Team:Exeter/Practices
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Delving into the problem of bTB in the UK is not something that we as a team took lightly. bTB is a challenging disease that is hard to treat, easily transmitted and currently illegal to vaccinate against. Put these three factors together with the highly complex social, political and economical situation the UK faces with eradicating TB, it is clear that bTB is a National problem that needs a solution.
Extremely early into our project we began to appreciate this. Therefore we agreed that during our project we wanted to make people more aware of the challenges farmers, vets and local communities face when dealing with bTB.
Establishing relationships with various experts early on was extremely important. Not only have these relationships shaped certain areas of our project but also gave us an unprecedented look into the issue of bTB in the UK. In the beginning these experts allowed us to understand everything to do with bTB in the field and as our project has developed we have been able to integrate their experiences, suggestions and feedback into the science we are doing in the lab.
Our Beyond the Bench became as much of a lesson for us as a team as it did have an impact on our Ribonostics project. Vets, farmers, politicians, the NFU and DEFRA are just to name a few of the people/organisations highly involved with our project.
What challenges does the UK face to eradicate Bovine TB?
This is the question that we as a team decided to ask. Not only does this question have many aspects, we believe it is the question that is best able to have a direct impact on the work we are doing. The timeline below shows a breakdown of how we decided to tackle this highly important question and how what we learnt helped shape our Ribonostic work...
Richard Sibley
Right at the start of our project we wanted to understand everything to do with current TB testing. Understanding the Tuberculin skin test, how the test is implemented in the field and some of the current issues with testing are all things we needed to appreciate. To do this we met with Richard (Dick) Sibley, director of a veterinary practice in Devon. Dick has worked directly with bTB, attending multiple Mycobacterium conferences and also focusing the work of his practice towards tackling bTB.
Read more Phase 1: Understand everything to do with current TB testing.Richard Sibley
Principal Vet and Director of West Ridge Veterinary Practice Ltd
We decided to visit a veterinary practice where we met with the director, Richard (Dick) Sibley, a highly respected vet with over 30 years experience across a wide range of veterinary practice. Dick and his practice have worked extensively with bTB, ranging from testing cattle through to offering bTB free programmes to farmers. After we outlined the concept of our Riboswitch, he explained more about the current bTB detection system, recent research into the disease and the work his practice does to tackle bTB. Below are the main points that Dick made us aware of at the start of our project.
Persistency and Contagiousness
Dick introduced some important concepts to us as a team. Firstly was the R0 value of bTB in cows. R0 is the disease reproduction number and is a mathematical way of explaining how contagious an infectious disease is. Although it can be hard to determine exactly, current research estimates the R0 value for TB in cows ranges from 1.0 - 4.91, 2. This means one infectious cow has the ability to infect up to 4 other animals meaning the transmission rate can be extremely high. Combine this with the close conditions farm animals are kept in, bTB spread throughout a herd is fast. Under the current bTB testing law, if a farm experiences a breakdown it has a 60 day period until a second test is conducted. Any false negative individuals that have been left in a herd from the first test won't get a chance to be detected for 60 days - more than enough time for those individuals to transmit the disease.
Persistency and Contagiousness
Mycobacterium bovis (M. bovis) is a very challenging pathogen. Not only is it incredibly difficult to treat, it has the ability to persist in the environment for months. Dust, dirt and soil are just some of the things that the bacterium is able to survive on. Clearly this creates a very challenging situation for both farmers and vets trying to eradicate bTB. If a farm is finally declared bTB free status, any area of the farm that may have been exposed to an infected animal (silage, buildings, equipment) may be able to transmit the infection back into the herd. Dick explained how some farmers face a situation where they have to isolate their entire farm, keep the cattle indoors and follow a strict regime to minimise the risk of bTB exposure. Also, Dick made us aware of some current research into the ability of M.bovis to persist in the environment.
