Impact case study database

Based on their novel organoid research, and patented bioprocess, the Cardiff team, together with their Bath collaborators, established spin-out company Cellesce Ltd in 2015. This has now matured from start-up to growth phase, with an estimated value of £15M, and new global biotechnology and pharmaceutical customers and partners.

4.1 Development of a growth-phase spin out biotech company

Cellesce Ltd was originally established as BBF BIO LIMITED in 2013. It lay dormant until 2015, when the company name was changed to Cellesce Ltd, and it became the vehicle to commercialise the joint Cardiff / Bath IP and organoid production process. This was based on a business plan developed by the Cardiff team, with Cardiff researcher Dale acting as the company’s Director of Organoid Biology since 2016 [5.1].

While some companies (e.g., Stemcell and Merck) have developed products in the organoid market, ranging from specialist growth media to organoids themselves, Cellesce Ltd was one of the first biotechnology companies to focus on the expansion of stable and reproducible human derived organoids at scale. While other manual methods of organoid culture systems support around 1000 assays per batch, the unique patented bioprocessing described in [3.6] allows Cellesce Ltd to offer 20-30,000 assays per batch, importantly containing uniform-sized organoids. The organoids available through the company are also validated for morphology, size range, viability, drug responses and genetics using techniques developed in the Cardiff lab [3.3, 3.4]. Further, [text redacted] [5.2].

4.2 Cellesce Ltd’s value and key partnerships diversifying market opportunities

The global organoid drug discovery screening market was valued at $1.45BN in 2020 (with colorectal cancer worth $136M and breast cancer $500M, source: Evolution Biosciences). Cellesce Ltd, operating from its base at Cardiff University’s Medicentre (a key University Innovation Hub for clinical and biomedical start-ups), is currently valued at £15M [5.3]. The company reported net assets of £720,841 for the 2019/2020 financial year, a twelve-fold increase on the £57,486 net assets reported in 2015/2016 [5.3]. The company has just finished a bridging round of fundraising, with a total of £6M raised in equity, convertible loan notes and grants. The company now employs 11 people (eight full-time, three part-time) [5.4].

In 2018, Cellesce Ltd formed a partnership with Repositive, a cancer model platform for researchers in all sectors which allows them to select relevant cancer model systems [5.5]. Repositive maintains an inventory of more than 8,000 cancer models and 24 contract research organisations (CROs). The platform matches researchers with the most appropriate cancer model/CRO, helping accelerate their research. Partnership with Repositive means that Cellesce Ltd products and services are visible to Repositive’s global customer base, almost half of which are in the US. 85% of Repositive’s customers are biopharmaceutical or pharmaceutical companies [5.5, p.6 ]. Dr Fiona Nielsen, Co-founder and CEO of Repositive explained that the collaboration with Cellesce Ltd is “ making it easier for oncology researchers and data providers to collaborate and speed up the development of new treatments” [5.5].

In addition, Cellesce partnered with the Hubrecht Organoid Technology (HUB) which hosts a living organoid biobank of more than 1,000 organoids derived from a variety of organs and disease models. Cellesce’s organoid expansion bioprocess is sufficiently flexible that it can be applied to any organoid. Via this partnership, Cellesce’s clients and other HUB licensees are scaling production of HUB organoids via Cellesce’s patented process [5.6]. This partnership provides significant expansion opportunities for Cellesce, as well as providing benefits for HUB. For example, HUB’s Managing Director Dr Rob Vries explained: “ HUB organoid technology will benefit from Cellesce’s innovative technology to expand large quantities of organoids such as breast cancer organoids” [5.6].

4.3 Cellesce’s customer base

By the end of December 2020, Cellesce Ltd had secured contracts with multiple customers, including pharmaceutical companies (e.g., GSK, Merck Millipore), biotechnology companies (e.g., Emulate Inc) and contract research organisations (e.g., Horizon), with initial revenues of £325K secured at the end of 2019 [5.4]. For example, Horizon Discovery Group plc is one of Cellesce’s commercial partners with an international customer base of over 2,000 organisations, including major pharmaceutical companies, and a revenue of £58.3M in 2019. Horizon is using Cellesce’s organoids for drug discovery assays [5.7]; Dr Tim Scales, Assay Services Manager at Horizon explained that the company is “ developing screens using organoids as…they offer the next-generation 3D model…which we believe suggests they might offer a better predictive outcome in the clinic” [5.8]. Scales confirmed the benefits of Cellesce’s technology: “ Cellesce have a proprietary bioreactor technology that allows them to produce organoids in far greater bulk than normal” [5.8]. He further explained why Horizon selected Cellesce to provide organoids: “ Cellesce’s technology allows us to overcome the problems of scalability that we require for high throughput screening but also variation between small batches” [5.8].

In summary, the Cardiff team applied their research expertise in cancer organoid models to develop a patented bioprocess that forms the intellectual property base of the joint Cardiff-Bath spin-out company, Cellesce Ltd. Since its establishment in 2015, Cellesce Ltd progressed from a start-up to a growth-phase spin-out with an estimated value of £15M, supported by new partnerships (e.g., Repositive) and customers (e.g., GSK and Horizon), who, in turn, command international markets in drug discovery and assay development.

Since 2014, Cardiff research: 1) led to policy change in Namibia to counter the detrimental impacts of intentional genetic manipulation on ecosystems; 2) changed species-specific conservation practice for the African rhinoceros, Bojer’s Skink and Monserrat Mountain Chicken Frog; and 3) generated global standards for monitoring biodiversity, used worldwide in conservation, and influencing the proposed EU Biodiversity Strategy 2030.

4.1 Combatting genetic manipulation in Namibia

Trophy hunting is a multi-million dollar industry in some Africa nations (article in The Conversation, ‘Counting the contribution of hunting to South Africa’s economy’, 15 November 2018), and creation of game animals with unnatural genetic traits, such as specific novel coat colours, has become a threat to natural biodiversity. The Namibian Government engaged with the International Union for Conservation of Nature (IUCN) Conservation Genetics Specialist Group (CGSG) to facilitate development of a robust policy designed to stop these genetic manipulations. Based on Cardiff research [3.5], the Namibian Government launched a National Policy on Selective and Intensive Breeding of Wildlife for Commercial Purposes [5.1] to “ protect the long-term viability of…wildlife populations” [5.2]. The policy committed to [5.1]:

• regulate the practice of selective and intensive breeding “through development of regulations…including the registration of selectively and intensively bred animals”;

• manage and mitigate “environmental aspects associated with intensive and selective breeding of wildlife”;

• monitor “genetic integrity of the selectively and intensively bred wild animals…and to protect free roaming wildlife from potential impacts of genetic manipulation”.

