Impact case study database

Brearley's research has had impacts on commerce, the economy and production, both directly and via knowledge transfer. The beneficiaries are commercial animal feed businesses on a global scale, specifically AB Vista and its partner companies, AB Enzymes, Germany, and Roal Oy, Finland, who produce the Quantum Blue enzyme. His research has also benefited other enzyme companies and the global poultry industry (both producers and nutritionists). As illustration, because of Brearley’s work with AB Vista, the term "Superdosing" has come to convey the benefits arising from provision of inositol through adding phytase to animal feed. As such, it has been accepted as a standard term in academia and industry, with more than 570 citations in Google Scholar since 2013.

Change in industry R&D strategy: Brearley’s research [R3-R6] and his collaboration with AB Vista [S1] have driven a key change in AB Vista's R&D strategy. This has involved the company shifting its R&D focus towards understanding the role of inositol [S1-S3], as evidenced by: AB Vista’s funding of Brearley’s consultancy contract [Grant A]; the company’s collaboration with Brearley in obtaining BBSRC LINK and Industrial Partnership Award funding [Grants B, C]; and the company’s funding of multiple PhD studentships both at UEA and internationally [S1]. In addition, AB Vista has commissioned research feed trials in 15 countries across four continents (e.g. Australia, India, USA, Germany, UK), from which it has sent samples to Brearley at UEA for analysis of inositol phosphate and inositol products of phytate degradation [R3-R5; S1-S2]. Overall, the involvement of Brearley has been a disruptive innovation for the industry's R&D. As AB Vista's Research Director stated, “By providing us with a first set of measurements of inositol in a digestive setting, something we had not considered ourselves, Charles opened up a new research area across the animal feed industry. This has been very significant for AB Vista and the industry as a whole” [S1].

Change in industry know-how: The metadata arising from analysis by Brearley of more than 10,000 samples from the AB Vista-commissioned feed trials have, by providing essential scientific underpinning, reshaped AB Vista's understanding of the Quantum Blue phytase and the benefits to be gained by Superdosing. To quote AB Vista's Research Director [S1], “Charles’ work on inositol and Superdosing has allowed us to progress from an understanding of the correlation of animal growth performance to inositol phosphate release, in different parts of the gut, to a sophisticated understanding of the extent of animal growth performance attributable to inositol” [S1].

Change in industry behaviour: marketing: AB Vista’s guidance on dosing of Quantum Blue has also been changed. The guidance to customers covers the range of poultry-raising regimes used worldwide for all the chickens (over 10,000,000,000 birds) fed AB Vista’s phytase products. “Our advertising strategy includes evidence generated by UEA showing that our products function at the intestinal level better than all other phytases, and the data generated enables us to explain why superdosing, for example, works in poultry and swine from a mechanistic viewpoint” (AB Vista's Research Director [S1]). Brearley’s data are also reported across AB Vista’s web pages [S3].

Change in industry behaviour: technology adoption and knowledge transfer: Brearley’s interaction with AB Vista has led to the company adopting his analytical methods. To quote AB Vista's Research Director [S1] “His analytical expertise with inositol phosphates and inositol has provided a route to analysis that was not available to us before on a scale relevant to our needs. In order to be able to respond rapidly to industry needs, we are now investing heavily in Charles’ methodologies in our analytical services division in the UK”. Separately, Brearley has provided training in analytical methods to AB Enzymes (a market leader as reflected in their turnover exceeding USD112,000,000 (08/2019)), partner on Grants A-C. This allowed for new methods to be adopted by the R&D department of AB Enzymes and in turn led to AB Enzymes testing novel applications of Quantum Blue [S4]. In addition, Brearley has transferred data on novel phytases for further investigation to Roal Oy, partner via AB Vista on Grant C.

Company success: The changes in R&D, know-how and marketing, all arising from the new understanding of AB Vista’s Quantum Blue phytase provided by Brearley's research, have enabled AB Vista to sell more of its product. This has been achieved by advertisement of the efficiency of Quantum Blue in degrading phytate and releasing inositol [S3]: “The credibility that UEA research brings to our products means that customers who are at the forefront of technology are far more likely to buy from us, …Charles’ analysis of inositol phosphates and inositol, his further development of methods suitable for tissues and organs and his interaction with our other academic partners contributes to our literature, presentations and conferences, informing existing customers regarding their use of our products, and keeping them abreast of technological developments” (AB Vista's Research Director [S1]). Brearley’s research has therefore been central to AB Vista’s growth to become a top three supplier of phytase [S1, S5], in a market projected to exceed USD2,000,000,000 (11-2019) by 2024. “I can confirm that the research undertaken at UEA has enabled AB Vista to move from being the 6-7^th largest enzyme supplier in the world to number 2-3 in the last seven years” (AB Vista's Research Director [S1]).