Herd Size Increase and Sensitivity Issues
Advances in technology have led to a huge increase in the size of farms in the UK. Not only has the number of cattle increased as a whole, the size of individual herds has also greatly increased. In 1996 the average size of a UK dairy herd was 75 cows3. In 2014 this had increased to 133 cows3. Increase in herd size has highlighted how the current Tuberculin skin test is simply not sensitive enough to allow for a strategy to eradicate bTB in the UK, as shown by the larger dairy farm herds, where recurrent bTB breakdowns are common. Dick highlighted how the current Tuberculin skin test can leave behind cows that are infectious and that in current farming conditions leaving behind even a single infectious animal can lead to bTB breakdown. Large high risk herds are particularly challenging to achieve bTB free status. Dick made it clear that our test would be most useful not as a stand alone, but as a tool that could be used in conjunction with the current test to achieve greater specificity in these high risk large herds.
Points to Consider
Our multiple meetings with Richard (Dick) Sibley helped us as a team understand exactly what situation the UK currently faces with eradicating bTB. Dick made it clear to us the situation of bTB in Devon and Cornwall. With 1.8 million animals tested in Devon and Cornwall in 2014 and 800 farms under bTB restriction, the problem our test is trying to solve is very relevant to our local area.
As well as highlighting some of the fundamental problems with the current Tuberculin skin test, Dick helped us gain an understanding of how our test might best be applied in the field.
Saved & Safe
A wide range of parties are involved with tackling TB in the UK. Important to our project was to really engage with those at the forefront of TB eradication. Central to this is a company called Saved & Safe and their director Michael Ross. Michael lives in New Zealand and was highly involved with the strategy that saw a decrease in TB incidence rate across New Zealand of 96% in just 10 years. Following this success Michael has approached the UK with a strategy that brings together all affected parties. With their 31 UK and international partners, Saved & Safe are taking a new and innovative approach in the fight against TB, something our test could offer great potential to.
Read more Phase 2: Look at what projects are at the forefront of tackling TB.Micheal Ross - Director of Saved & Safe
A company at the forefront of bTB eradication in the United Kingdom
Michael was extremely excited by our project. Having been heavily involved with New Zealand's Animal Health Board's highly successful strategy to eradicate bTB from New Zealand, his unique approach gave us many ideas as a team. Saved & Safe are at the forefront of TB eradication in the UK with 31 UK and international partners involved on a handful of 'demonstration farms' across the UK. A number of University research groups are also involved in this project. Michael explained some of the key principles behind the work that is occurring at these demonstration farms and told us how our project, if successful, would fit into the work they are doing.
Common Goals
Michael made it clear Bovine TB affects a wide range of people from a wide range of backgrounds. For each individual party associated with the fight against bTB comes a different set of priorities. In order for the UK to develop an effective strategy to manage and eradicate bTB it is important that common ground is established between groups. For example, the NFU represents the farming community of the UK. For them, a bTB breakdown has an immediate negative impact on their livelihood, an impact that they have limited control over. For vets, bTB testing is a continuous cycle that has to be highly organised and can be highly time consuming. For academics, bTB is not only a highly challenging disease, it is a disease where advancements have been slow to non existent.
However, each group is working towards the common goal of eradicating bTB, all from different approaches. Saved & Safe is working to bring these approaches together... Something our test may be able to assist with.
Smart Solutions
One of the problems to do with bTB in the UK is the issue of how the disease is dealt with. In its simplest form if an animal tests positive for TB it is immediately sent to slaughter, the farm is put under restriction and a second test will be conducted in 60 days. This routine will continue until the farm has no positive reactors for two successive tests. Apart from restrictions to the farm, no other measures are put in place to try and aid with clearing bTB from the farm. Any further action has to come from the farmer individually. Where is the solution?
Yes, some farms will take a number of usually expensive and difficult measures. This can involve building a wall around the farmyard to isolate it from the environment outside - something that can cost up to £250,000. Keeping any cattle indoors all year around is also a common method to limit the effects of bTB. However none of these measures offer a genuine solution to the problem of bTB.
Michael made it clear that smart solutions are the way forward. Rather than the situation being left for the farmer to deal with, a coordinated effort that offers a motive for the farmer is needed, and this is where the UK can learn from Saved & Safe...