Deputy Director of Wildlife Monitoring and Research in the Ministry of Environment and Tourism, Namibia confirmed: “The involvement of the IUCN Conservation Genetics Specialist Group via Professor Mike Bruford…and the recent publication of the article ‘Intentional Genetic Manipulation’ as a conservation threat’ **[3.5]**… has played a central role in the development of our policy thinking in this arena” [5.2].

4.2 Species-specific genetic conservation

Through leadership of the IUCN CGSGs, and a long-term collaboration between the Cardiff team and the Durrell Wildlife Trust, Cardiff research changed conservation management plans for the following endangered species:

a. Bojer’s skink

Found only in Mauritius, conservation of the Bojer’s skink was a critical priority for the Mauritian Wildlife Foundation (MWF). Working in conjunction with the National Parks Service of Mauritius, the MWF’s Conservation Director confirmed that Cardiff research [3.3] analysing the genetic diversity of the local population “ supplied the evidence required to assist our conservation efforts” [5.3]. The Foundation used the 2018 analysis [3.3] to support translocation of populations between Mauritius’ islands. This evidence helped “ in managing the re-establishment of the skink populations on Il de la Passe and Ile aux Fouquets”, two islands where the native populations had significantly diminished [5.3] . “ A further two skink translocations from the other islands” were since undertaken [5.3].

b. Montserrat Mountain Chicken Frog

The Durrell Wildlife Trust used Cardiff research on the genetic diversity of the Montserrat Mountain Chicken Frog [3.4] to improve their captive breeding programme. The Trust’s Head of Herpetology, notes that Cardiff’s study was the “ first to describe the impact of the [chytridiomycosis] disease on the genetic diversity of an affected species” [5.4]. Cardiff’s confirmation that the Trust currently held “ a representative sample of genetic diversity from the species” [5.4] allowed the organisation to design a new captive breeding programme which avoided the need for additional animals. The research “ was essential in developing our captive breeding strategy for the species, excluding the need for further collections of individuals, with the focus now on maintaining the diversity already present” [5.4].

Further, having discovered that the two remaining populations of frog on Dominica and Montserrat had the same mitochondrial haplotype, the Trust consolidated their species management across the two islands: “ Using this finding as evidence… we moved from managing the populations independently, to managing them as a single unit. This has freed up resources” [5.4]. The Trust committed to use the insights beyond the frog population: “ In Durrell’s wider work, this has made us more cognisant of the need for pre-emptive action in securing genetic diversity in populations facing similar disease threats” [5.4].

c. African rhinoceros

Cardiff research on the African rhinoceros [3.2] was also highly prized by the IUCN African Rhino Specialist Group. A joint statement from the Chair and Scientific Officer of the group confirmed: “ *Our genetics education has been advanced thanks to the understandable and clear way…[Bruford] presented and explained the latest genetic issues and concepts (especially to those of us rhino conservationists who are not geneticists)*” [5.5]. Previously absent, genetic data is now used in conservation strategies for these critically endangered animals. For example, it was used to inform a decision “ to move away from the static idea of a subspecies to the dynamic idea of populations” [5.5]. The Africa Rhino Specialist Group committed to use the insights to “ inform future translocation planning”, in particular information about when genetic exchange in specific situations is and is not an optimal conservation option [5.5].

4.3 Global impact on biodiversity policy and standards

a. Global standards for monitoring genetic biodiversity

Cardiff researchers partnered with the Group on Earth Observations (GEO), a global collaboration of 111 world governments and a further 129 ‘participating organisations’, including UNEP (United Nations Environment Programme). GEO uses big data to tackle some of the world’s most complex challenges in sustainable development and environmental management. Working directly with the GEO Biodiversity Observation Network initiative, the Cardiff team played a key role in the production of The GEO Handbook on Biodiversity Observation Networks, a manual setting out global standards for genetic monitoring of biodiversity [3.1, 3.2, 5.6].

The Handbook has been downloaded 251K times since its 2017 publication [5.7]. ‘Chapter 5: Monitoring Changes in Genetic Diversity’ (co-authored by Bruford and informed by Cardiff’s genetic conservation research **[3.1]**) was cited in a UN Environment Program policy document highlighting the importance of genetic diversity “in maintaining and enhancing the diversity of cultivated plants and breeds of livestock underpinning the resilience of agricultural systems and food security” [5.8, p153 ].

**b. EU Biodiversity Strategy 2030

In January 2020, the UN Convention on Biological Diversity (CBD) started consultation on a draft Post 2020 Global Framework on Biodiversity. Bruford’s research highlighting the deficiencies of the draft Framework [3.7] also influenced the EU Biodiversity Strategy 2030. While finalisation of the Global Framework was impeded by Covid-19, the EU Biodiversity Strategy 2030 launched in May 2020 [5.9].

The EU Biodiversity Strategy implements Bruford’s recommendations [3.7] to ensure a broader focus on species outside of agriculture. Moving beyond agricultural species protection, the EU Strategy further commits to “no human-induced extinction of species” and establishes a target that “[t]here is a 50% reduction in the number of Red List species [the IUCN’s species at risk of extinction] threatened by invasive alien species” [5.9]. To achieve this, the Strategy commits that (a) the EU should “set up ecological corridors to prevent genetic isolation” and (b) each member state should “ensure no deterioration in conservation trends and status of all protected habitats and species by 2030” [5.9].

In summary, Cardiff research on genetic diversity and conservation shaped policy, recommendations and engagement work of the IUCN CGSGs, a critical platform which transformed conservation policy, and practice in endangered species management, around the world.