Benefiting the global poultry and pig industry: The impact of Brearley’s work extends beyond AB Vista to its customers and competitors in the poultry and pig sectors. For example, industry-wide adoption of Superdosing and the contribution of inositol to this technique is evidenced in a competitor’s 2017 marketing presentation, which stated, ‘ Use of Ronozyme® HiPhos increases blood levels of myo-inositol by a quick break-down of phytate in the gut’ [S6]. Moreover, phytase sales benefit customers as well as producers. AB Vista’s Global Sales Director has quantified the value of phytate degradation to customers, " Estimates suggest the anti-nutritional effects of phytate could be costing the industry as much as €2 billion [EUR2,000,000,000 (05/2014)] per year in lost performance, and that the potential still to be captured from near-complete phytate destruction is as high as €5 [EUR5.00 (05-2014)] per tonne of feed manufactured” [S7] . Lastly, Brearley's research on the role of inositol in the aetiology of two muscle diseases in chicken, "Woody Breast" and "White Striping" [R5], hold potential for substantial future benefits to the industry. As AB Vista's Research Director has stated of Brearley's presentation of this work to an industry conference in Taiwan in 2019, "The event in Taiwan helped more than one hundred participants… The sales increment could be substantial if we find that dosing two to three times higher than current 'superdosing' norms prove beneficial" [S1].

The research of Wormstone and team in developing and enhancing the capsular bag model has achieved significant impacts on commerce, production and practitioners in the health sector, so improving the health and wellbeing of people. Specifically, it has: (a) enabled the rapid testing of novel clinical concepts, leading to the development and marketing of ocular products for a number of companies, so generating significant revenue; (b) positively impacted practitioners (surgeons); and (c) led to better outcomes and improved vision in many patients worldwide, immensely benefiting their quality of life.

(a) Impact on development and marketing of ocular products: The capsular bag model has played a key role in the development and evaluation of several intraocular lenses (IOL) including: the "bag-in-the-lens" intraocular lens (Morcher Type 89™); AnewOptics Zephyr™; Hoya Vivinex™; and Hoya Nanex™ [R5, R6; S1-S5]. These form part of a global intraocular lens market whose size was estimated to reach USD4,200,000,000 (12-2017) in 2020. To take the leading examples:

Bag-in-the-lens intraocular lens: Wormstone's research facilitated the development of this highly successful intraocular lens, which, since 2014, has been implanted in patients in more than 10,000 cataract operations in Europe [S1]. The Emeritus Head and Chair of the Department of Ophthalmology, Antwerp University Hospital, Belgium, who is the inventor of this lens and regularly implants it into patients in cataract surgery, stated, “The capsular bag model was an invaluable tool in translating my original concept to a clinical product” [S1]. The clinical outcomes from the large number of implantations of this lens are impressive. Specifically, in a five-year follow-up study, under 10% of children required additional surgical treatment after receiving the bag-in-the-lens intraocular lens [S2], whereas, with conventional surgery and standard intraocular lens implantation, 100% of children would have required it.

HOYA Vivinex™ and HOYA Nanex™ intraocular lenses: Since 2017, following an approach by the company on the basis of his research record and expertise, Wormstone has served as a consultant for HOYA Surgical Optics, one of the largest intraocular lens manufacturers globally, to aid their product development programme [S3]. Wormstone’s graded culture suspended capsular bag model [R6] found that the HOYA Vivinex™ intraocular lens had an overall better level of anti-posterior capsule opacification performance than the market-leading intraocular lens. The data from these studies, obtained within months [R6], predicted clinical outcomes that took years to obtain [S4]. As the HOYA Surgical Optics Global Product and Marketing Directors stated, “The capsular bag model is, therefore, a very powerful clinically relevant tool that can be used to evaluate and develop IOL performance” [S3]. They also stated, “The quality of the work and the significance of the published findings provided by Prof. Wormstone, using the capsular bag model, have greatly aided our ability to market our products” [S3].

In 2018 Wormstone presented his work on the capsular bag model as a keynote speaker at the HOYA symposium in Vienna, Austria, to an audience of approximately 300 ophthalmic surgeons, assembled as potential end-users of HOYA products. This presentation, along with follow-up content, was then used by the company for its marketing. As the HOYA Surgical Optics Global Product and Marketing Directors stated, “ The presentation in Vienna was recorded and is available in the HOYA collection on the Eyetube web platform. Prof. Wormstone’s work was also a key element in an advertorial published in ‘The Ophthalmologist’ which was followed by a feature article highlighting the capsular bag model and its demonstration of the performance of Vivinex™. A further feature article was published in ‘Eurotimes’ [magazine of the European Society of Cataract and Refractive Surgeons] . Collectively these publications have a readership of over 50,000 internationally, the majority of which are ophthalmic surgeons” [S3, S5]. In his capacity as consultant, Wormstone also used the capsular bag model in the preclinical development and assessment of the HOYA Nanex™ IOL (designed for microincision cataract surgery), which was added to the HOYA clinical product portfolio in 2019 [S3].

