THE RISE OF

epigeneticsepigenetics

22 | QUALITY WORLD | SEPTEMBER 2019

THE RISE OF

epigeneticsepigenetics

The study of epigenetics, how the expression of your complete set of DNA is controlled, has gained a lot of interest from scientists and has even made its way to mainstream media. This is largely due to the role epigenetics plays in serious

diseases such as cancer.

Quality World talks with Heather Tudor, Director of Quality Assurance at Cambridge Epigenetix, a biotechnology company developing tests for gene activity in disease, about how the company uses quality principles to enhance human health, through earlier diagnosis, improved patient stratification and the development of liquid biopsy-based tests.

Words: Anna Thomasson

Image: Heather Tudor, Director of Quality Assurance at Cambridge Epigenetix, Cambridge, UK

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What is epigenetics?Since the discovery of the structure of DNA in the 1950s by Franklin, Watson and Crick, we have known that our genetic code is made up of four nucleobases that pair together to form the double helix structure of DNA. The total DNA content in our cells is our genome, our recipe book, which is the same in every cell. And just like a recipe book which contains many recipes, our genome is made up of distinct recipes of genes. If every cell contains the same basic genetic code, how can different cells types look different? Hair is different to skin, which is different to muscles.

Epigenetics is the control layer of the genome, directing which genes are to be expressed by any specific cell type. This can change as we age, in response to the environment and in disease. There are many epigenetic mechanisms by which we control the way we utilise our genome: the modification of the nucleotide bases in DNA being just one form of epigenetic control.

There is currently a lot of research taking place in this fast-developing field, particularly the role of epigenetic changes in the onset of cancer and what this means for new treatment.

After a number of years working in quality across biotechnology, pharmaceutical, medical device and various testing environments, Heather Tudor joined Cambridge Epigenetix in 2018 to lead their quality implementation. For her it was the ideal opportunity to combine her quality management knowledge with her initial training in clinical laboratory testing.

Cambridge Epigenetix is looking to change the way medicine is practised

by reducing several routine and important diagnostic screening tests to

a simple blood draw. The company’s epigenetics

discovery platform enables the identification of sensitive and

disease-specific epigenetic markers from blood and tissue samples.

QW: How is the field of epigenetics developing?HT: The human genome was first sequenced in 2003. This came with high expectations within the clinical, scientific and pharmaceutical communities for exciting diagnostic advances and use of genetic-based therapies. However, 15 years later, it became clear that our genes alone could not explain or predict human development, ageing and disease progression. Recent discoveries identified the presence of epigenetic modifications which affected the control of critical gene functions and many cellular pathways within the body.

Epigenetic modifications are highly potent and specific chemical changes within genomic DNA, ribonucleic acid (RNA – a molecule similar to DNA but containing ribose rather than deoxyribose), and proteins. Epigenetic modifications are heritable and can also be added, removed or disrupted in response to external factors such as lifestyle, environmental pollutants and other stressors. These modifications do not alter the DNA sequence of the genome itself, rather they influence the behaviour and regulation of the genes. Any epigenetic disruptions can have disastrous consequences for the body, potentially accelerating age-related illnesses, while contributing to the development of cancer and a wide range of other diseases.

Specific epigenetic patterns or signatures are important disease markers in the body. To date, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) have been proven to play pivotal roles in the development and progression of cancers and other serious diseases. These markers are additionally specific for both disease state and tissue type, allowing accurate assessment of disease progression and tissue of origin.

QW: What is your company developing in this area?HT: Cambridge Epigenetix is pioneering the field of clinical epigenetics. We are aiming to change the way medicine is practised by developing a non-invasive diagnostic test to detect pre-cancerous abnormalities and cancer through a simple blood test.

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We are currently using our proprietary technology to quantify and analyse specific circulating biomarkers in blood as a test for the early detection of colorectal cancer. Detection of this disease remains a challenge, and the availability of a non-invasive, easy to administer and affordable screening test could transform the diagnosis, detection and treatment of pre-cancerous lesions and colorectal cancer.

The company was founded in 2012 by Professor Sir Shankar Balasubramanian and Dr Bobby Yerramilli-Rao. It is privately held and supported by investors including GV [Google Ventures], New Science Ventures, and the University of Cambridge.

QW: What role does quality management play at Cambridge Epigenetix?HT: Quality is built into systems, processes and products right from the start to ensure that a safe and effective diagnostic test is being developed for all patients.

About two years ago, we decided to transition from research into diagnostic design and development. A quality management system was needed to support this transition and provide confidence in the results generated. I was brought into the organisation with the initial tasks of implementing and managing a quality system, which was compliant to the requirements of the various standards for medical devices.