The Cardiff team are members of the International Union for the Conservation of Nature (IUCN) Giraffe and Okapi Special Interest Group. In May 2013, under the auspices of this newly formed group, key stakeholders including the Institut Congolaise pour la Conservation de la Nature (ICCN, a Congolese government department) and the Zoological Society of London, met in Kisangani to discuss future approaches to okapi conservation. Presentation of Cardiff’s research findings at this meeting delivered new conservation impacts as follows: (1) establishment of a new national park in DR Congo, designed to protect the newly discovered okapi population in the South West; (2) improved strategies for genetic management of captive okapi breeding; and (3) upgrading of the okapi conservation status to ‘Endangered’, as well as development of the first ten-year okapi conservation strategy.

1. Establishment of the Lomami National Park in DR Congo

As part of the DR Congo TL2 project, the discovery of okapis south of the Congo river [3.3], transformed understanding of the geographical extent of the species. The map below **[**from 3.3] shows where the Cardiff team identified okapi dung in their studies (small grey circles). As well as dung present in the already protected Okapi Faunal Reserve, okapis were clearly active south of the Congo River adjacent to the Lomami River.

Stuart Nixon, Africa Field Programme Coordinator (Chester Zoo) and Co-Chair of the IUCN Giraffe and Okapi Specialist Group, explained that Cardiff research “ unequivocally confirmed the presence of the okapi in the Lomami basin of central DRC-­‐ a significant range extension” [5.1] .

The Cardiff discovery led to the establishment of Lomami National Park in 2016 by the DR Congo Government, the first national park to be created in the area for over 40 years [5.1], covering 5.4 million hectares (shaded grey area at the bottom of the diagram). This new Park aimed to bolster conservation of the okapi population south of the Congo river, but also granted protection to other critical species, including forest elephants, bonobo, the recently discovered Congo peafowl ( Afroparvus congensis, the only African representative of the peafowl) and a previously unknown primate, the lesula [5.1, 5.2, 5.3].

Notably, Lomami National Park is the first Congolese protected area to be set up in a participatory manner, facilitated by the TL2 project and Institut Congolaise pour la Conservation de la Nature. Conservationists and government officials work directly with local communities within and around the park to ensure protection of the region and promote sustainable livelihoods, such as recruitment as local park guides [5.2, 5.3]. John Hart, from the Frankfurt Zoological Society (an NGO operating in the Lomami National Park), noted “the willingness of this community to collaborate with Congolese national park authorities and TL2 project staff in protecting the buffer zone, and in particular their okapi” [5.2].

Nixon noted the critical importance of Cardiff research in this new conservation initiative: “ This discovery [of okapi in the region] provided important evidence used in the 2016 creation of the 8,900km² Parc National de la Lomami, DRC’s first new national park for over 40 years” [5.1]. He further states that the Cardiff research showing the unique genetic diversity of the Lomami population “carried additional conservation significance” which was “also a potentially valuable piece of information for additional conservation prioritisation such as the IUCN's Key Biodiversity Areas initiative” [5.1].

4.2 Improved management of the captive population

Captive breeding programmes are vital to the survival of endangered species. Cardiff research showed that, while captive okapi breeding programmes had been relatively effective at preventing inbreeding, substantial genetic diversity had been lost [3.3, 3.4]. Through the provision of Cardiff genetic tools and research, including analysis of microsatellite loci and novel insights into biodiversity in wild [3.1] and captive [3.3] okapi populations, Bruford improved the ability of European and US captive breeding programmes to make breeding selections that maximised genetic diversity and long-term species viability.

The Okapi International Studbook Keeper (an international record kept by Antwerp Zoo with genetic information on every okapi that has ever lived in a zoo) confirmed that Cardiff research [3.3] “ allowed us to examine the genetic diversity of the captive population, compare with the wild population and additional captive populations” [5.4]. The research transformed the captive breeding programme in Europe, in collaboration with Antwerp Zoo (KMDA) and the European breeding program (EAAP). Antwerp Zoo confirmed that the new insights would “ result in a revised genetic management strategy for the ex situ populations” [5.4].

They further noted that “ these new insights…[are] guiding the breeding programme and including more efficient exchange of individuals between Europe and the US – a strategy recommended in the recent IUCN species assessment, which followed from the publication **[3.6]**” [5.4].

4.3 Change in conservation status and creation of conservation strategy

The joint meeting in Kisangani in May 2013, when the Cardiff research findings were presented, led to two further critical positive impacts on okapi conservation: a change in the IUCN conservation status of the okapi, and publication of the first ever okapi conservation strategy.

a. From ‘Near Threatened’ to ‘Endangered’

In November 2013, the IUCN changed the conservation status of the okapi from ‘Near Threatened’ to ‘Endangered’ [5.5]. Notably, the change to ‘Endangered’ grants access to funding sources for conservation, such as the People’s Trust for Endangered Species, the US Government’s Critically Endangered Animals Conservation Fund, and the UN’s Global Wildlife Program. Based on the okapi status change, a successful application was made to the IUCN Save Our Species fund by local conservation organisations including Institut Congolaise pour la Conservation de la Nature, for a project combating threats to okapi and African forest elephants in DR Congo [5.6].

b. A new international strategy for the protection of the okapi

In 2015, the IUCN published the first ever okapi conservation strategy and status review [5.7]. Co-written by the Cardiff team, the document drew strongly on Cardiff research, and cited Cardiff-led studies [3.4, 3.5, 3.6] over 30 times. The ten-year strategy calls for urgent government and international commitment to ensure that key Congolese conservation areas are protected from armed militia and illegal activities [5.8]. This document is the first-ever coordinated global strategy to protect the okapi [5.5, 5.9].

Via the MRC-funded CLIMB infrastructure, Cardiff researchers developed key methodological innovations delivering sensitive and rapid analysis of large-scale pathogen datasets. Working with Public Health Wales (PHW), the research led to the establishment of a bespoke NGS bioinformatics infrastructure for PHW’s Pathogen Genomics Unit (total investment over £5M), a key component in delivering the Welsh Government’s Genomics in Precision Medicine Strategy. This enhanced clinical and policy outcomes through, for example, improvements to HIV and influenza diagnostic services in Wales, and significant contributions to global surveillance of influenza and SARS-CoV-2.