Providing the Missing Mechanism
Saved & Safe offer the mechanism for coordination of the elements that are needed to eradicate bTB from a farm. Taking a field by field, farm by farm, county by county approach allows for a coordinated, strategic approach to achieving officially bTB free status for the UK. M.bovis has been shown to persist in the environment for up to 21 months - during this time it is crucial an infected farm has a way to manage the infection. Isolation of the farm, disinfection of the entire area and protection of the border around the farm offers this management tool. Taking a strategy that saw a reduction of bTB incidence by 96% in just 10 years in New Zealand and bringing it to the UK makes Saved & Safe a world leader in the fight against bTB.
Phil Leighton
Our test will be cell free meaning all testing can be done 'in the field'. There were a number of important things to consider when designing exactly how our test would work. This is where Phil Leighton came into our project. A highly experienced vet, we accompanied Phil to a TB test on a Cornish farm and also spoke extensively about our project. Blood testing in cattle, the size of needles/tubes to collect samples and also blood clotting were all things Phil highlighted to us.
Read more Phase 3: Look at the real life design of our test.Phil Leighton
Penbode Farm Vets
We hosted Phil Leighton at the University to explain to him what our project aims to do. As Phil is involved with XL Farmcare, a company responsible for all bTB testing in the South West, we wanted to know the practicalities we would have to consider for our test to be effective. Phil invited us to a TB test on a farm in Cornwall where we saw the testing of 11 Bullocks and also got the chance to chat with the owner of the farm.
Sample Collection
The target of our test is RNA meaning a blood sample is required from each animal that is being tested. Prior to our meeting with Phil, we believed as a team that the simplest way to collect blood from a cow would be a skin prick. However Phil made it clear to us that this is not possible due to the depth you would have to penetrate with a needle. Current blood testing is done from the base of the underneath of the tail. As cows are in a crush during bTB testing, collecting a sample of blood from the tail is easier and safer than the current Tuberculin test that occurs at the neck of the animal. Phil explained how cows are much more accepting of a vet approaching and working with their tail as oppose to their necks.
Sample Collection
Furthermore Phil showed us the current needle and tube that is of standard use for collection of blood from a cow. Initially we believed the components of our test would be in a tube the size of a standard Eppendorf. Logistically Phil said this would not be possible. Collection of blood from the tail into a tube the size of an Eppendorf would not only be extremely difficult it would not contain the blood in a sterile environment - something highly important.
As a team this gave us a number of things to consider when designing how best to contain the cell free aspect of our test. The tube has to contain our test, collect a sample in an efficient and sterile manner and also only allow a small amount of blood to reach the area of the tube our test is contained within.
The Public
bTB in the UK is a highly contentious issue with many different sides to the argument of how it is spread, what the current problems are and also what is the best way to eradicate it from our farming industry. As opposed to debating this issue, we as a team took to the streets with some simple facts, aiming to make people more aware of exactly how damaging bTB is to the UK. When we started we believed that not enough people were aware of some of these key facts. The best way for us to demonstrate this as a team was to engage with the general public armed with clipboards and a simple survey. Our results were interesting to say the least...
Read more Phase 4: Understand the public perception of bTB in the UK.Survey
We conducted surveys in Exeter as well as in Wadebridge, a small town in the North of Cornwall. The survey was simple. It asked how aware the individual believes they are about the issue of TB in cattle in the UK. It then goes on to provide some of the facts that we as a team found most shocking about bTB. Although the majority of people believed they were aware of the issue of bTB, only 5% of people knew it is against EU law to vaccinate cows against bTB. This backed up our theory as a team - not enough people are aware of the devastating impact bTB has on the UK farming industry.
Interviews
As well as conducting the survey, we wanted to film members of the public in order to gauge some of their reactions to the facts in the survey. We also asked them to make any comments on what they had just been told. Our facts were:
Response
George Eustice
Minister of State for Farming, Food and the Marine Environment
The Department for Environmental, Food and Rural Affairs (DEFRA) is committed to eradicating bTB from the UK by 2038. As our project developed it was important that we had a clear understanding of the current work DEFRA is doing to eradicate bTB. To do this we met with George Eustice, the Minister of State at DEFRA and also the Conservative MP for Redruth and Camborne. We discussed in detail with George the most recent advancements DEFRA have made with bTB testing as well as explaining how we believe our test may have an impact. Furthermore we wanted to gauge how imminent policy changes may be for the UK.
