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EngD students with bioreactor

Extraordinary advances in the life sciences have great potential to improve our quality of life through better medicines, improved sustainability and a cleaner environment. Biochemical, biological and bioprocess engineering provide the foundations for translating such exciting new discoveries into products and processes for improved health and wealth creation. 

UCL was the founding laboratory of the discipline of Biochemical Engineering and established the first UK department.

It is now the largest international research centre with over 75% of staff rated as "World Leading" or "Internationally Excellent" in the last UK Research Assessment Exercise.

The CDT in Bioprocess Engineering Leadership provides a focus for cutting-edge, industry-collaborative research. Current doctoral programmes address fundamental bioprocess issues underpinning the UK bioprocess-using industries:

Industrial Biotechnology

This involves the synthesis of biorenewable chemicals and complex chiral pharmaceuticals via the integration of biocatalysis and chemistry with engineering to achieve greater selectivity and improved environmental sustainability.

Biopharmaceuticals

This involves the manufacture of biopharmaceutical human proteins, genes and vaccines addressing next generation therapies and important issues of global healthcare as part of the EPSRC Innovative Manufacturing Centre (IMRC) for Bioprocessing.

Regenerative Medicines

This involves interdisciplinary academic-industrial-clinical collaborations underpinning the bioprocessing of human cells and engineered tissues for therapy particularly in response to conditions associated with the ageing population in Western countries.

Research in each of the above areas is highly collaborative and includes major themes of micro biochemical engineering (including microfluidics and automation), biological engineering (including metabolic and protein engineering), fermentation and cell culture, downstream processing and formulation. Studies in each of these areas are underpinned by work on intelligent design of experiments and are integrated via whole bioprocess modelling and simulation.

Ultra Scale-Down Methods for Enhancement of Domain Antibody Recovery

Researcher: Alex Chatel

Graduated in 2014

Domain antibodies form a potential new class of therapy being developed by GSK. They are of low molecular weight (ca 12 to 15 kDa compared with 150 kDa for whole antibodies) providing scope for higher doses of the active molecular entity and greater access to therapeutic targets (e.g. tumours) in the patient. They may be produced in recombinant E.coli providing the opportunity for high titres in rapid fermentation operations. Ultra scale-down (USD) methods were used to create and characterise a novel, patented, flocculation process to greatly enhance domain antibody recovery.

Background: What Was the Problem Being Addressed?

In order to realise the potential for high productivity E.coli fermentations forming domain antibodies it is necessary to devise means for recovery at high yield from complex and very viscous fermentation broths. It is recognised that flocculation might achieve a rapid, low cost process for the selective removal by aggregation of sub-micron sized cell debris and precipitation of nucleic acids, colloidal proteins and endotoxin materials. In order to translate such an operation from the laboratory to industrial scale, the research objective was to examine the use of UCL USD methods to characterise how the flocculated material may best be recovered at full scale in high-speed, continuous-flow centrifuges imparting conditions of extreme shear stress to the material.

How Did the CDT Help?

The EngD project with GSK provided a first access for the CDT to a new class of protein therapeutics and the opportunity to develop novel operations of relevance to the future of the bioprocessing sector both for therapeutic molecules and for purification agents. The partnership also provided for GSK a first in-house application of UCL proprietary USD technology. This EngD project formed a pivotal part of a £1.3 m GSK-UCL Centre of Excellence in Bioprocessing providing access for the CDT researcher to advanced analytical resources at GSK and the ability to verify USD predictions at scale.

What Were the Project Outcomes?

The project created a novel USD approach to demonstrate how flocculation was able to treat difficult viscous suspensions containing significant proportions of sub-micron particulate materials capable of rapidly fouling expensive chromatography columns. The treated broth was demonstrated to be suitable for processing at full industrial scale in a high-speed continuous centrifuge without loss of the advantages gained by flocculation and resulting in greater than 200-fold reduction in carry-over of damaging particulate material. The research resulted in three key publications in leading refereed journals, two international conference presentations and a patent (WO2014118220 A1). The Research Engineer was subsequently employed on a £3m HEFCE Catalyst Fund award aimed at commercialisation of the USD devices.