4.1 A new NGS bioinformatics service for PHW Pathogen Genomics Unit

In response to the Welsh Government’s Genomics for Precision Medicine Strategy, PHW recognised the need to provide a more advanced microbiology genomics service. The Head of PHW’s Pathogen Genomics Unit, Dr Sally Corden, identified Connor as a key expert to provide the required bioinformatics expertise to implement NGS as a routine diagnostic and surveillance tool. Corden noted that Connor was “somebody who understood how to write the code to translate information from the sequencer and put it back together into something that’s a readable format for a clinician” [5.1]. Corden initiated Connor’s secondment to PHW from Cardiff University in 2017 (0.2 FTE, rising to 0.8 FTE in 2019-20) . Dr Quentin Sandifer, Director of Public Health Services at PHW confirmed that Connor’s appointment resulted in “ key impacts on our service, including the development of the Pathogen Genomics Unit” [5.2].

Connor used his research expertise to benchmark and support the development of laboratory processes for a new sample processing pipeline, while also designing a new computational infrastructure to meet requirements for large-scale data analysis, reproducibility and archiving, based on elements of the CLIMB infrastructure [3.1, 3.2].  Connor also built an end-to-end bioinformatics analysis and reporting platform to meet clinician requirements around diagnoses. Sandifer explained that PHW “ benefited enormously from Dr Connor’s expertise in the area of bioinformatics and pathogen genomics which has underpinned the development of the bioinformatics pipelines that produce the reports that are then communicated to clinicians and other healthcare staff” [5.2].

PHW’s novel microbiology genomics system resulted in new accredited services with automated reporting of pathogen sequence data directly to international repositories, including CLIMB and GISAID (influenza). Based on the success of Connor’s work, PHW invested in four specialist bioinformaticians as part of a new PHW Pathogen Genomics Unit bioinformatics team (led by Connor) [5.2]. Connor also assisted the Unit in writing a successful multi-million pound business case to the Welsh Government for further funding to expand the NGS clinical service; this was awarded in 2019-2022 [5.2]. The Chief Scientific Advisor for Health in Wales, Dr Rob Orford, confirmed the link between Connor’s research and the investment made in the Unit: “The confidence the Welsh Government has in Dr Connor’s work is reflected in the overall level of investment we have made/committed to the Pathogen Genomics work within Public Health Wales – of which he and his team are a core and leading part – which stands at over £5M to date” [5.3].

Orford explained the significance of Cardiff’s research for the delivery of the Welsh Government’s Genomics in Precision Medicine Strategy, noting that it has “ improved the ability of NHS Wales to diagnose, monitor and treat patients across a range of conditions” and that the systems created by Connor “provide situational updates to Welsh Government to support policy making” [5.3] .

4.2 Advancing clinical services for HIV, influenza and SARS-CoV-2

Application of Cardiff’s research [3.2, 3.3], alongside the new computational architecture and analysis pipelines Connor established at the PHW’s Pathogen Genomic Unit [3.1], enabled PHW’s pathogen genomics service to deliver the following improvements to clinical services:

a. A new ISO accredited HIV service

New capabilities within the Pathogen Genomics Unit allowed PHW to launch a national HIV screening and monitoring service in July 2018. Prior to the service, patients’ RNA samples were sent to Birmingham, creating a 6 week wait for results. Further, the central facility in Birmingham was not able to analyse samples with a low viral load [5.2]. PHW’s Pathogen Genomic Unit’s new HIV service, using Cardiff research pipelines and methods [3.1, 3.2, 3.3], conducts HIV sequencing in-house, reducing sample turnaround to 7 days, and is able to provide more detailed and sensitive sequencing information than was previously available [5.2]. A further benefit of the new service is enhanced engagement with clinicians, allowing emergencies to be handled quickly, in a way that was not previously possible. Corden cites the example of, “an HIV positive lady who was pregnant, and was late booking into the service. As the service is local, we were able to work during a weekend to turn around the report for the clinician within six days, as the treatment of the unborn baby was critical” [5.1].

Cardiff’s testing methods also enhanced clinical services for patients with low viral load: “ We are able to detect resistance mutations below the 20% standard: down to 10%, and this allows us to detect resistance to anti-viral drugs at an earlier point, and allow clinicians to make changes to a patient’s treatment” [5.1]. This innovation delivers important public health benefits: once patients are receiving appropriate, tailored treatment, they are no longer at risk of transmitting HIV. The new service implemented by Connor and colleagues is also considerably more cost-effective for the NHS: analysis of each sample now costs £150, compared to the previous £250 per sample [5.2]. A PHW Surveillance Report into HIV and STI trends in Wales (2018) estimated there were 1,585 patients being treated for HIV in Wales; this reduced cost therefore represents a saving of approximately £159K per year to NHS Wales. In July 2019, the service received formal accreditation (ISO 15189) [5.4], making it the first ISO-accredited NGS-based HIV typing service in the UK [5.2]. Sandifer confirmed that the service “ …has been built thanks to Dr Connor’s research and expertise, which have allowed us to offer integrase inhibitor sensitivity screening as standard, at improved turnaround time, and lower cost” [5.2].

b. Improved and rapid influenza surveillance

The whole genome sequencing approach of PHW’s Pathogen Genomics Unit also enabled more advanced and rapid sequencing of seasonal influenza, both of which are vital for successful global vaccine development. In 2017-2018, the Wales Specialist Virology Centre was awarded £90K by the Welsh Government to pilot the use of whole genome sequencing for influenza surveillance, “ based on Dr Connor’s pioneering next generation sequencing and analysis approach” [5.5]. Dr Catherine Moore, Consultant Clinical Scientist, Public Health Wales and Wales National Virology Lead for Respiratory Virus Surveillance confirmed “ as a result of the success of the pilot, we implemented changes in our influenza surveillance methods to make use of whole genome sequencing in time for the 2018-19 influenza season” [5.5]. Wales is now able to provide extra information by sequencing all eight segments of the influenza virus genome (compared to the two via Sanger sequencing, as had been used previously). This enhances monitoring for resistant mutations within segments PB1, PB2, and PA, which have the potential to affect new classes of influenza antivirals [5.5].