Read more Phase 5: Look at DEFRA's bTB strategy.George Eustice
Minister of State for Farming, Food and the Marine Environment
bTB is the UK’s largest animal health problem. As a team we decided it would be important for us to meet Mr George Eustice. We travelled down to the Penryn Campus (Exeter’s Cornwall Campus) where we hosted George. In 2014 DEFRA released the Strategy for achieving Officially Bovine Tuberculosis Free status for England4, a document that outlined exactly what the current problems are and how DEFRA is planning to tackle each individual problem. After a long morning we made sure George fully understood our work, and that we fully understood where out test may fit in with DEFRA’s work.
DEFRA Strategy
George told us how the main aim of DEFRA is to get to a stage where it is possible for the BCG vaccine to be used in the UK. Under current EU regulation it is illegal to vaccinate cattle as the Tuberculin Skin test can not differentiate between infected and vaccinated cattle. Development of a DIVA (Differentiated of Infected and Vaccinated Animals) test is a main priority for DEFRA as this would lay foundations for return of the BCG vaccine. Policy change through the EU takes years. George explained how if the UK wanted to bring the BCG vaccine back sooner it would be possible but it would mean that any UK production would be limited to the UK. The strategy states “bTB-vaccinated cattle would not be able to be traded within the EU” until a ban was lifted across the EU. UK Dairy and Beef trade with the EU is vital to the UK economy, particularly in our local South West area. One of the main benefits of our test is the fact it is detection of the causative organism (M. bovis) meaning it would have the ability to act as a DIVA test. Our test relies on the presence of RNA from the bacterium so a positive result will definitively tell you the animal is a carrier of M. bovis, regardless of if the animal has been vaccinated or not.
Genetic Immunity
George explained to us some of the most recent advancements DEFRA has made. One of these that related to our test is the investigation of Genetic Immunity against M. bovis. In research led by the University of Edinburgh, scientists compared the genes of healthy and infected female Holstein-Friesians (cows) to identify any genetic traits that through selective breeding could be easily incorporated to the majority of animals. Selection of animals with genotypes that offer a better resistance to bTB would allow another way of controlling the disease in cattle. However one current problem with this research involves the ability to detect if the animal actually shows a higher degree of bTB resistance or if the animal is simply better at masking the symptoms of bTB. George explained how a test that could definitively conclude if an animal is carrying bTB would allow greater understanding of whether the individual is simply masking the symptoms of bTB or whether the animal actually has a genetic code that offers bTB resistance. Identifying the animals that have a genuine genetic resistance to bTB is highly important for this strategy.
Others
In addition to the individuals that we were in constant contact with, there were also several organisations that were involved to various degrees in our project. The National Farmers Union (NFU) were aware of the work we were doing during the initial stages of development, and through our contacts, we were able to gain an understanding of the issues that farmers themselves face when dealing with bTB. Furthermore, we had the opportunity to meet with two farmers who both had personal experiences with bTB within their herds. This early interaction with farmers who had been directly affected was important because as it helped us to appreciate the impact bTB has on them. Being exposed to the devastation this disease caused to their respective businesses motivated us, as a team, to reach out to public, and educate people within Devon & Cornwall about the devastating impact bTB. To respect their privacy, we chose not to include them specifically in their timeline.
We also worked with a handful of the partners from Saved & Safe. This included members of Save Me, the NFU along with Professor Liz Wellington, the leading academic in the work Saved & Safe are doing. Because one of our main goals was to increase the awareness of the increasing prevalence of bTB within the South West, we visited several schools in the local area. Here we had the opportunity to talk to A level students about the potential of Synthetic Biology and the things that have been and can be made possible. As part of our discussion with the students, we were able to emphasise how difficult bTB eradication has been within the South West, and what we, as undergraduate students, are doing to tackle real world issues. These sessions were valuable for us in terms of outreach as the students were highly receptive and inquisitive towards the work we are doing.
