Manchester Institute of Discovery through innovation

Professor Nigel Scrutton Manchester Institute of Biotechnology Director

Dr Rosalind Le Feuvre MIB Overview

MIB is a purpose-built interdisciplinary research institute and home to a unique multi- and inter-disciplinary community of researchers trained in physics, chemistry, mathematics, computation, engineering and biology committed to working across discipline boundaries.

• 47 academic interdisciplinary research groups

• 450 interdisciplinary researchers

• The UK’s first interdisciplinary bioscience institute

• A vibrant international and intersectorial hub

MIB Grant Funding

Current research grants totaling ca £90M

Research in MIB

Grand Challenges

Industrial Biotechnology Uses biological resources for producing and processing materials and chemicals for non-food applications. A multidisciplinary approach draws on disciplines such as organic and synthetic chemistry, , molecular biology, kinetics, genomics, proteomics, bio- informatics and bioprocessing

Biomedical and Healthcare The development of modern medicines requires understanding of molecules and networks at the molecular and systems levels which involves imaging and spatial mapping of cell responses in health and disease and in response to drug challenges.

Biofuels and Energy Our contribution to this agenda focuses in particular on the biological aspects of energy including fuel cells, solar energy and 2nd/3rd/4th generation biofuels. Research into alternative biofuels includes utilising biomass from both agricultural and marine sources to the development of novel biocatalysts.

Discovery Through Innovation MIB 10 Year Anniversary

As we approach the 10 year anniversary – what impact has MIB had?

High Impact Publications

Approx. 3000 publications since 2006 including: 14x ; 9x Nature Chem Biol; 4x Nature Chem; 9x Nature Communs; 3x Nature Protocols; 8x Nature Biotech; 23x PNAS; 67x JACS; 47x Angewandte Chemie; 8x Science Centres of Excellence and National / (Inter)national Leadership

MIB Centres of Excellence Leading National Centres CoE for , Biotransformations and Biocatalytic Manufacture (est. 2005)

MCISB: Manchester Centre for Integrative Systems Biology (est. 2006)

MBCCMS: Michael Barber Centre for Dynamic Structural Science Collaborative Mass Spectrometry (est. in MIB Consortium (est. 2012) in 2006)

NaCTeM: National Centre for Text Mining (est. 2006) Biocatalysis and M MCBC: Manchester Centre for C Biotransformations at the BC and Catalysis (est. 2009) National Catalysis Centre (coordinated by MIB/Harwell) CoEBP: Centre of Excellence in (est. 2015) Biopharmaceuticals (est. 2011)

SYNBIOCHEM: Centre for Synthetic Biology of Fine and Speciality Chemicals (est. 2014) BBSRC NIBBs

MIB is home to four BBSRC funded NIBBs (est. 2014)

Network in Biocatalyst Discovery, Development and Scale-up.

Glycoscience Tools for Biotech. and Bioenergy Network.

Natural Products Discovery and Bioengineering Network.

Bioprocessing Network.

National Networks in Industrial Biotechnology and Bioenergy

NIBB Activities • Building industry-academe partnerships in the IB space relevant to the network • Workshops, open meetings, consortium building meetings • Pump-priming research activity coordinated jointly by academic and industry partner • Accelerating take up of basic discovery science by industry • Preparing larger funding bids to UK agencies (e.g. IB Catalyst) • Supporting technology transfer (IP, due diligence, patents etc)

MIB Spin-Out Companies

8 spin out companies have been established from the MIB research base. International Outreach

Research Impact on the world-wide stage

Over 1,000 publications in last 3 years 46% publications with international collaborations 70 different countries

BBSRC International Partnering Awards

Impact European : CoEBio3 • Collaborative research links Exchange of scientists South Africa: Combing biophysical and • 'omics methods for understanding the • Access to expertise and facilities basis of blood clotting and haemostasis and how to modify it - Goodacre

US: Carbohydrate Sequencing Consortium - Flitsch

Cuba: Application of 'omics in the metabolic study of high cell density continuous cell cultures of recombinant NS0 myeloma cell lines - Dickson China: Supercomputing systems biology – Westerhoff