Referring to the UEA capsular bag studies, HOYA Global Product and Marketing Directors stated, “These activities have contributed to the continued growth and success of HOYA Surgical Optics and our products. HOYA Surgical Optics is now the world’s third largest IOL manufacturer globally, and has been the fastest growing of the largest IOL manufacturers in recent years. Professor Wormstone and his work on the capsular bag model continue to impact on the success of our company...” [S3].

(b) Impact on practitioners: Wormstone has delivered several invited talks at practitioner-based events, including: 100% Optical (2017) [S6]; the Cambridge Ophthalmological Symposium (2019) [S7-S8]; and two HOYA symposia (2017 and 2018), allowing him to present his research directly to ophthalmic surgeons [S3]. Wormstone's presentations, in addition to his publications in peer-reviewed journals and practitioner-based magazines, have achieved impact through informing clinicians of relative intraocular lens performance [S3, S6-S8]. For example, the Associate Professor of Ophthalmology, Ludwig-Maximillians-University of Munich, Germany, a distinguished and experienced cataract surgeon, approached Wormstone following a keynote lecture. Wormstone then visited her in Munich to pass on his knowledge of the capsular bag model and provide practical feedback. This technique has been fundamental in this practitioner's research strategy and clinical practice from 2014 onwards and, as she has stated, “The capsular bag model developed by Prof Wormstone has had a marked impact on cataract surgery....The data provided using the capsular bag model, therefore, provides scientifically rigorous findings that can inform the surgeon and aid their selection of IOL for their patients” [S9].

(c) Impact on patients: The ultimate beneficiaries of advances made using the capsular bag model as an experimental and evaluation tool are patients. As detailed above, the bag-in-the-lens intraocular lens has led to much improved clinical outcomes for children [S1, S2]. To quote further the Emeritus Head and Chair of the Department of Ophthalmology, University Hospital, Antwerp, Belgium, it “...has provided and maintained vision in tens of thousands of cataract patients” [S1]. In addition, of the best-selling intraocular lenses, HOYA Vivinex™ continues to increase its market share and offers improved clinical outcomes relative to the current market leader, such that posterior capsule opacification is better managed and the need for laser surgery is reduced [R6, S4]. Ultimately, benefits to patients across the world result from decisions made by surgeons and the impact the capsular bag model has on this process is highlighted in the following statement by the Associate Professor of Ophthalmology, Ludwig-Maximillians-University of Munich, Germany: “I have drawn on my knowledge from capsular bag studies to guide colleagues on their IOL choices, which I believe have positively impacted on many patients since 2014” [S9].

The research of Jones and team on Resistance gene discovery and exploitation has led to impacts on commerce, the economy, production and public policy, benefiting companies, agricultural practitioners, the public and government nationally and internationally:

Impact on commerce, the economy and production via crop improvement: **Jones'**s research enabled isolation of the late blight Resistance genes Rpi-vnt1, Rpi-amr1 and Rpi-amr3 [R1, R2, R4; S1], and showed that Rpi-vnt1 functions well in the field in the UK. Patents for all three of these genes have been filed [S1] and licensed by Simplot [S2]. A patent for the potato virus Y Resistance gene ( Ry_sto) has also been filed [R5, S1]. Jones's close relationship with Simplot, which arose following an approach by the company, has included two BBSRC Industrial Partnership Awards in which the company has been a 10% contributing partner [e.g. Grant C]. Jones collaborated with Simplot and UK biotechnology company BioPotatoes Ltd to bring the three late blight Rpi genes to field trials in Maris Piper potatoes. This project is in its fourth year (currently supported by BBSRC Super Follow-on Funding, Grant D), with trials on ten advanced lines having taken place in 2020 at the National Institute of Agricultural Botany, enabling selection of the elite "PiperPlus" line. Jones is now advancing this line towards regulatory approval and commercialisation. As the Plant Biology and Molecular Biology R&D Directors at Simplot Plant Sciences stated, "Prof. Jonathan Jones, in partnership with BioPotatoes Ltd, has enhanced the UK potato variety Maris Piper with robust late blight resistance and improved processing qualities. The combination of resources resulted in a Maris Piper potato that has a lower cost of production, higher marketable yield and significant benefits for British producers, processors and consumers. Late blight resistance was accomplished via expression of resistance genes Rpi-vnt1, Rpi-amr3 and Rpi-amr1 cloned and characterized in the Jones lab." [S2].

In addition, Simplot is already selling a genetically modified (GM) blight-resistant potato, Innate^® 2.0, carrying Jones's Rpi-vnt1 in the USA [S2], with this variety having been approved by the United States' Department of Agriculture (USDA), Environmental Protection Agency (EPA) and Food and Drug Administration (FDA) for commercial growing and human consumption [S3]. This represents a breakthrough for the deployment of GM methods as it is the first ever commercial deployment of a cloned Resistance gene in a major crop. Simplot will also use Rpi-amr3 in their next generation of Innate^® 3.0 potato lines. Simplot project that use of Innate^® potatoes will save growers tens of millions of dollars in money otherwise spent on fungicidal prevention of late blight, and result in a more sustainably grown potato [S2]. Potatoes with Resistance genes from Jones's work are also being field-trialled in Africa [S4], Bangladesh and Indonesia [S2], underlining their potential to increase food security in low- and middle-income countries [S2].