Impact

  • A USD method has been created for the full characterisation and understanding of the potential for flocculation for the recovery of novel therapeutic targets and in particular domain antibodies from high cell density recombinant E.coli broths.
  • Granting of a patent (Method of producing a protein) to enable GSK to secure a future potential processing route i.e. for domain antibodies.
  • Enabled GSK to support a follow-on EngD project (McInally) to investigate complementary molecular biology routes to enhance domain antibody recovery as tested using the established UCL USD technology.
  • Enabled testing and verification of UCL USD technologies in a commercial context and helped lead to the formation of a UCL USD spin-out co-led by the EngD researcher.

Development of a Pressurised Transmural Decellularisation Method for GMP Manufacture of Tissue Engineered Tracheas

Researcher: Leanne Partington

Graduated in 2015

Tissue engineered airways emerged in the last decade as a potential solution for an unmet clinical challenge: treating patients with airway disease. However the clinically used method for tracheal decellularisation received mixed success. This EngD project examined the standard detergent-enzymatic method of decellularisation, a highly manual process that took 28 days to complete. The resulting scaffolds were mechanically weak and so a new bioreactor was created that accelerated decellularisation. This method reduced processing time to 4 days and increased retention of critical structural components that provide mechanical strength. Subsequently, a trachea engineered under GMP conditions was successfully transplanted into a patient.

Background: What Was the Problem Being Addressed?

Tissue engineered airways emerged as a potentially life-saving treatment for patients with end-stage airway disease. Significant media attention led to UCL clinical work, carried out at Great Ormond Street Hospital, being in the spotlight. However, the tissue engineering approach was ad hoc and not standardised resulting in failure in many of the transplants performed elsewhere. This EngD project therefore sought to: a) identify areas for improvement in the current tissue engineering process; b) create new bioreactors and processing methods to address such needs; and c) test those bioreactors to determine their suitability for creating an improved process and product for use in clinic.

How Did the CDT Help?

As a newly emerging area that had a poorly understood engineering basis for the manufacture of tissue engineered airways, the EngD project allowed us to make some critical early insights that highlighted significant flaws in the standard methodology. Subsequent RE work devised a new bioreactor that met several key criteria including: 1) reduced processing time to produce the decellularised scaffold; 2) production of scaffolds with superior mechanical properties to the conventional process; 3) retention of critical biologic components to levels consistent with the conventional process. The structure of the EngD enabled the RE to work closely with clinical partners.

What Were the Project Outcomes?

The project resulted in published observations that the gold standard airway tissue engineering method was sub-optimal, resulting in poor mechanical integrity that is highly likely a cause of failure in the reported clinical cases. It also resulted in the creation of a new method that can reduce processing time and deliver airway scaffolds that have superior biophysical and mechanical properties to those created using the conventional “gold standard” method. The collaboration enabled the RE to spend time in the GMP labs at the Royal Free Hospital and was part of a team who created airways that were transplanted into patients. This was featured on the BBC2 television programme, Great Ormond Street, in the episode, Experimental Surgery in 2012. Our early insight research was published in 2013 (Partington et al, 2013, Acta Biomater 9(2):5251-61).

Impact

  • Advanced understanding of the mechanical limitations of current surgical methods.
  • Development of new tools to create tissue engineered airways with superior properties.
  • Engineering of new airways that were transplanted into patients and featured on a BBC television programme about experimental surgery for children with congenital defects.
  • Provided the Research Engineer with an early exposure to working under GMP conditions that led to a job at the Cell and Gene Therapy Catapult as a Senior Process Development Scientist.
  • Led to follow-on MRC (RegenVOX) and EU-funded projects worth £2.1m.

