis HENCHMAN, Richard - biomolecular MICKLEFIELD, Jason - chemical biology and the life sciences: Bioconjugation and surface BBSRC David Phillips Fellowship Catalysis in motion: accessing how fast structure and dynamics. synthetic biology. chemistry towards nanoscale protein arrays. Development and application of next motions facilitate catalysis through pump- generation synthetic biology tools probe and fast time resolved spectroscopies

School of Computer Science

ANANIADOU, Sophia – biomedical text KING, Ross - interface between computer MENDES, Pedro - computational systems biology. MIB Fellowship Opportunities mining, information extraction, terminology science and biology/chemistry. NENADIC, Goran- text mining and automatic management, semantic interoperability of MCNAUGHT, John – text mining. knowledge structuring (ontologies, concept resources. maps) in life sciences and health-care. The MIB actively promotes new career and culture, all specifically designed to remove reach their full potential. Additional start up track research fellowships at the interface the barriers between disciplines and to monies may also be available depending on between engineering, the physical sciences promote innovative science. the nature and level of the externally funded and bioscience. Applications are encouraged research fellowship. These fellowships are School of Materials We offer an attractive fellowship extension from proactive individuals keen to participate seen as early stage entry into independent scheme for fellows bringing in 4-5 years of BLANFORD, Chris - sensitive measurements of protein–surface SAIANI, Alberto - understanding the chemical architecture - in interdisciplinary research and interact in academic careers at Manchester. Throughout external funding (regardless of the source of interactions in electrocatalytic enzymes. thermodynamic - structure - physical property correlations in complex key societal and strategic research areas of the 6-year period you will benefit from close the fellowship, BBSRC/EPSRC etc), whereby polymeric systems. interest to the MIB. For further information manager and mentor support from senior we will top up fellowships by 1 or 2 years on our fellowship scheme visit our web colleagues in the MIB. You will become a additional support. We are confident in the pages at www.mib.ac.uk. member of one of the University Faculties - quality of the fellows we wish to recruit Human and Medical Sciences (FMHS), Life School of Mechanical, Aeronautical and Civil Engineering Our research facilities are outstanding offering and recognise the importance of stability at Sciences (FLS) or Engineering and Physical a unique infra-structure, research environment this career stage to enable our fellows to BARTOLO, Paulo - biomanufacturing and computer-aided design of scaffolds for tissue engineering Sciences (EPS).

54 55 Douglas Kell honoured in Queen’s New Year’s Honours 2014 Professor Douglas Kell CBE MS DPhil FSB FLSW FAAAS Chair in Bioanalytical Science

Douglas Kell was awarded a CBE for services to science and research in the Queen’s New Year’s Honours 2014. He has been a pioneer in many areas of computational biology and experimental metabolomics, including the use of evolutionary, closed-loop methods for optimisation. He also contributed to the discovery of the first bacterial cytokine, currently on trial as part of a vaccine against tuberculosis.

Douglas studied at Oxford University focusing on the development and exploitation of novel methods for the study of (mainly microbial) bioenergetics. He was awarded a Personal Chair at the University College of Wales (now ) in 1992 and from 1998-2002 was Director of Research of the Institute of Biological Sciences. He co-founded Aber Instruments, that received the Queen’s Award for Export Achievement in 1998.

In 2002 he accepted an RSC/EPSRC-funded Chair in Bioanalytical Sciences at UMIST. From 2005-2008 he was Director of the Manchester Centre for Integrative Systems Biology at The University of Manchester. From 2008 until 2013 he was Chief Executive of the Biotechnology and Biological Sciences Research Council (BBSRC). Selected Publications He has a Doctor of Science Honoris Causa from Cranfield University (2011), and is a Fellow of the Learned Society of Wales (2012), of the American Association for the Advancement of Science (2012), and of Aberystwyth University (2013). He has published over 400 scientific papers with Amaral M, Levy C, Heyes DJ, Lafite P, Outeiro TF, Brewster VL, Ashton L, Goodacre R. Monitoring Dunstan MS, Barkauskaite E, Lafite P, Knezevic CE, Giorgini F, Leys D, Scrutton NS. Structural basis of guanidinium-induced structural changes in Brassington A, Ahel M, Hergenrother PJ, Leys D, >18,000 citations in WoK (H-index 72). In H=83 and citations >26,000. kynurenine 3-monooxygenase inhibition. Nature ribonuclease proteins using Raman spectroscopy Ahel I. Structure and mechanism of a canonical 2013 496(7445):382-5. and 2D correlation analysis. Anal Chem. 2013 poly(ADP-ribose) glycohydrolase. Nat Commun. 85(7):3570-5. 2012 3:878. doi: 10.1038/nature12039 doi: 10.1021/ac303265q doi: 10.1038/ncomms1889