Integration and Design
Risk Assessment
Our project had a number of important factors that had to be considered in terms of risk. Firstly we designed a test that is meant to be used in the field by vets on a day to day basis. Clearly this poses concern for the containment of any genetically modified organism in our test. However, as our test is planning to be cell free it removes the issue of organism containment. Phil Leighton explained to us the process of blood sampling a cow and also showed us a current standard blood tube. We decided to contain our test within the current blood collection tubes that are used universally in veterinary practice, removing the need for specialist training to use our test. Our RNA based test has a number of factors that also reduce risk.
Our test would use either a blood sample or dairy sample from each individual cow to test for bTB. Blood samples are taken from the base of a tail. Phil and Dick explained how cows are particularly anxious of people approaching and feeling their neck area, yet are much more comfortable with blood being taken from the tail. As most bTB tests are done in a crush (a safe way to contain the animal), they were unanimous in agreeing our test offers a safer alternative to the current Tuberculin skin test. Also, if our test could work with milk as a sample, risk of injury to the vet during sample collection is completely minimised due to the highly automated milking process that is seen across the UK Dairy Industry.
Feasibility Assessment
Due to the large scale use of our test, calculating a cost was important. Cell free kits are currently expensive to buy. Due to time constraints this is the method that our team used during our project, a method that would not be sustainable if our test was to be manufactured and used. To understand and try to combat this, we collaborated with Bielefeld iGEM 2015, a team who have been working on developing their own cell free kit. After multiple Skype meetings they sent us a spreadsheet with a cost breakdown for each cell free reaction using what they have developed. See the cost section on the design page of our wiki for more information.
End-User Assessment
One of the most interesting aspects of our project is how our test would be used. For vets it offers a faster and more accurate way to diagnose bTB infected cattle. Currently with the Tuberculin skin test there is a 72 hour period from injection to detection. This means bTB testing is highly time consuming and also limited. Phil explained how his practice can only bTB test from Monday to Wednesday in order to allow for sufficient time to pass before the second part of the test can be done during his practices working week. As our test would offer a result in a matter of hours, a whole farm could be completed within one day of bTB testing. Dick explained how his vets are able to test up to 1000 cows a day, yet these cows then have to be diagnosed three days later. The benefit of our test for his practice was the idea that our test would mean the whole testing routine could be completed within one day. Not only does this save his vet's time, it also saves a lot of hassle for the farmer as herding and bringing in cattle only once as opposed to multiple times is significantly easier.
Furthermore containing our test within the current blood sample collection tubes means there is no new technology being introduced to the primary end user, the vets. Blood collection is uniform across veterinary practice and our test does not require any additional training, due to the considerations we made when designing our prototype .
Away from the veterinary side, our test could have potential application for use by farmers as an animal health management tool. Michael Ross explained to us how the UK is in a situation with bTB where everyone has a reliance on everyone else. Farmers have to rely on the testing regime that is run by vets, and the testing regime is set centrally at a government level by the Department for Environmental, Food and Rural Affairs. In New Zealand the Animal Health Board (the body responsible for the mass progress in bTB eradication) had a heavy farming representation and testing was not carried out by vets. Farmers have a clear motive to be bTB free. Giving them the tools to manage the disease on their farm is one of Michael's primary aims, and our Ribonostics test could have an application for this.
Social Justice
Bovine TB is the UK's largest animal health problem and a truly challenging disease to try and combat. However the UK also manages the situation of Bovine TB in a way that is currently not working. When looked at simply, the main strategy the UK has to deal with Bovine TB is the use of the Tuberculin Skin Test to identify and immediately remove TB infected cattle. This test has an estimated sensitivity of around 80%. This means out of 10 infected animals 2 will not be detected and will therefore remain within the population, able to spread the disease. Dick made it clear that his practice has larger herds in high risk areas that are chronically infected with bTB because the current test is simply not sensitive enough to identify infected but not yet infectious animals. As vaccinating cattle with the BCG vaccine is banned under EU law, dealing with the disease in cattle is highly difficult. Identifying and removing infected animals is a strategy that deals with the symptoms of the disease as opposed to the root cause. This is where Michael Ross and his company Saved & Safe aim to make a change to the UK strategy to deal with bTB. Michael made it clear how our test could fit into his company's current strategy and helps allow development of a strategy that begins to deal with the infection (the root cause).