Evidencing Jones's overall contribution, Simplot Plant Sciences stated, "The discoveries of Dr. Jones have enabled Simplot … to achieve its commercial and philanthropic goals." Moreover, "[Jones] … played a pivotal role in this potato late blight protection breakthrough and Simplot looks forward to further collaborations in the future. Having accomplished what we consider a genetic solution to late blight for the United States and perhaps most of the world, we anticipate moving on in collaboration with Dr. Jones to solve other potato diseases including potato virus Y." [S2].

Impact on commerce, the economy and production via new technologies: Jones's work has enabled researchers to investigate immune receptor diversity and accelerate the cloning of useful Resistance genes in crops. In particular, Jones's methods are now widely used by publicly-funded laboratories working on other crop species, including wheat [e.g. S5]. In the private plant breeding sector, RenSeq has become standard practice for investigators working on disease resistance. Evidencing this, following Jones's publication of the RenSeq method [R2], the US molecular biology development and manufacturing company Arbor Biosciences has been marketing commercial RenSeq kits (since 2014) and services (as “myReads^®” since 2016) [S6]. Arbor Biosciences reported that: "Our customer base for the RenSeq technology is made up of academics, industry [and] governmental organizations (in the USA, Europe and Oceania) … and has led to a general expansion of disease resistance gene cloning capabilities beyond cereals." [S6]. Furthermore, "Jones’ RenSeq technology has had a substantial beneficial impact on our company. Arbor’s annual NGS [Next Generation Sequencing] services income represents roughly 30% of our overall turnover, and RenSeq accounts for roughly 20% of this in the last fiscal year, and roughly 10% of our services income in total since RenSeq was first offered in 2016” [S6]. The total RENSeq “myReads^®” services revenue from launch in 2016 to financial year end 2020 was [redacted text] and for financial year 2020 alone was [redacted text] [S6].

Jones's work underpinning the intellectual rationale for gene stacking [R6, S4] has been used to develop a wheat variety carrying a stack of five stem rust resistance genes. The 2Blades Foundation, a not-for-profit company partnered with The Sainsbury Laboratory, has collaborated with the International Maize and Wheat Improvement Center (CIMMYT) in Mexico to deploy this wheat rust resistance gene stack in CIMMYT wheat lines [S7].

Impact on public policy via outreach and advocacy: Jones is a long-standing advocate of using GM methods for crop improvement and, in this context, is highly active in public education and policy arenas. Jones regularly publicly advocates for GM methods in press interviews and articles [S8]. In addition, Jones has contributed to the evidence that policy changes on GM regulation would be in the public interest. For example, he was a co-author of a 2014 report cited in the Council for Science and Technology's letter advising the Prime Minister's office on the risks and benefits of GM technologies and has also presented the GM case to UK parliamentarians [S9].

Evidencing the reach of such advice, in his first speech as Prime Minister, Mr Johnson said, "let’s start now to liberate the UK’s extraordinary bioscience sector from anti-genetic modification rules, and let’s develop the blight-resistant crops that will feed the world" [S10]. More specifically, a member of the House of Lords with expertise in the field stated, *"*[Jones's advocacy] has an enormous impact on the debate within the UK, in Europe and globally. I have attended many meetings in which parliamentarians, civil servants, government ministers, government scientific advisors, media commentators and others have benefited from [his] … presentations and discussions, and these have had a real impact on decisions taken. … A good instance of his impact can be found in the current government consultation on changing the regulations to allow gene editing in agriculture, and to consider how to regulate genetic modification after that. This consultation was announced by the government in response to an amendment to the agriculture bill in the Lords. The amendment and many of the speeches in favour of it benefited directly from advice given by Prof Jones, and the shape of the consultation since has also benefited from his wisdom and advice." [S10]. The Agriculture Bill was passed into law in November 2020 [S10].

Yu’s research has had a large number of impacts on a global scale, including the direct impacts of NatureMetrics Ltd on commerce and the economy, which have been followed by downstream impacts via the effects of NatureMetrics on clients, practitioners, production, public policy and the environment.