The Unit’s new bioinformatics analysis methods also enabled more effective geographic mapping of outbreak transmissions [5.5]. Moore explains: “ Our new system, developed in partnership with Dr Connor rapidly demonstrated its effectiveness, enabling us to sustainably sequence and share Influenza genome sequences with international surveillance databases...” [5.5].

As a result, Welsh influenza samples can be typed and submitted to international surveillance systems GISAID and ECDC within 7 days [5.5]. This improved analysis pipeline resulted in PHW sequencing 147.4 influenza genomes per million people in Wales, compared to only 44.6 and 2.2 influenza genome sequences per million people in England and Scotland, respectively (over the same period of time, the 2018-19 and 2019-20 influenza seasons) [5.5]. Moore confirmed that “ the sequences we submitted that have been generated using Dr Connor’s methods will have been used to inform the design of the 2018, 2019, and 2020 influenza vaccine”, contributing to global efforts to protect those most vulnerable to influenza [5.5].

c. Rapid sequencing of all Welsh SARS-CoV-2 samples

Sequencing of SARS-CoV-2 is vital for effective tracking of virus spread, identification of mutations, and design of successful vaccines. During the current coronavirus pandemic, the PHW Pathogen Genomics Unit is responsible for sequencing all Welsh SARS-CoV-2 samples, feeding these data into the COVID-19 Genomics UK Consortium (COG-UK). This work was facilitated by Connor and his team establishing a new dedicated CLIMB-COVID platform, which directly enables COG-UK to analyse and integrate UK-wide SARS-CoV-2 data.

At the start of the first UK-wide lockdown (between March 22-31, 2020) PHW’s Pathogen Genomic Unit had sequenced the highest number of SARS-CoV-2 genomes in the UK [5.6a]. This work ensured that the UK led the world in terms of genetic knowledge of coronavirus, having sequenced 806 samples by March 31, 2020 (compared to 744 in the USA and 296 in China) [5.6a]. By December 2020, PHW continued to lead global sequencing efforts (20,736 sequences), more than any other country in the world, except for England (130,325) [5.6a] and the USA (51,212) [5.6b]. [Text redacted]

d. Informing government decision-making to minimise SARS-CoV-2 transmission

Based on his significant pathogen and bioinformatics expertise, Connor is a member of Wales’ Technical Advisory Cell (TAC), which provides scientific advice to the Welsh Government on coronavirus [5.8a]. In July 2020, TAC advised the Welsh Government to include genomics in its list of ‘Early Warning Indicators’ for SARS-CoV-2 in Wales [5.8b]. An October 2020 report by Connor, identifying the entry and westward spread of new SARS-CoV-2 strains across Wales [5.9], was also used by the First Minister Mark Drakeford to justify travel restrictions into Wales from October 16, 2020 [5.9]. Orford confirmed that the research “directly influenced Welsh government policy at the highest level of Government, demonstrating the spread of infection geographically and supporting decision making around restrictions such as the ‘5 mile rule’ and travel from high-prevalence areas in order to protect the Welsh population” [5.3].

[Text redacted]

The outcomes from Cardiff and Unilever’s joint research programme minimised the risk of bacterial contamination within Unilever’s manufacturing processes on a global scale. Unilever’s Beauty and Personal Homecare business has an annual turnover of €37.2BN, with consumers across the globe using their products [5.1]. The research resulted in safer products for consumers and substantial financial savings for the company. Impact was delivered as follows:

4.1 Providing accurate identification of bacteria contaminants and reducing costly contamination incidents

Unilever used Cardiff’s research to set industry-leading standards in accurately identifying contaminants and managing the associated risks. The standards adopted by Unilever were considerably more robust than deemed necessary by regulatory compliance, since industry guidelines and European regulations do not require manufacturers to identify Burkholderia bacterial contaminations. As noted by Unilever’s Peter Carew (R&D Director) and Stuart Campbell-Lee (Research Scientist) [5.1, 5.2]:

• “Cardiff University researchers have assisted us in the development of a comprehensive database of 269 contaminant strain genomes, including 68 Burkholderia ” [5.2]. This represents approximately a 17-fold increase in Unilever’s identified contaminant strains since 2016.

• “The new methodology and accompanying genomic knowledge of microbial contaminant strains goes above and beyond regulatory requirements for preservation evaluation to ensure protection against Burkholderia” [5.2].

The research has been used by Unilever to:

• identify two Burkholderia contamination incidents in 2014 (a cosmetic product) and 2016 (a non-cosmetic product), which Unilever’s commercial contract research provider (CRO) for microbial contamination was unable to identify [5.1]. The Cardiff team provided Unilever with accurate identification of these Burkholderia contaminants using MLST, genome sequencing, and resources not available to the CRO. Informed by Cardiff’s expertise and high-resolution analysis, Unilever was able to address these incidents with targeted clean-up procedures [5.1];

• implement robust strategies to combat bacterial contamination, based on Cardiff-derived data. Carew noted that: “ Since 2014 Unilever cosmetics have not endured a Burkholderia microbial contamination incident as a result of the actions taken from knowledge development achieved through this partnership, specifically improving factory hygiene practices and preservation system design” [5.1]. This has prevented contamination and future product recalls. These normally cost in excess of £750K per contamination incident, as well as “intangibles such as loss of future customer sales due to bad PR” [5.1].

4.2 Informing the development and patenting of new preservative compositions

Manufacturers face new challenges as consumer and regulatory demands move towards products with milder, more natural preservatives or preservative-free formulations. These are, however, at greater risk of microbial contamination [5.1]. Cardiff research provided Unilever with an understanding of antimicrobial susceptibility and synergy testing methods (a chequerboard assay) which led to the company developing and patenting three new preservative compositions for their products (2019 international patents: WO 2019/233753 A1, WO 2019/233757 A1, and WO 2019/233752 A1) [5.2]. These preservative compositions are designed to guard against contamination (based on Cardiff research **[3.3, 3.5]**), and will be used in a wide range of Unilever’s personal care and hair care products, with a global market value of over US$10BN. As Unilever stated [5.2]:

• “A method transfer was performed introducing synergy assessments using a ‘chequerboard assay’ for preservatives during Dr Laura Rushton’s (Cardiff University) Knowledge Transfer Partnership (KTP) project.”