The Department for Environmental, Food and Rural Affairs (DEFRA) has the development of a DIVA (Differentiation of Infected and Vaccinated Animals) test as a main priority for the strategy to eradicate bTB by 2038. A successful DIVA test would allow the use of the BCG vaccine and take steps forward towards establishing a bTB free UK. Our meeting with George Eustice helped us to understand how our RNA based diagnostic tool meets the criterion for a DEFRA DIVA test. DEFRA is responsible for all bTB testing across the UK meaning they are able to assess and implement the approach they see best. Developing a test that offers a new and unique approach to bTB testing was important for us but it was also important that our test could fit into the Strategy for Bovine TB Eradication document that they released in 2014.
In this document there are a number of key points relevant to the development of our test. The bTB research programme states how “Evidence [related to the development of new vaccination tools] needs to be multidisciplinary to provide a comprehensive understanding of the disease epidemic”. It also states the importance of “developing new diagnostics tests for surveillance”. We have approached solving the issue of bTB in the UK from a multidisciplinary approach due to the interdisciplinary members of our iGEM team. The fact our test offers a scientific solution that acts as a DIVA test, it paves the way for political change as a valid DIVA test would eventually allow for the reintroduction of the BCG vaccine.
Bovine TB clearly presents a number of important social issues also. Our public engagement was important to help us as a team understand the contentious issue of Badger-Cattle transmission of bTB. DEFRA has recently undertaken a number of Randomised Badger Culling trials to assess the effect tackling the natural reservoir of M.bovis has on the cattle incidence of bTB. This trial was highly controversial. Our focus as a team was the detection of the bacterium in cattle that in a way that doesn’t interfere with the BCG vaccine, allowing the reintroduction of the BCG vaccine and therefore taking a step that is widely accepted to be necessary to eradicate bTB from the UK. In our public interview and surveys we deliberately avoided the topic of Badgers to avoid controversy. However a number of individuals, unprompted, made it clear that they are strongly against Badger culling. Similarly the farmers we visited had completely different views on Badger culling. The situation with bTB in the UK is highly controversial, however our test aims to identify infected animals with an extremely high degree of sensitivity, allowing the definitive identification of infected animals. With any disease it is important that healthy animals are protected and infected animals are identified. New Zealand, a country that saw a reduction of bTB incidence rate of 96% in 10 years had a clear strategy to deal with the natural reservoir, possums. Our test is a tool that offers a potential solution to a problem that currently costs the UK economy £1 billion every year, and finding this solution is what drove our Human Practices. Whether our test leads the way for social change is not for us as a team to decide due to the highly complex social aspect of our work.
Although each individual party of our Human Practices was unique, our Human Practices naturally overlapped for one main reason. Each party wants a solution to the problem that is bTB. Establishing this common ground and bringing together affected parties will eventually lead to an officially bTB status for the UK. It also allowed us to integrate the most important aspects of each party into the design and implementation of our Toehold test.
References
[1] Anderson, R.M. and Trewhella, W. 1985. Population Dynamics of the Badger (Meles meles) and the Epidemiology of Bovine Tuberculosis (Mycobacterium bovis. Phil. Trans. R. Soc. Lond. 310(1145) pp. 327-381.
[2] O'Hare, A. et al. 2014. Estimating epidemiological parameters for bovine tuberculosis in British cattle using a Bayesian partial-likelihood approach. Proc. R. Soc. B.281: 20140248. http://dx.doi.org/10.1098/rspb.2014.0248
[3] AHDB. 2015. DairyCo - Average Herd Size. [Online] [Accessed 15 September 2015]. Available from: http://dairy.ahdb.org.uk/resources-library/market-information/farming-data/average-herd-size/#.VfzMEpfqMzf
[4] Defra, 2014. The Strategy for achieving Officially Bovine Tuberculosis Free status for England. [Online] [Accessed 3 September 2015] Available from: https://www.gov.uk/government/publications/a-strategy-for-achieving-officially-bovine-tuberculosis-free-status-for-england