Direct impact on commerce and the economy: NatureMetrics began trading in 2016, starting with the use of aquatic eDNA to detect Great Crested Newts at building sites. Related to this, NatureMetrics developed a filter kit for aquatic eDNA and filed a patent, now at international application Patent Cooperation Treaty (PCT) stage (WO2020128503A1). The company has grown very rapidly. By 2019, its third full year of operation, it was processing 4,750 samples from 92 clients and over 15 countries, with approximately 60% of revenue coming from commercial organisations, 20% from government, 10% from NGOs and 10% from grant-funded projects [S1a]. In 2020, despite the COVID-19 pandemic, it processed 3,285 samples from 90 clients [S1b], with approximately 68% of revenue coming from commercial organisations, 6% from government, 8% from NGOs, 10% from grant-funded projects and 8% from universities and research institutes [S1a]. By the end of 2019, it had doubled gross profit [S1b]. In June 2019, NatureMetrics raised GBP2,500,000 [S1c] in a Series A investment round that was oversubscribed by 2.5 times, valuing the company at GBP7,500,000 [S1d]. NatureMetrics then implemented a growth plan, which has been slowed but not interrupted by the COVID-19 pandemic. Revenue in 2019 was GBP713,796, and revenue in 2020 was GBP1,000,976 [S1b]. The company's size in terms of numbers of people employed has also increased rapidly. As at December 2020, NatureMetrics had 33 employees (headcount 33, FTE 31.4), including 15 with PhDs (headcount 15, FTE 14.8) [S1e].

Impacts on clients, practitioners, production, public policy and the environment: NatureMetrics helps clients undertake work that would be far more costly, or outright impossible, without the company’s services. The eDNA sampling kits and analysis services offered by NatureMetrics make biomonitoring safer for clients and their employees to conduct in challenging natural environments. The following is a selection of leading examples of clients and spheres of activity that have benefited from NatureMetrics:

NatureSpace Partnership: NatureMetrics is a key service provider to and investor in the NatureSpace Partnership, a private company operating the UK’s largest biodiversity offset market. NatureMetrics’s eDNA service makes it possible for NatureSpace to rapidly survey hundreds of ponds to model the distribution of the Great Crested Newt, a species protected in the UK under the Wildlife and Countryside Act, 1981. Builders in surveyed areas can buy a licence to offset the effects of developments on Great Crested Newt populations, the fee rising with their modelled impact on the newt. This arrangement reduces costs and risk compared to newt relocation, while also funding the creation of four new ponds per affected pond. As of 2020, NatureSpace have raised GBP1,000,000 and created 100 new ponds, operating across 40 Local Planning Authorities in the UK. As NatureSpace Partnership’s Chief Executive has stated, “ Without NatureMetrics’ technical expertise and early investment, we would not have succeeded” [S2].

Environmental Resources Management: NatureMetrics gives the multinational environmental consultancy ERM “ a competitive edge over consultants using conventional survey techniques alone,” as stated by ERM’s Chief Ecologist [S3]. A large part of ERM’s work consists of surveys of aquatic habitats to establish baselines for future monitoring (e.g. to detect pollutant spills), to identify offset sites and to select amongst alternative project sites. In 2016-17, ERM piloted NatureMetrics’s kits in Sierra Leone. Relative to their standard methods, ERM sampled more safely, covered a larger area, detected four times as many fish species and halved survey costs [S3]. In 2020, ERM used NatureMetrics for surveys in Russia and Serbia and is now considering eDNA for further projects around the world. As ERM’s Technical Director stated, “ ERM believes that eDNA provides both business and conservation benefits, and NatureMetrics role in developing the new technology has included assisting ERM to become a more informed consumer and user of eDNA” [S3].

Environmental charities: In 2019, the Freshwater Habitats Trust (FHT) used NatureMetrics’s kits to survey 21 New Forest sites where they had data from conventional surveys. Using eDNA, volunteers were able to detect more species and “ [a]t low cost, collected data in a couple of days from a network of stream sites that would otherwise have taken a conventional 2-3 person survey team most of the summer to visit,” as stated by FHT’s Director [S4].

Internationally, in 2018, Worldwide Fund for Nature (WWF) Peru surveyed a 390 km stretch of the Marañon River in Amazonian Peru and “ fully achieve[d] their survey goal of detecting the spatial distributions of six culturally and commercially important aquatic species…, and we exceeded our goal by also detecting hundreds of additional vertebrate species, which we can now start to take into account in designing a sensitive index of basin-ecosystem health….NatureMetrics has made it possible for WWF Peru to generate baseline biodiversity data much more efficiently and comprehensively,” as stated by WWF Peru’s Associate Ecosystem Services Research Officer [S5].

In 2020, Fauna and Flora International (FFI) collected aquatic eDNA in the transboundary Wonegizi-Ziama Massif Protected Areas between Guinea and Liberia. A total of 112 vertebrate species were detected, including the endangered White-bellied Pangolin. As FFI's Senior Programme Manager for West and Central Africa stated, “ The key benefits to FFI are increased biodiversity data…reduced survey costs…and ease of sampling.…[W]e can increase the…coverage of our sampling at a reduced cost, and we can more fully involve local people in conservation monitoring” [S6].

The British Trust for Ornithology (BTO) is using NatureMetrics’s metabarcoding service for arthropods to measure the efficacy of restoration projects in Polesia (a wetland running from Poland to Russia). Reduced costs allowed doubling of sample size from 120 to 240 sites. As BTO’s Senior Research Ecologist stated, “ Without NatureMetrics, we at BTO would not have had the capacity to carry out this part of the project, whereas with NatureMetrics, we anticipate an increased probability of success in achieving the aims of the Polesia project” [S7].