• “This methodology and the panels of well characterised, genetically typed contamination strains have since become part of a valuable method to Unilever in order to establish synergistic preservative combinations as part of intellectual property filings impacting at an international level in 2019.”

• “The use of these proprietary preservative combinations in a range of Unilever consumer products will ensure business continuity is maintained in this multi-billion Euro business sector.”

4.3 Informing risk prevention and Unilever’s global research priorities

From April 2016, Unilever developed an internal research strategy entitled ‘Genomic Preservation Science’ from April 2016 [5.2]. Prior to Cardiff’s research, Unilever was using conventional bacterial assays to identify bacteria, rather than advanced genomic techniques. This new strategy outlined Unilever’s commitment to move away from conventional assays to adopt a robust genomic approach, aligned to benefits demonstrated by Cardiff research [3.2, 3.3, 3.5, 3.6].

This strategy resulted in a closed industry-academia workshop to define Unilever’s long-term capability roadmap (held in April 2017). The Cardiff team acted as academic consultants for Unilever, informing development of their strategy and advising on the invited academic delegate list, which included research leaders from Liverpool, Southampton and Cardiff Universities [5.3]. Unilever’s genomic strategy for identifying, monitoring and eradicating potentially harmful bacteria has now been rolled out across Unilever’s major research and development centres, within the UK, the United States, China and India [5.2].

Cardiff’s research enabled Unilever to: accurately identify contaminants and essentially stop Burkholderia contamination incidents occurring in their products; develop new preservative compositions to avoid bacterial incidents; and implement robust monitoring and a global genomic preservation research strategy designed to avoid costly product recalls. Campbell-Lee noted that the research has “empowered the preservation team” and is driving “ industry to a more prudent destination to ensure cosmetic and household goods are adequately preserved” [5.2].

Cardiff research led to detailed understanding of forest use by endangered animals in Sabah, Malaysia, and provided critical evidence for implementation of new approaches designed to provide enhanced protection for the Bornean elephant, Bornean banteng, proboscis monkey and Sunda clouded leopard.

1. Species-specific State Action Plans

The Cardiff team co-wrote four State Action Plans based on the Cardiff research in collaboration with the Sabah Wildlife Department, the key government authority responsible for the protection of wildlife in Sabah. Three of the Action Plans were new and focused on the Bornean banteng, proboscis monkey and Sunda clouded leopard (all 2019-2028). The fourth Action Plan, on the Bornean elephant (2020-2029), was an updated version continuing from the prior 2012-2016 plan (which had been previously developed with the Cardiff team) [5.1a-d]. The Action Plans outlined key steps designed to support all four endangered Sabah species, based on requirements identified from the Cardiff research [3.1-3.6]. For example, recommendations included safeguarding of appropriate habitats by:

• improving landscape connectivity for all four species to access suitable habitats [5.1a, p.18, 5.1b p.iv, 5.1c p.iii and 5.1d, p.iv ];

• working with NGOs, the palm oil industry and local communities to recover underproductive palm oil plantations and return these sites to degraded forest suitable for Bornean elephants [5.1a, p.18-21 ];

• preventing “any loss and degradation of suitable habitat (open grassy and sedge areas and forest shade) for bantengs” and planning the development and maintenance of pastures within the range of existing herds [5.1b, p.25 ];

• increasing mangrove and riparian forest areas suitable for proboscis monkeys [5.1c, p.iii ];

• halting loss and degradation of habitats used by Sunda clouded leopards (such as forest canopy cover) [5.1d, p.iii ].

The Plans also included objectives to support wildlife enforcement and reduce poaching [3.1, 3.5, 3.6], for example:

• a commitment to “improve protection and halt elephant killing to reduce current levels of elephant deaths” [5.1a, p.10 ], through improving local coordination and field enforcement [5.1a, p.13 ];

• increased measures to combat poaching including to “hire and train crime analysts, investigators and intelligence gatherers” to track poaching and assess the levels of hunting in Sabah [5.1b, p.23 ].

The Action Plans for the Bornean banteng, proboscis monkey and Sunda clouded leopard were officially launched by the Minister of Tourism, Culture and Environment in September 2018 and approved by the Sabah State Government in June 2019 [5.2, 5.3]. Sime Darby Foundation Governing Council Member, Caroline Christine Russell, noted her hope that the Action Plans would be implemented as part of conservation policy, and that the “launch of the state action plans will serve as a catalyst for other organisations to come in and be part of these important efforts to conserve” the endangered species [5.3].

The total investment from the Sabah Government for all four ten-year Plans, approved by the Sabah Ministry of Finance, is RM37.84M (£7M) for the ten-year period, which includes funding of RM10M (£1.8M) for an Endangered Species Conservation Unit and RM20M (£3.75M) for an Enforcement Unit [5.1a-d].

1. Forest recovery and wildlife enforcement

To date, implementation of recommendations outlined in the four Action Plans have focused on forest recovery and replanting, as well as improved wildlife enforcement.

**a. Forest recovery and replanting

Following the publication of the Action Plans, which contained specific commitments and measures for forest recovery and replanting, the Sabah government started the first phase of reforestation in 2019 with the planting of a million trees on over 4,000 hectares of degraded forest land [5.4a]. The Action Plans also provided a framework to coordinate replanting efforts by NGOs and the government, for example in 2020 the Rhino and Forest Fund (RFF) worked with the Sabah Wildlife Department to purchase a 65 hectares oil palm plantation for replanting. This will benefit Bornean elephants and banteng, as well as reconnect two key protected areas of forest [5.4b].

The Cardiff DGFC team further facilitated implementation of the Action Plans’ measures for reforestation; in 2020, the team worked with the local community to replant three hectares of forest with 4,100 trees, with a further 8,400 saplings ready to be planted in 2021 after seasonally flooded areas dry out [5.5, p.5-6 ]. Planting is planned with, and carried out by, members of the local community through the DGFC’s partner, KOPEL Bhd, which represents four local villages and supports sustainable livelihoods and training for local people through biodiversity conservation [5.5, p.5 ].

b. Improving wildlife enforcement

Cardiff research findings on poaching and wildlife trafficking [3.1, 3.6] improved wildlife enforcement through the Sabah Forestry Department’s Protect Team. The Team monitors 2M hectares of protected conservation areas with the aim of reducing illegal forestry activities and encroachment on forest reserves, as well as poaching and wildlife trafficking [5.6a].