Bester J, Buys AV, Lipinski B, Kell DB, Pretorius E. High ferritin levels have major effects on the Castangia R, Austeri M, Flitsch SL. Enzymatic amine Durigon R, Wang Q, Ceh Pavia E, Grant CM, Lu H. morphology of erythrocytes in Alzheimer’s disease. acyl exchange in peptides on gold surfaces. Angew Cytosolic thioredoxin system facilitates the import Paulo Bártolo joins the MIB Front Aging Neurosci. 2013 5:88. Chem Int Ed Engl. 2012 51(52):13016-8. of mitochondrial small Tim proteins. EMBO Rep. 2012 13(10):916-22. Professor Paulo Bartolo BEng, MSc, PhD doi: 10.3389/fnagi.2013.00088 doi: 10.1002/anie.201205404 doi: 10.1038/embor.2012.116 Chair in Advanced Manufactuirng Blanford CF. The birth of protein electrochemistry. Cawley A, Warwicker J. eIF4E-binding protein Paulo Bártolo joins the MIB in Spring 2014 from Polytechnic Institute of Leiria, Portugal. Paulo Chem Commun (Camb). 2013 49(95):11130-2. regulation of mRNAs with differential 5’-UTR Ellis DI, Brewster VL, Dunn WB, Allwood JW, holds a PhD degree in Polymer Physics from the University of Reading (UK) and a Master of secondary structure: a polyelectrostatic model for a Golovanov AP, Goodacre R. Fingerprinting food: doi: 10.1039/c3cc46060f. Science and “Licenciatura” in Mechanical Engineering, both from the Technical University component of protein-mRNA interactions. Nucleic current technologies for the detection of food Acids Res. 2012 40(16):7666-75. adulteration and contamination. Chem Soc Rev. of Lisbon (Portugal). His research interests focus on biomanufacturing and computer-aided 2012 41(17):5706-27. design of scaffolds for tissue engineering. He developed different bottom-up and top-down Barkauskaite E, Brassington A, Tan ES, Warwicker J, doi: 10.1093/nar/gks511 Dunstan MS, Banos B, Lafite P, Ahel M, Mitchison doi: 10.1039/c2cs35138b approaches for bone, cartilage and skin applications. The design of smart and functionally TJ, Ahel I, Leys D. Visualization of poly(ADP-ribose) graded scaffolds to promote tissue interfaces is also an important topic of his research. He bound to PARG reveals inherent balance between Chesters C, Wilding M, Goodall M, Micklefield J. investigated the relationship between the material processing and the mechanical, biological exo- and endo-glycohydrolase activities. Nat Thermal bifunctionality of bacterial phenylalanine Ghislieri D, Green AP, Pontini M, Willies SC, Rowles Commun. 2013 4:2164. aminomutase and ammonia lyase enzymes. Angew I, Frank A, Grogan G, Turner NJ. Engineering an and degradation characteristics of scaffolds, as well the fabrication of scaffolds with controlled Chem Int Ed Engl. 2012 51(18):4344-8. enantioselective amine oxidase for the synthesis of anisotropy. Different materials (PCL, PLA, PCL/PLA, PCL/HA, PCL/TCP, PCL/graphene, PCL/ doi: 10.1038/ncomms3164 pharmaceutical building blocks and alkaloid natural doi: 10.1002/anie.201200669 bioglass, Alginate, Dextran) and cell lines (fibroblasts, keratinocytes, osteoblasts, chondrocytes products. J Am Chem Soc. 2013 135(29):10863-9.

and hMSCs) were used in these research works. Both P, Green AP, Gray CJ, Sardzík R, Voglmeir J, doi: 10.1021/ja4051235 Fontana C, Austeri M, Rejzek M, Richardson D, Field Cowcher DP, Xu Y, Goodacre R. Portable, Paulo Bartolo is author and co-autor of more than 400 publications in journal papers, book RA, Widmalm G, Flitsch SL, Eyers CE. Discrimination quantitative detection of Bacillus bacterial spores chapters and conference proceeding papers. He also edited 13 books and holds 10 Portuguese of epimeric glycans and glycopeptides using IM-MS using surface-enhanced Raman scattering. Anal Gray CJ, Weissenborn MJ, Eyers CE, Flitsch SL. and its potential for carbohydrate sequencing. Nat Chem. 2013 85(6):3297-302. Enzymatic reactions on immobilised substrates. Patents. His research work has been published in high impact factor journals like Progress Chem. 2014 (1):65-74. Chem Soc Rev. 2013 42(15):6378-405. in Polymer Science, Nanomedicine, Acta Biomaterialia, Biofabrication Journal, Carbohydrate doi: 10.1021/ac303657k doi: 10.1038/nchem.1817 doi: 10.1039/c3cs60018a Polymers. He is also Editor-in-Chief of Virtual and Physical Prototyping Journal published by