Synthetic Biology for Biotechnology of Fine Chemicals – SynBioTech - Scrutton Brazil: Integrated enzyme discovery and pathway optimisation for bagase Japan: Application of MS-Imaging and valorisation – Dixon (BBSRC-FAPESP) Metabolomics in Synthetic Biology Based Strain Improvement of Synthetic biology of transporters and Industrially Important Microbes - other in yeast - Kell Takano Diverse PhD Training Programmes

Approx. 173 current PhD students and 36 MSc/MEng students Different funding sources: • BBSRC DTP (22) • iCASE (13) / Industry funded (CoEBio3) Providing a unique • EU Networks (MAGIC, TINTIN) and consortium inter-disciplinary, inter- sector, inter-national • Self funded and International training environment Industry supervisors and placements Future Prospective for MIB

Driving impact: • Bio/logical materials agenda (Royce, GEIK – sustainability; additive manufacturing; biological materials for energy, medicine, drug delivery)

• MIB Centre of Excellence in Antimicrobials (Therapy and Resistance) - harnessing Sys/SynBio and analytical platform capabilities in MIB

• Systems and synthetic biology into formulation science

• Creating a seamless pipeline with sustainable manufacture of chemicals / materials / bio- therapeutics – to align with engineering strengths in bioprocessing / fermentation science Research in MIB

Grand Challenges

Industrial Biotechnology Uses biological resources for producing and processing materials and chemicals for non-food applications. A multidisciplinary approach draws on disciplines such as organic and synthetic chemistry, biochemistry, molecular biology, , genomics, proteomics, bio- informatics and bioprocessing

Biomedical and Healthcare The development of modern medicines requires understanding of molecules and networks at the molecular and systems levels which involves imaging and spatial mapping of cell responses in health and disease and in response to drug challenges.

Biofuels and Energy Our contribution to this agenda focuses in particular on the biological aspects of energy including fuel cells, solar energy and 2nd/3rd/4th generation biofuels. Research into alternative biofuels includes utilising biomass from both agricultural and marine sources to the development of novel biocatalysts.

Manchester Synthetic Biology Research Centre for Fine and Speciality Chemicals

Nigel Scrutton (PI/Director) Eriko Takano (Director) Nick Turner (Director)

Manchester Institute of Biotechnology Discovery through innovation Leadership and Management

At the core of MIB strategy: Building teams of interdisciplinary scientists and industrial partners to address challenge-led innovation in the bio-based chemicals and industrial biotechnology sectors

29 Research group leaders SynBio Research portfolio >£58M live grants Academic Strong interdisciplinary international profile Research Publication profile >567 in the last 3 years

Director SYNBIOCHEM Directors of Operations

SYNBIOCHEM Cabinet

DESIGN BUILD TEST CPI Gene DATA RRI Mill Experimental Team

Dedicated office and lab space 1st Floor MIB

DATA DESIGN BUILD TEST RRI

PDRA SRSE Neil Swainston Adrian Jervis Cunyu Yan Kate Bulpin Donal Fellows Parts/Devices Pathway Assembly Targeted Analytics

SRSE Alan Williams Christopher Robinson Research Fellow Pablo Carbonell Regulatory toolkit in Science Ethics Catherine Rhodes Pathways Nik Rattray Norman Morrison Untargeted Analytics Natalie Stanford PDRA Mark Dunstan Yanchao Li Robotics Reynard Spiess Maria Vinaixa MS / Microfluidics Data Analytics and Metabolomics Andrew Currin Rehana Sung GC HPLC

Sandra Taylor Christopher Cowan Technical Support Centre Administration SYNBIOCHEM Approach

Transforming the SynBio of fine and speciality chemicals production through  Access to wide range of chemical diversity  Rapid delivery of new chemical targets  Predictability:‘dial a molecule”

Early Chemical targets

• Alkaloids • Flavonoids • Terpenoids

Projects tackled as grand challenges MIB DrivingEarly Worldimpact Leading Discovery Science

Synthetic Biology and Industrial Biotechnology

 80 peer reviewed publications, 3 patents in year 1  Significant outputs with our industrial partners

Single-step synthetic biology/fermentative production route to the cholesterol lowering drug pravastatin.