Regulatory standards-setting and end-user education: In her role as NatureMetrics’s first CEO, from 2017-2020, Bruce co-led a working group of a European Union Cooperation in Science and Technology (EU COST) action, DNAqua.Net, that submitted to the European Committee for Standardization the first European Standard related to eDNA [S8]. Bruce will also be on the steering committee of the soon-to-be-launched UK Business and Biodiversity Forum, a government-supported initiative exploring ways businesses can act to reverse biodiversity declines. In 2019, Yu wrote a contracted “Think Piece” for the UK Government’s Environment Agency for England to design an R&D strategy for incorporating DNA-based methods in the agency’s reporting [S9]. Lastly, in 2020, NatureMetrics was competitively selected as one of five small companies to join the UK’s High Speed 2 rail (HS2) Innovation Accelerator programme, the purpose of which is to accelerate the uptake of new technologies in building the HS2 railway. NatureMetrics was chosen to ensure the quality of HS2’s green corridor, including newly-created woodland [S10].

Providing evidence for UK Government interventions to aid pollinators: Bourke's research has had impact through informing public policy with research evidence. This had led to changes in government regulations to enhance pollination services and biodiversity, so aiding pollinators and thereby benefiting agricultural practitioners and the environment.

In 2015 the UK Government launched a new version of Countryside Stewardship, its agri-environment scheme for England, to run to 2020 [S1]. Countryside Stewardship provides financial incentives to farmers, foresters and land managers to care for and improve the environment, including wildlife habitats. Via regular dialogue between the team and contacts in Natural England/Defra, the research of Bourke and collaborators [R1-R3] provided a key component of the evidence base for Countryside Stewardship's pollinator-focused actions. In particular, the team's finding [R2] that a coverage of 1-3% of agricultural landscape by flower-rich habitat would allow bumblebee workers to forage at or below their species-average foraging distance directly informed the Wild Pollinator and Farm Wildlife Package within Countryside Stewardship. This Package is the set of farmland management options, including the planting of floral margins alongside arable fields, designed to benefit wild pollinators and other farm wildlife. Specifically, the finding defined the minimum area threshold for option coverage within the Package, i.e., at least 3% total area to be planted with floral margins, this threshold being mandatory for the scheme's Mid-Tier version or higher [S1]. It also informed the package's advice to select a combination of options and to distribute them spatially within farms [S1]. Evidencing this, the Countryside Stewardship Manual stated, "Recent evidence suggests that applying the right combination of options over 3 to 5% of the arable, temporary grass or permanent grass included in an application will deliver meaningful benefits to farm wildlife" [S1]. In addition, as Natural England's Nature Recovery Team stated, "The research findings of the IPI bumble bee project team helped to set the 3% minimum threshold for option coverage in the CS Wild Pollinator and Farm Wildlife Package" [S2]. Moreover, the package has "helped in an overall increase in the delivery of land management options such as flower-rich grass margins and pollen and nectar mixes, which are crucially important in helping to provide the year-round life cycle needs of pollinating insects" [S2]. Although it is too early to determine if any interventions since 2015 have increased UK bee numbers, a 2019 study concluded that, against general trends for pollinators, crop-pollinating bees increased by 12% in Britain between 1980 and 2013 and that this could be due to previous agri-environment schemes, which were similar in kind if not in scale to those implemented by Countryside Stewardship [S3].

Stimulating global policy development to aid pollinators: Dicks's research has had a suite of primary and downstream impacts stimulating and influencing the policy and practice of governments and international agencies as regards safeguarding pollinators and pollination services, so benefiting agricultural practitioners and the environment on a global scale.

The primary impact has been that the UN's multilateral treaty body for biodiversity, the Convention on Biological Diversity, agreed two formal decisions that draw heavily on the work of the global IPBES pollinator assessment [S4] and outputs [R4-R6] co-authored by Dicks [S5]. This followed an approach to Dicks and co-authors by the secretariat of the Convention [S5]. As a UN treaty, this Convention has 196 party countries and 168 signatories. Its Decision XIII/15 [S6], taken at the Convention conference in Mexico in late 2016 (COP13), formally endorsed the key messages of the assessment [S4] that were included and further developed in [R4] and [R5]. It also listed specific actions for Governments to follow, and these included all 10 policy recommendations in [R5]. In short, each policy recommendation in [R5] by Dicks and collaborators has been incorporated into a formal decision of a UN treaty body [S6]. As the Deputy Executive Secretary of the Convention on Biological Diversity stated, "… I approached a number of the authors [of the IPBES assessment] , including Dr. Dicks, for scientific inputs in drafting policy recommendations for Governments with a view to including these in a draft SBSTTA [Subsidiary Body on Scientific, Technical and Technological Advice to the Convention] recommendation. … At the same time, Dr. Dicks led the development of a scientific paper published as [Dicks et al. 2016 Science, R5] . The thinking behind the paper informed the development of the SBSTTA policy recommendations, and indeed, the policy recommendations in the Science paper and the SBSTTA recommendations are very closely aligned. The paper [R5] also helped … give added scientific weight to the Convention's draft recommendations, helping their formal adoption by Governments at the thirteenth meeting of the Conference of the Parties [COP13] . With only minor changes, the policy recommendations were subsequently adopted by the COP as decision XIII/15 in December 2016" [S5].