Supporting Development of the UK’s Leading Synthetic Biology Start-Up (Synthace)

Researcher: Chris Grant

Graduated in 2012

Recent advances in Synthetic Biology have improved our understanding of biological systems and how they might be applied to address future biomanufacturing challenges. A UCL spin-out, Synthace, was formed that sought to exploit these opportunities and a series of EngD projects enabled continuous knowledge exchange and helped Synthace grow into a leading SME that now employs 20 people and collaborates on projects worth £1.1m. The Rt Hon David Willetts (then Universities and Science Minister) noted that “Companies like Synthace can help the UK exploit the massive potential that synthetic biology has both here and abroad. By making investment in technology now, it will ensure that in ten years’ time the UK is at the forefront of the global race.”

Background: What Was the Problem Being Addressed?

Synthetic Biology offers unparalleled opportunities to facilitate the rational design and engineering of biological systems to address real world, biomanufacturing problems. The challenges are: (i) to provide the experimental tools and quantitative framework in which the benefits of Synthetic Biology can be assessed and (ii) to link these with the necessary bioprocess engineering to translate the findings into commercial scale manufacturing processes. To address these challenges requires a marriage of biology and engineering that is only possible with a critical mass of multidisciplinary researchers as found in a CDT.

How did the CDT Help?

The CDT supported the EngD training one of the original co-founders of Synthace (Grant). He subsequently won a UCL EPSRC Doctoral Prize Fellowship (2 year PDRA position, £100K) to further develop his membrane transport technology and explore IP protection. This led to a first InnovateUK grant (£500k) to develop Synthace's platform for the rapid construction of cellular factories and apply the membrane transporters for production of high value chemicals. The CDT also provided space to incubate Synthace while they grew which led to further EngD projects to widen the repertoire of biological systems (Aisha) and facilitate the engineering and scale-up of oxidative conversions (Rutley). Involvement of Synthace staff in delivery of UCL MBI programme modules provided a platform to promote Synthace technology and contribute to EngD cohort training.

What Were the Project Outcomes?

The individual EngDs with Synthace (http://synthace.com) led to new ways of getting hydrophobic molecules into and out of cells (Grant), enhancing oxygenating biocatalysts (Rutley) and developing new bacterial chasses (Aisha). The latter led to a second InnovateUK grant worth £350k (Ward). Together these projects demonstrated an integration of technologies that were central to Synthace’s success. Synthace has now established a range of patented, cutting-edge technologies including the software platform Antha. This has led to funding of over £10m supporting 20 employees and a move into dedicated bioincubator space in 2015. Synthace continues to be a strong supporter of the CDT providing lectures and hosting Masters project student projects. In 2016 Synthace was the only UK company to have been selected as one of the world’s 30 most promising Technology Pioneers by the World Economic Forum.

Impact

  • Identification of a novel alkane transporter for biocatalyst sensing and productivity enhancement.
  • Creation of a robust, generic platform for the rapid scale up of protein-based synthetic biology products from microbial expression systems.
  • Development of a library of commercial cell chasses for synthetic biology applications.
  • Assisting the growth of Synthace to become a world leading Synthetic Biology company.

UCL-MedImmune Centre of Excellence (CoE) on Predictive Multivariate Decision-Support Tools for Mammalian Cell Manufacturing Processes

Researchers: Allen Joseph, Christos Stamatis, Roman Zakrzewski, Martina Sebastian, Max Baron

The previous CDT award established two EngD projects with MedImmune (2011 & 2012) that were complemented by an associated BRIC PhD studentship. The success of these collaborations led to creation of a UCL-MedImmune CoE (2014-present, £0.8M) supporting a further three linked EngD projects coordinated by a MedImmune-funded PDRA. The CoE mechanism has enabled UCL and MedImmune to have multiple successful collaborative projects delivering greater synergy and leverage between researchers. The linked projects have created frameworks combining microscale experimentation, statistical correlations and cost modelling to enhance early stage drug development.

Background: What Was the Problem Being Addressed?