Taylor&Francis, and member of the Editorial Board of several Journals like the Biofabrication Dixon N, Robinson CJ, Geerlings T, Duncan Journal, the Rapid Prototyping Journal, the International Journal of Precision Engineering and Bouwman AS, Kennedy SL, Müller R, Stephens JN, Drummond SP, Micklefield J. Orthogonal Hamrang Z, Rattray NJ, Pluen A. Proteins behaving Manufacturing, the Journal of Biomaterials and Tissue Engineering, the ISRN Tissue Engineering RH, Holst M, Caffell AC, Roberts CA, Brown TA. riboswitches for tuneable coexpression in bacteria. badly: emerging technologies in profiling Genotype of a historic strain of Mycobacterium Angew Chem Int Ed Engl. 2012 51(15):3620-4. biopharmaceutical aggregation. Trends Biotechnol. and the International Journal on Mechatronics and Manufacturing Systems. tuberculosis. Proc Natl Acad Sci U S A. 2012 2013 31(8):448-58. 109(45):18511-6. doi: 10.1002/anie.201109106 doi: 10.1016/j.tibtech.2013.05.004 doi: 10.1073/pnas.1209444109

56 57 Hansen SU, Miller GJ, Jayson GC, Gardiner JM. Leys D, Adrian L, Smidt H. Organohalide Šardzík R, Green AP, Laurent N, Both P, Fontana First gram-scale synthesis of a heparin-related respiration: microbes breathing chlorinated C, Voglmeir J, Weissenborn MJ, Haddoub R, odecasaccharide. Org Lett. 2013 15(1):88-91. molecules. Philos Trans R Soc Lond B Biol Sci. 2013 Grassi P, Haslam SM, Widmalm G, Flitsch SL. 368(1616):20120316. Chemoenzymatic synthesis of O-mannosylpeptides doi: 10.1021/ol303112y in solution and on solid phase. J Am Chem Soc. doi: 10.1098/rstb.2012.0316 2012 134(10):4521-4.

Hansen SU, Miller GJ, Cole C, Rushton doi: 10.1021/ja211861m G, Avizienyte E, Jayson GC, Gardiner JM. Mabbott S, Correa E, Cowcher DP, Allwood Tetrasaccharide iteration synthesis of a heparin-like JW, Goodacre R. Optimization of parameters dodecasaccharide and radiolabelling for in vivo for the quantitative surface-enhanced Raman Sattelle BM, Shakeri J, Almond A. Does tissue distribution studies. Nat Commun. 2013 scattering detection of mephedrone using a microsecond sugar ring flexing encode 4:2016. fractional factorial design and a portable Raman 3D-shape and bioactivity in the heparanome? spectrometer. Anal Chem. 2013 85(2):923-31. Biomacromolecules. 2013 14(4):1149-59. doi: 10.1038/ncomms3016 doi: 10.1021/ac302542r doi: 10.1021/bm400067g