Following up, in a further decision on pollinators, Decision 14/6 [S7] taken at the Convention on Biological Diversity's conference in Egypt in 2018 (COP14), the Convention mandated the UN's Food and Agriculture Organisation to implement a joint Plan of Action for the conservation and sustainable use of pollinators. This plan [S7] again included the actions recommended by [R5], and cited [R6] as major support, i.e. Dicks's collaborative research synthesising the contributions of pollinators beyond their agricultural value such as value for society and quality of life.

Prompted by the Convention on Biological Diversity's formal Decision XIII/15, two major, global-scale downstream impacts have also occurred. One is that a collaboration of Governments across the world created "Promote Pollinators, a Coalition of the Willing on Pollinators". With a founding membership (including the UK) of 14 countries in 2016, by 2020 this coalition included 30 countries, each committed to developing its own national pollinator strategy [S8]. Evidencing this, its website states: "Promote Pollinators was established in December 2016 as the result of deliberations during [COP13, = Decision XIII/15 conference] . During this conference, …, fourteen countries decided to unite and collaborate in an international coalition, in order to bring about progress in the protection of pollinating species and their habitats" [S8]. The other downstream impact is that, in 2018, citing Decision XIII/15, the European Commission launched its own European Union Pollinators Initiative [S9]. This is an EU-wide strategy to address pollinator declines across Europe, which from January 2019 has been implemented in collaboration with the International Union for the Conservation of Nature and the Institute for European Environmental Policy [S10].

Overall, both the primary and downstream impacts of the work of Dicks and collaborators have had a positive and ongoing effect on UN and Government actions for pollinators. As the Deputy Executive Secretary of the Convention on Biological Diversity has stated, Decision XIII/15, [S4] and [R5] "have fostered increased efforts by Governments and stakeholders on this crucial issue for biodiversity, and the issue of pollinators and pollination is likely to feature explicitly in the post-2020 global biodiversity framework currently in development under the Convention" [S5].

Baulcombe’s research and its associated intellectual property have proved fundamental to the development of RNAi-based therapeutics that target previously intractable diseases [S1-S3]. Acting on behalf of Baulcombe and colleagues, Plant Bioscience Limited licensed Baulcombe's patent to Alnylam Pharmaceuticals [R6], and this has ensured Alnylam's freedom to operate, since 2013, to develop, trial and release three RNAi-based drugs that target human genetic disorders, along with a fourth to treat inherited high cholesterol (familial hypercholesterolemia) [S4]. In particular, to target genetic disorders, Alnylam has registered and commercialised the two drugs ONPATTRO^® and GIVLAARI^®, and it has obtained permission for early release of a third drug, OXLUMO^TM, through the UK Medicines and Healthcare Products Regulatory Agency's Early Access to Medicines Scheme [S5] and the United States Food and Drug Administration (FDA) [S6]. It has also received approval of the familial hypercholesterolemia treatment drug LEQVIO^® from the European Commission [S4].

As detailed below, these drugs are providing treatments that patients have described as transformative in their impact on individual lives [S4, S7-S9]. They have also helped underpin the growth of Alnylam Pharmaceuticals as a company and yielded important patent revenues. In this way, the research has had substantial impact on the health and wellbeing of people and on commerce and production in the health sector. As the Managing Director of Plant Bioscience Limited has stated, "the impact of the discovery of siRNAs and understanding of their role in RNAi interference contributed by Sir David Baulcombe and Dr Andrew Hamilton has opened up a new generation of therapeutics. After pioneering development by PBL’s licensing partners these are now having a huge impact across the world, in a wave of new and diverse treatments for previously intractable indications, treating millions of patients with a series of important life-threatening conditions." [S3].

ONPATTRO® (patisiran): The disease hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) is a life-threatening, autosomal dominant neurodegenerative disease driven by the deposition of misfolded transthyretin protein (TTR protein) in the heart, nerves and gastrointestinal tract. Approximately 50,000 people, aged mainly between 20 and 40, suffer from the disease worldwide [S4]. Without treatment, sufferers typically die between 5 and 15 years after the onset of symptoms. Treatment options are limited, and many cases remain undiagnosed. RNAi therapeutics allow transcripts (messenger RNA) from the faulty gene to be silenced, thereby decreasing the amount of misfolded TTR protein in the body. ONPATTRO^® has been approved by the European Union and United States, along with Brazil, Canada, Israel, Japan, Switzerland and Taiwan, for the treatment of hATTR amyloidosis [S4]. Based on a large-scale randomised clinical trial, ONPATTRO^® significantly reduced patients' symptoms and improved their quality of life, such as walking ability, nutritional status and the ability to perform activities of daily living [S7, S8]. As a result, as at the third quarter of 2020, over 1,150 patients were taking ONPATTRO^® [S4]. In terms of improvement in quality of life, a patient treated with ONPATTRO^® stated, "I'm so much more than this disease, and I can put it in its place and do the things that I love to do with the people who I most love and adore in my life." [S4].