High throughput (HT) methodologies are increasingly being developed and applied in bioprocess development. However the large quantities of data generated from such studies as well as from historical batch records are not fully harnessed for their potential insights. It is critical to have methods to leverage such datasets and improve process understanding. This has been the driver behind the creation of the CoE between UCL and a global biotechnology company, MedImmune. The CoE is focused on harnessing HT datasets to develop predictive cause-and-effect models integrated with process economics optimisation algorithms. This will help determine causes of process deviations and identify manufacturing improvement opportunities.

How Did the CDT Help?

The EngDs within the UCL-MedImmune CoE have helped to build a rolling programme of research that links Medimmune’s leadership in antibody production with UCL’s leadership in bioprocess decisional tools and scale-down techniques to tackle intricate process-business decisions. The EngDs have created technologies that allow greater process understanding, simultaneous optimisation of upstream and downstream processes and capacity planning decision-making. The ability of the EngD researchers to move between academic and industrial sites facilitated knowledge exchange between MedImmune and UCL. This has enabled selection of the optimal bioprocess strategies early in the development cycle by accounting for process interactions.

What Were the Project Outcomes?

The CoE projects have created novel high throughput workflows that combine scale-down experimentation with advanced multivariate data analysis and process economics for antibody manufacture e.g. methodologies created in the first EngD were used to predict successfully the performance and robustness of large-scale centrifugation and depth filtration leading to significant R&D material, time and cost savings for MedImmune. This CDT project resulted in two key publications in leading peer-reviewed journals with two more submitted for review, two international conference presentations and underpinned a follow-on EngD project. The Research Engineer is now employed by a leading contract manufacturer based in the UK (Fujifilm Diosynth Biotechnologies).

Impact

  • The CoE enabled leverage of an additional £0.8m funding and facilitates sustained collaboration and rapid knowledge exchange between the partners.
  • Novel experimental and software tools embedded at the company site providing the ability to predict the performance of process options earlier in the development cycle.
  • Enhanced industry input into training with sustained MedImmune investment in industry placements, expert industrial lectures and scenarios at UG, MSc and MBI levels.
  • The rapid translation of EngD project outputs provided the basis for a Decisional Tools impact case study submitted to REF2014.

Commercialisation of Novel Photobioreactor Technology for Intensified Production of New Animal Vaccines (Axitan)

Researcher: Kane Miller

Graduated in 2017

Novel photobioreactor technology developed within an EngD project underpinned creation of a RE-led spin out, Axitan, in 2016. The company has already raised over £500k and employs three staff. Building on collaborative research on the synthetic biology of protein expression in microalgae, Axitan is focused on the development and commercialisation of a unique range of microalgae based vaccines targeted at the $30 billion p.a. animal health industry. Microalgae constitute the perfect vaccine delivery system. The vaccine products are simply incorporated into the animal feed overcoming the need for injections and the negative side effects associated with the use of antibiotics in animal husbandry.

Background: What Was the Problem Being Addressed?

By the year 2050, the world will need to double food production to feed an estimated global population of 9.7 billion. This, coupled with the increasing standards of living in the developing world, has led to the demand for improved nutrition, particularly for more animal protein that will need to be produced at levels 70% greater than at present. A related issue is the use of antibiotics in animal husbandry that accounts for nearly 70% of antibiotic consumption globally. The concern is the rise in antibiotic resistance with infections caused by drug resistant bacteria now killing more than 700,000 people per year and predicted to rise rapidly. As a result, we there is a need to be even more efficient with our resources, ensuring that livestock is not lost at the hands of disease. Axitan’s technology to produce animal vaccines in edible microalgae has the potential to render the use of many animal antibiotics redundant.

How Did the CDT Help?

The original EngD project enabled the core photobioreactor technology to be designed, built and tested. CDT training provided fundamental expertise in bioreactor design and scale-up while the host department provided access to outstanding mechanical and electrical workshop facilities to manufacture the final 20L pilot scale bioreactor. Elective modules enabled the RE to consider commercialisation of the technology, IP protection and the steps involved in spin-out company formation. Support from CDT staff enabled key collaborations to be established across UCL. These included access to vaccine expression technology (Prof. Saul Purton and the Algae@UCL network) and to colleagues in Computer Science that helped develop the bioreactor control software.