A novel cascade biocatalytic approach for the production of chiral amines New route to biosynthetic menthols using synthetic biology Novel enzymes involved in fuels/alkene production. Mentha New SynBio routes to gaseous biofuels (propane).

 SYNBIOCHEM DESIGN methods GeneGenie and SpeedyGenes used in commercial DNA synthesis platforms (GeneArt ThermoFisher) MIB Driving World Leading Discovery Science

Analysis, collaboration and deliberation to anticipate, prepare for, or mediate impacts Policy, Responsible of emerging new technologies in society, Research and Innovation economy, and the environment.

 EU Opinions on Synthetic Biology: Breitling /Takano part of expert working group (EU and USA) - 3 EU Opinions on SynBio “Judging SynBio risks” published in Science 347, 107 (2015)  Manchester Policy Week (2-6/11/15) SYNBIOCHEM hosted “Synthetic biology: Reshaping the future?”  Research and Innovation Systems Assessment End-to-End Project – “Menthol in Everyday Life” – use, industrial production  Sustainability, economics, ethic and perceptions of incumbent new technologies and applications  RRI Infrastructural Development –– established a UK RRI & SynBio Platform  Media Blogs, Outreach and Engagement workshops Technology platforms

MASS SPECTROMETRY Platforms DESIGN: Bioparts mining/pathway prediction (antiSMASH, Retrosynthesis), machine learning directed evolution (DE), pathway modelling Waters Synapt G2-Si: (Copasi, Monte Carlo), prediction of metabolic tracking the specific flux, genome-scale modelling SynBio reaction.

High Throughput Robotics Platforms Waters TQ-S: high sensitivity and accurate 3 x Hamilton STAR platforms quantification data DNA assembly Culture handling Protein purification Thermo Q-Exactive: Assay/reaction set-up Untargeted LCMS Detection – UV/VIS workhorse Solid phase extraction

Tecan EVO 200 system Non-microbial work Agilent 6560 IMS-MS: Automated RNA/SELEX monitoring target reactions

MicroCal Auto-ITC bio-molecular interactions Agilent 7020GCQ-ToF: Pico-droplet single cell assay system untargeted analysis Cell encapsulation Sorting, fusing and splitting Infors fermenation platform 6 x 1lt set up with turbidostat Manchester Institute of Biotechnology Discovery through innovation

Chemical (in)compatibility? Chemical (in)compatibility? Present routes: ‘blend-in’ biofuels; 1st-2nd generation

Ethanol

FAME/biodiesel

New routes: advanced biofuels; ‘drop-in’ biofuels; 4th generation biofuels

‘Drop-in’ biofuels: 3 examples

Enzyme/pathway engineering

Central metabolism Cn-hydrocarbons

Outcome: Biomass driven in vivo production of Cn-fuels/precursors

• The UbiX/Ubi system: alkene production from unsaturated fatty acids • The ADO enzyme: alkane production from aldehydes • The OleT enzyme: alkene production from saturated fatty acids

Distinct Distinct Distinct enzymes products substrates

4 The UbiX-UbiD system: new biochemistry

UbiX?/UbiD?

UbiDUbiX

UbiX UbiDUbiX Karl A.P. Payne, et al.(2015) Nature 522, 497–501 Mark D. White et al. (2015) Nature 522, 502–507 The ADO enzyme: reprofiling for C3

Khara et al ChemBioChem 14, 1204 (2013) Menon et al Biotech for Biofuels 8, 61 (2015) The OleT enzyme: a family portrait

?

Belcher et al. J Biol Chem 289, 6535-6550 (2014) New routes to biofuels @ MIB

• The UbiX/Ubi system: alkene production from unsaturated fatty acids • The ADO enzyme: alkane production from aldehydes • The OleT enzyme: alkene production from saturated fatty acids

Distinct Distinct Distinct enzymes products substrates

8 Structure Understanding Application