GIVLAARI® (givosiran): Acute hepatic porphyria (AHP) consists of a group of four inherited diseases of the liver with acute neurovisceral symptoms that are often missed or delayed in diagnosis because the clinical symptoms mimic those of other common disorders. Acute intermittent porphyria is the most severe of the set, with 20% of patients with recurrent symptoms developing chronic and ongoing pain. It occurs in about 1 in 1,600 people with a Western European genetic background and, in the EU and US, the patient population is estimated at 3,000 people [S4]. Previously, long-term solutions for treatment involved either infusion with blood products (e.g. IV hemin) or liver transplantation. GIVLAARI^® was developed to treat adults with acute hepatic porphyria and was approved by the US Food and Drug Administration in November 2019 [S4]. It has also been approved for use in the European Union, Brazil and Canada [S4]. This drug significantly reduces the rate of porphyria attacks that require hospitalisations, urgent healthcare visits or infusion with blood products at home. A patient receiving the drug for acute intermittent porphyria stated, “I've had pain for 10 years, I didn't expect that could go away. I'm seeing friends and they're [asking] 'you're not taking any painkillers?' and I was [saying] 'no!'.” [S9]. As at the third quarter of 2020, over 150 patients were being treated with GIVLAARI^® [S4].

OXLUMOTM (lumasiran): This drug is an RNAi therapeutic for the treatment of primary hyperoxaluria type 1 (PH1). In the EU and US, the patient population is estimated at 3,000 symptomatic individuals [S4]. The disease is caused by the build-up of oxalate, which is normally excreted in the urine. In affected people, the accumulated oxalate is deposited in the kidneys and urinary tract, where it combines with calcium to form the main component of kidney and bladder stones (calcium oxalate). Lumasiran is currently under approval and has been granted a "positive scientific opinion" (i.e. approved for use by the National Health Service) through the UK Medicines and Healthcare Products Regulatory Agency's Early Access to Medicines Scheme [S5].

LEQVIO® (inclisiran): LEQVIO^® is the first siRNA drug that reduces low-density lipoprotein cholesterol (LDL-C) in patients with familial hypercholesterolemia. Approximately 3,900,000 people die annually in Europe from cardiovascular disease, of which high cholesterol (hypercholesterolemia) is a leading cause. While reducing low-density lipoprotein cholesterol levels using statins is a common treatment for high-risk patents, the majority of these patients (80%) do not experience reductions to below recommended levels. LEQVIO^® conferred effective and sustained low-density lipoprotein cholesterol reduction of up to 52% in patients. It was approved by the European Commission in December 2020 [S4]. It is estimated that approximately 50,000,000 people with atherosclerotic cardiovascular disease or familial hypercholesterolemia could benefit from treatment with LEQVIO ^® in future [S4]. For example, in the UK, the Managing Director of Plant Bioscience Limited reported that: “NHS projections estimate the drug will save 30,000 lives for every 300,000 patients treated” [S3].

Overall, the scope of using RNAi for drug development is limited only by the identification of sequence targets relevant to a given disease. As such sequences are identified, drugs based on RNAi are being developed to target genes for an increasing range of diseases, including cancer (e.g. vascular endothelial growth factor, VEGF), and to target viruses underpinning viral diseases, including Hepatitis B and the recent pandemic disease COVID-19. Similarly, drugs targeting specific genes are being developed to treat diseases such as haemophilia, Alpha-1 liver disease, hypertension and cerebral amyloid angiopathy [S2, S4]. Hence, RNAi-based drug development has an extremely promising future.

Economic impact of RNAi-based therapeutics. As a young and rapidly growing development, the market in RNAi-based therapeutics has yet to realise its full economic potential. Nonetheless, in 2018, the global size of this market was already estimated to be approximately USD1,090,000,000 (12-2018) [S10]. RNAi drugs have also contributed substantially to the income and financial growth of Alnylam Pharmaceuticals. Specifically, for ONPATTRO^®, the company's quarterly revenues increased from USD46,100,000 (12-2020) in the third quarter of 2019 to USD82,500,000 (12-2020) in the third quarter of 2020 [S4]. In addition, in the third quarter of 2020, GIVLAARI^® earned the company USD16,700,000 (12-2020) [S4]. For Baulcombe and colleagues, the patent [R6] issued for RNAi technology and managed by Plant Bioscience Limited has generated GBP10,000,000 in licensing income since 01-2014 [S3].