Following the specific Action Plan measures on enforcement capacity, often successfully delivered via investment in intelligence officers, in June 2019 the Sime Darby Foundation awarded RM4M (£750K) to enable employment of 25 new rangers and a crime analyst [5.6a]. Sabah’s Chief Conservator of Forests, Datuk Mashor Bin Mohd Jaini, noted that the funding would: “ boost the enforcement capacity of the State Government, especially Sabah Forestry Department to reduce the number of poaching cases in Sabah, in particular within forest reserve areas” [5.6a]. Building on this, in September 2019 the US State Department’s Bureau of International Narcotics and Law Enforcement Affairs committed a further RM4M (£750K) of funding for a new Intelligence Unit within the Sabah Wildlife Department, designed to combat poaching and conduct genetic wildlife forensic work [5.6b]. The new Unit employs eleven staff from the Sabah Wildlife Department and is developing a new forensic lab designed to “ maintain a wildlife crime database that will be shared effectively with the relevant national and international agencies” [5.6b].

Evidencing the success of this investment, linked to delivery of Sabah’s new Action Plans, 200 enforcement operations were carried out between January-December 2020, resulting in more than 68 arrests, the prosecution of two suspects for possession of elephant tusks and confiscation of RM3.1M (£560K) worth of illegally-obtained forest products [5.6c, 5.6d].

4.3 Conservation legacy

Additional conservation legacies delivered by Cardiff’s DGFC team during the REF period included:

a. Successful campaigning against the construction of the Sukau Bridge

Cardiff’s research into the Bornean elephant’s movements [3.1] led Goossens, as Director of DGFC, to campaign strongly against the planned construction of a bridge over the Sukau river, which would further fragment the elephant’s habitat. This campaign raised the profile of the issue, attracting Sir David Attenborough’s support, and as a result, the bridge was scrapped [5.7]. Wildlife Impact’s independent DGFC Evaluation Report stated: “DGFC delivered scientific evidence regarding impacts of the proposed Sukau bridge to the Minister of Tourism, Culture and Environment, particularly based on satellite data of elephant movements, which helped contribute to rejection of the proposal” [5.8, p.7 ].

b. Advocating sensitive development of the Pan Borneo Highway

Based on DGFC’s research data, and following advice from Coalition 3H (Humans, Habitats, Highways), an alternative route for the Pan Borneo Highway is now being considered by the Sabah government [5.9]. The Highway was due to cross mangrove forest reserves which the Cardiff research had identified as the last remaining habitat of the proboscis monkey [3.4], as well as forest reserves critical for the Bornean elephant and Sunda clouded leopard [3.3, 3.5, 3.6]. Building the highway would have led to further fragmentation of these important habitats and a decline in the endangered species.

Movement and distribution maps from the four flagship species, created from the Cardiff research, were used to develop new proposals for the highway, including road alignment changes, eco-links and wildlife overpasses to mitigate the impact on wildlife. This was supported by Coalition 3H, who advised the Sabah government on how to minimise the environmental impact of road expansion, with the Highway now currently under construction in line with these revised plans [5.9].

In summary, Cardiff’s work secured greater protection for four key endangered species in Malaysian Borneo. Wildlife Impact’s DGFC Impact Evaluation Report notes that through the DGFC, Cardiff research “has been instrumental in advocating and providing data for rare species action plans, particularly charismatic megafauna such as clouded leopards, banteng and proboscis monkeys” [5.8, p.5 ].

Cardiff’s research linking biodiversity and freshwater ecosystem services resulted in two key impacts: 1) it was integral to a $250M fund protecting one of the world’s last remaining near-pristine river systems in Africa; and 2) it transformed policy and practice of freshwater ecosystem management in Wales via the Environment (Wales) Act 2016 and a new, catchment-driven approach implemented by Wales’s national water utility provider and Natural Resources Wales.

1. Protecting CORB UNESCO World Heritage Site (Angola, Botswana and Namibia)

Cardiff’s research [3.5] provided the tools to justify protection of the Cubango-Okavango (CORB) River Basin. This is one of the world’s last remaining undisturbed river systems, currently threatened by development, as well as a UNESCO World Heritage Site and Wetlands of International Importance (Ramsar Site). The CORB Fund states it is a $250M fund set up in perpetuity to address “the risk of degradation” to the CORB’s source waters from demands including energy development, population expansion and significant planned water extraction. “The Fund sees numerous opportunities to respond creatively to these demands and threats by supporting the sustainable use and conservation of water resources and betterment of livelihoods in the CORB” [5.1].

Cardiff’s research defining non-material benefits of ecosystem services on which the poorest depend (e.g. clean drinking water) was used to develop an economic valuation framework central to the CORB Fund Business Case. CORB was set up by the Climate Resilient Infrastructure Development Facility, whose Team Leader stated: “CORB is unique in its trans-boundary nature with many competing demands and the delivery of significant non-material benefits…The CORB fund project thus implements the concepts set out in the Durance paper *[3.5] to understand the valuing of ecosystem services, particularly those with non-material, non-monetary benefits” [5.2].

The CORB Fund was established in Dec 2019 and is currently in its initial two-year demonstration phase, with $900K of preparation co-funding raised to date [5.1]. The Permanent Okavango River Basin Water Commission (OKACOM) is a joint Angolan, Botswanian and Namibian organisation which advises the Fund. In April 2020, OKACOM held consultations with local communities to discuss the most pressing challenges for communities living in the basin, capture strategies for sustainable livelihoods, and plan interactive mapping to identify livelihood vulnerability hotspots [5.3]. Community leaders noted that the collaborative work is important to “ change the future and preserve the livelihoods of people in our society” [5.3].