Hay S, Scrutton NS. Good vibrations in enzyme- catalysed reactions. Nat Chem. 2012 4(3):161-8. Miwa M, Ohta T, Rak R, Rowley A, Kell DB, Pyysalo Sjuts H, Dunstan MS, Fisher K, Leys D. Structure S, Ananiadou S. A method for integrating and of the cobalamin-binding protein of a putative doi: 10.1038/nchem.1223 ranking the evidence for biochemical pathways by O-demethylase from Desulfitobacterium hafniense mining reactions from text. Bioinformatics. 2013 DCB-2. Acta Crystallogr D Biol Crystallogr. 2013 29(13):i44-52. 69(Pt 8):1609-16. Hay S, Johannissen LO, Hothi P, Sutcliffe MJ, Scrutton NS. Pressure effects on enzyme-catalyzed doi: 10.1093/bioinformatics/btt227 doi: 10.1107/S0907444913011323 quantum tunneling events arise from protein- specific structural and dynamic changes. J Am Chem Soc. 2012 134(23):9749-54. Nicolaou N, Xu Y, Goodacre R. Detection and Thirlway J, Lewis R, Nunns L, Al Nakeeb M, Styles quantification of bacterial spoilage in milk and M, Struck AW, Smith CP, Micklefield J. Introduction doi: 10.1021/ja3024115 pork meat using MALDI-TOF-MS and multivariate of a non-natural amino acid into a nonribosomal analysis. Anal Chem. 2012 84(14):5951-8. peptide antibiotic by modification of adenylation domain specificity. Angew Chem Int Ed Engl. 2012 Kell DB. Scientific discovery as a combinatorial doi: 10.1021/ac300582d 51(29):7181-4. optimisation problem: how best to navigate the landscape of possible experiments? Bioessays. 2012 doi: 10.1002/anie.201202043 34(3):236-44. Munro AW, Girvan HM, Mason AE, Dunford AJ, McLean KJ. What makes a P450 tick? Trends doi: 10.1002/bies.201100144 Biochem Sci. 2013 38(3):140-50. Turner NJ, O’Reilly E. Biocatalytic retrosynthesis. Nat Chem Biol. 2013 9(5):285-8. doi: 10.1016/j.tibs.2012.11.006 Kell DB. Large-scale sequestration of atmospheric doi: 10.1038/nchembio.1235. carbon via plant roots in natural and agricultural ecosystems: why and how. Philos Trans R Soc Lond Pang J, Li X, Morokuma K, Scrutton NS, Sutcliffe B Biol Sci. 2012 367(1595):1589-97. MJ. Large-scale domain conformational change Weissenborn MJ, Castangia R, Wehner JW, Šardzík is coupled to the activation of the Co-C bond R, Lindhorst TK, Flitsch SL. Oxo-ester mediated doi: 10.1098/rstb.2011.0244 in the B12-dependent enzyme ornithine native chemical ligation on microarrays: an efficient 4,5-aminomutase: a computational study. J Am and chemoselective coupling methodology. Chem Chem Soc. 2012 134(4):2367-77 Commun (Camb). 2012 48(37):4444-6 Kell DB, Goodacre R. Metabolomics and systems pharmacology: why and how to model the human doi: 10.1021/ja210417k doi: 10.1039/c2cc30844d metabolic network for drug discovery. Drug Discov Today. 2013 pii: S1359-6446(13)00248-1. Pudney CR, Guerriero A, Baxter NJ, Johannissen LO, Wu MC, Law B, Wilkinson B, Micklefield J. doi: 10.1016/j.drudis.2013.07.014 Waltho JP, Hay S, Scrutton NS. Fast protein motions Bioengineering natural product biosynthetic are coupled to enzyme H-transfer reactions. J Am pathways for therapeutic applications. Curr Opin Chem Soc. 2013 135(7):2512-7. Biotechnol. 2012 23(6):931-40. Kemp LR, Dunstan MS, Fisher K, Warwicker J, Leys D. The transcriptional regulator CprK detects doi: 10.1021/ja311277k doi: 10.1016/j.copbio.2012.03.008 chlorination by combining direct and indirect readout mechanisms. Philos Trans R Soc Lond B Biol Sci. 2013 368(1616):20120323. Pudney CR, Lane RS, Fielding AJ, Magennis SW, For further publications please visit Hay S, Scrutton NS. Enzymatic single-molecule www.mib.manchester.ac.uk doi: 10.1098/rstb.2012.0323 kinetic isotope effects. J Am Chem Soc. 2013 135(10):3855-64.

Khara B, Menon N, Levy C, Mansell D, Das D, doi: 10.1021/ja309286r Marsh EN, Leys D, Scrutton NS. Production of propane and other short-chain alkanes by structure- based engineering of ligand specificity in aldehyde- Pyysalo S, Ananiadou S. Anatomical entity mention deformylating oxygenase. recognition at literature scale. Bioinformatics. 2013

Chembiochem. 2013 14(10):1204-8. PubMed PMID: 24162468

doi: 10.1002/cbic.201300307 Russell HJ, Jones AR, Hay S, Greetham GM, Towrie M, Scrutton NS. Protein motions are coupled to the reaction chemistry in coenzyme B12-dependent Levene C, Correa E, Blanch EW, Goodacre R. ethanolamine ammonia lyase. Angew Chem Int Ed Enhancing surface enhanced Raman scattering Engl. 2012 51(37):9306-10. (SERS) detection of propranolol with multiobjective doi: 10.1002/anie.201202502 evolutionary optimization. Anal Chem. 2012 84(18):7899-905.

doi: 10.1021/ac301647a

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