What Were the Project Outcomes?

The primary project outcome was the novel photobioreactor technology that enabled a nearly 2-fold increase in the productivity of microalgae cultures previously reported in the literature. The photobioreactor performance was proven to be scaleable while its design meant it could be steam sterilised making it compliant with the rigorous regulations surrounding the veterinary health industry. This therefore provided a robust platform from which to genetically engineer and grow microalgae in a cost effective and sustainable manner. A Business Interaction Voucher awarded by the BBSRC PHYCONET biotechnology network supported early proof-of-concept studies.

Impact

  • Patentable photobioreactor technology and creation of valuable know-how associated with its design and manufacture.
  • Establishment of new collaborations in the area of microalgae synthetic biology.
  • Creation of a spin-out company to facilitate technology commercialisation (see http://axitan.com).
  • Generation of over £500k of investment and creation of 3 new jobs.
  • Creation of new research and commercial collaborations with animal health companies.

Commercialisation of Novel Nanofibre Adsorption Technology for Therapeutic Antibody Formation (Puridify)

Researcher: Iwan Roberts

Graduated in 2015

Antibody therapeutics are the fastest growing class of new medicine but can be expensive to manufacture. CDT supported research led to creation of patented nanofibre adsorption technology that enables super-speed separation of antibodies exploiting the vast nanofibre surface area. This technology has the potential to reduce biopharmaceutical manufacturing costs by a quarter, making savings for the NHS and increasing patient accessibility to this important new class of medicine. CDT funding and training enabled two REs to form a successful UCL spin-out company, Puridify, to exploit the technology.

Background: What Was the Problem Being Addressed?

Half of the manufacturing costs associated with complex therapeutics like antibodies lie in product separation and purification. This is due to the current reliance on bead-based chromatography, which is limited by diffusion. Separating biotherapeutics is difficult because the molecules are large and delicate, prone to degeneration. During affinity chromatography, the most expensive stage of separation, the biotherapeutic must slowly diffuse into the beads; a process that takes ~8 hours to complete during which time product can be lost due to degradation. The EngD research and subsequent spin-out company sought to address this problem by exploring a new separation material to speed up the process and reduce manufacturing costs.

How did the CDT Help?

The cohort development and collaborative research environment of the CDT was critical to the creation of Puridify. The original patented nanofibre technology was developed by Dr Oliver Hardick in a previous CDT grant. He joined forces with Dr Iwan Roberts to commercialise the technology. Both undertook entrepreneurship courses at the London Business School as part of their EngD training. Both also benefitted from the CDT network to gain further skills training. Roberts undertook a placement in the UK Parliamentary Office of Science and Technology developing a range of skills briefing ministers and understanding the regulatory environment while Hardick used a Royal Society of Edinburgh STFC Enterprise Fellowships to develop the business case for Puridify.

What Were the Project Outcomes?

The CDT research led to creation of nanofibre based adsorption materials that enable high speed and high efficiency bioseparations. The process takes just 10 minutes and can be configured in a continuous rapid cycling format that intensifies this stage of biopharmaceutical manufacturing reducing the size and costs of unit operation. The work has led to 4 peer reviewed journal publications and 2 patents to date. Puridify, co-founded by Roberts and Hardick, continue to work intensively with UCL via 3 Innovate UK grants (total value £5m) and 1 new EngD project (Jordan Turbull) in collaboration with the Clinical BioManufacturing Facility (CBF) at Oxford University. These projects seek to address how the technology can be applied to next generation therapies such as viral vectors that are currently the subject of intense interest and activity.

Impact

  • Generation of patented nanofibre adsorption technology.
  • Creation of the spin-out company (Puridify) which now employs 19 people (see: http://puridify.com).
  • Generation of venture capital and Innovate UK grants totalling £8m including £2.2m Series A funding in 2015. Investors include Imperial Innovations, SR One and UCL Business.
  • Winners of multiple awards, most recently the 2016 BioProcess International Award for best collaboration with GlaxoSmithKline.