1. Transformation of freshwater ecosystem management in Wales

Cardiff research also led to a new, holistic approach to the management of freshwater ecosystems in Wales encompassing policy, industry practice and natural resource management. This marked a step change away from focusing on the short-term benefits of meat and timber production, resulting in pollution and higher water treatment costs, to longer-term landscape management promoting healthy ecosystems. Matthew Quinn, Welsh Government Director of Environment and Sustainable Development stated that the research [3.1, 3.4, 3.5] “ has given confidence that a new, more holistic approach will deliver on biodiversity interests rather than being a threat to them” [5.4].

a. Environment (Wales) Act 2016

The Environment (Wales) Act 2016 is the basis for natural resource management in Wales. Cardiff’s research [3.1, 3.6] was fundamental to principles outlined in the Act, in particular providing quantified evidence of the importance of biodiversity and healthy functioning ecosystems [3.2, 3.3] . Steve Spode, Welsh Government Head of Ecosystem Management and Implementation, stated that DURESS provided evidence to test some of the more novel thinking taken forward in the Act, including “the connections within and between ecosystems in Wales and need to manage whole systems” [5.5]. Many of Welsh Government’s key partners (Natural Resources Wales, Dŵr Cymru Welsh Water, and Welsh NGOs) contributed to DURESS, which “helped raise further awareness around ecosystem-based management, and made its outputs more relevant to Wales” [5.5].

The Environment (Wales) Act 2016’s guiding principles for the sustainable management of natural resources reflect Cardiff research, in particular specifying that environmental interventions should aim to increase ecosystem resilience and benefits to people, “in particular the following aspects (i) diversity between and within ecosystems; (ii) the connections between and within ecosystems; (iii) the scale of ecosystems; (iv) the condition of ecosystems (including their structure and functioning); and (v) the adaptability of ecosystems” [5.6, p2 ]. The research also had further lasting impact on Welsh Government policy. Following Brexit, Welsh Government is using the Cardiff research to “ guide the development of our CAP [Common Agricultural Policy] replacement land management scheme” [5.5]. The CAP scheme is a system of agricultural subsidies and programmes covering farming, environmental measures and rural development.

b. Changing practice for Wales’ national water utility provider

Dŵr Cymru Welsh Water (DCWW) is the sixth largest of the ten regulated water companies in England and Wales, serving over three million people. As a direct result of DURESS’s research on the link between catchment management, river biodiversity and ecosystem services [3.1-3.6], DCWW changed its practice to a catchment-driven approach. DCWW’s Director for Environment stated: “ the outputs of the DURESS project have brought to our attention the importance of catchment management to sustain Welsh headwaters and the services they provide – e.g., water free from pollutants for the production of drinking water” [5.7]. This led to a number of changes in DCWW operation, for example:

• A new DCWW catchment team which employs 20 staff, described by DCWW as “a significant change to our business” [5.7].

• The launch of the Beacons Mega Catchment Partnership in 2017; this involves DCWW working with upland land managers on a nature-based approach to improving water quality in the Brecon Beacons National Park area, which supplies almost all DCWW’s water [5.7, 5.8].

• Significant investment into catchment management through DCWW’s 2020-2025 Asset Management Plan. Every five years, water companies develop Asset Management Plans which are agreed and funded by the regulator. DCWW’s 2020-25 now contains an agreement to: “ invest more than £20m over 2020-25 on developing our catchment knowledge and scientific understanding”; and “we are also to invest a similar amount (circa £20m) in developing alternative nature-based solutions which will reduce the nutrient levels in our rivers” [5.7].

Further Cardiff work, commissioned by DCWW “ formed one of the key building blocks” for DCWW’s Welsh Water 2050 vision document, which “ sits at the centre of DCWW investment and other thinking…referred to by numerous organisations in Wales and the water utility sector” [5.7]. The work examined what considerations the company should make when planning improvements to make systems, people and assets more resilient, and came as a direct result of the DURESS resilience and scenario research [3.1, 3.6].

c. New sustainable approach to Wales’s natural resources management

Cardiff’s research influenced Natural Resources Wales (NRW), the organisation responsible for all Wales’ natural resource management. Ceri Davies, NRW’s Executive Director for Evidence, Policy and Permitting, explained: “ The DURESS team had extensive exchanges with NRW during the life of the project from 2012 to 2015 which influenced the way NRW prepared for implementation of the Environment (Wales) Act and the Wellbeing of Future Generations Act” [5.9] . In particular, Davies noted that NRW used the DURESS Scenarios Report [3.6] to [5.9]:

• ensure understanding of the practice of integrating ‘environmental futures’ (which could identify different emerging threats and opportunities) into strategic planning;

• begin identification and consideration of specific issues from the external environment that could influence how NRW delivers its purpose over the short, medium and long term until 2050.

NRW had not previously used scenarios routinely to frame thinking for the future, and the work underpinned the first State of Natural Resources (SoNaR) report in 2016 [5.9]. The NRW website describes the SoNaR report as “ground-breaking”, as “for the first time – the report links the resilience of Welsh natural resources to the well-being of the people of Wales” [5.10]. Quinn (Welsh Government) noted that: “ NRW are specifically charged under the Environment Bill with producing a statutory State of Natural Resources Report…The same themes that you see in DURESS, you’ll see those in those documents, around the understanding of the connections, and particular emphasis around identifying key systemic interventions” [5.4].

Quinn also noted that DURESS research findings, on the connection between freshwater biodiversity, ecosystem services and human wellbeing [3.3, 3.4], were used to shape NRW’s Area Statements. These Statements outline the challenges and strategies for the management of natural resources in each of the seven Welsh areas. Quinn noted that “ the Area Statements (informed by the State of Natural Resources Report) will feed directly into the work of the [local] public service boards”, and that “like DURESS, this will enable [WG, NRW] to link action in the natural environment to wider well-being” [5.4].

In summary, Cardiff’s research on freshwater ecosystems and their vital role in energy transfer, human wellbeing, and natural resource management, provided critical evidence to establish protection of the Cubango-Okavango (CORB) River Basin. They also transformed freshwater ecosystem management in Wales, through the Environment (Wales) Act 2016, and DCWW and Natural Resources Wales’s critical moves towards more holistic and sustainable approaches to natural resource management.