As Cambridge Epigenetix was founded in the research sector, quality management was a new concept for many, and to begin with, hurdles were evident during the quality implementation process. My tasks soon extended into leading the management team through quality concepts, quality strategies and enabling the development of a quality culture.

I have found it rewarding to witness the positive change and embedding of quality as a fundamental requirement in everything the company does.

QW: How is quality structured at the organisation?HT: The company has developed the 5hmC Profiling (HMCP) platform that enables the accurate quantification of

5hmC and mapping of critical epigenetic signatures, which cannot be identified and quantified by traditional molecular genetic research methodologies.

As the HMCP product is in the early stages of the product development lifecycle, our quality department is independent of operational functions with a reporting line direct to the CEO. The team is small, focused, and proactively collaborates with all departments to ensure that product quality is achieved through each daily task. These tasks include ensuring that the right product, consumable and equipment are identified, purchased and perform within our required specifications. Also, where quality failures arise, we ensure that they are properly documented and investigated, and actions are identified to mitigate recurrence.

QW: How do you drive continuous improvement?HT: To ensure quality communication and drive continuous improvement, the organisation uses electronic communication

"We are aiming to change the way medicine is practised by developing a non-invasive diagnostic test to detect pre-cancerous abnormalities and cancer through a simple blood test”

Identifying biomarkersMethylation (forming 5mC) and hydroxymethylation (forming 5hmC) are just two of the epigenetic modifications that occur within our genome, expanding our genetic code beyond the four nucleobases.

Dr Joanne Mason, Vice President Biomarker Discovery at Cambridge Epigenetix, explains: “5hmC is a great biomarker because it is found in discrete areas of the genome correlating to areas of active gene expression. It is a stable mark but is found in different regions of the genome dependent of cell or origin and disease states, which means it has the potential to be used to monitor an individual’s health.”

Liquid biopsyLiquid biopsy is an exciting field with the potential to change diagnostics and monitoring of cancer. Currently, cancer diagnosis and treatment decisions are based on tissue biopsies, invasive procedures that involve taking a small sample of the cancerous tissue. Liquid biopsy instead uses a blood sample to look for small fragments of DNA from the cancer shed into the bloodstream.

Looking for epigenetic changes from the cancer has the possibility to diagnose a patient earlier and follow a patient’s response to treatment prior to physical symptoms and without the need for a tissue biopsy. There is growing evidence that epigenetic biomarkers, and especially 5hmC, show real promise to be successful biomarkers for the early detection of a number of cancers from liquid biopsy samples.

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screens to display live updates of quality system health, quality training events and other activities in the business.

Monthly quality meetings are held with executive management to discuss system performance, upcoming quality events and continuous improvement initiatives. For example, the quality system is currently paper-based. With increased work activities and a growing organisation, an electronic system is the way forward.

The team spent almost two months scoping and refining the processes for the implementation of an electronic quality management system (eQMS). These meetings provide information on the overall health status of the quality system, failure trends and upcoming quality training events, which are in turn cascaded to the various functional departments.

QW: How does the company aim to enhance human health?HT: Conventional diagnostic screening tests for cancers can be invasive, costly, time-consuming, and often require specialist procedures. In addition, accuracy and efficacy of diagnostic technologies are variable, often leading to delays in detection and poor clinical prognoses.

We aim to improve these diagnostic screening approaches by developing minimally invasive techniques which target the presence of sensitive and specific biomarkers for early-stage cancers and other diseases. The use of a simple blood sample would support a practical and cost-effective approach which is accessible and acceptable to the patient. With increased patient access and willingness of the patient to be screened, cancer identification at very early-stage development, well before genetic changes are apparent, will improve treatment outcomes.

Similarly, disease progression or possible relapse may be identified using this same approach. Significant changes in epigenetic biomarkers, for example 5hmC, provide insight into metastatic risk, tumour recurrence and overall disease prognosis. Such information will enable clinicians to stratify patients according to risk and their epigenetic profile to offer

more accurate prognoses and provide appropriate treatment.

QW: What impact might this have on the NHS?HT: In both the public and the private healthcare sectors, funding and resources are limited or often restricted to cancer treatment and its ongoing management, representing a significant financial burden.

Technologies that use blood draws alongside automated analyses will reduce healthcare costs and patient impact. For example, blood collection removes the cost of hospitalisation, as well as specialist involvement, enabling efficient use of resources on treatment and supportive care. Patient risk is reduced due to less invasive screening approaches and where treatment is required, fewer complications or toxicity issues occur due to treatment intervention at early-stage cancer. Finally, individualised therapies may be prescribed, supporting optimal prognosis.

QW: What kind of innovative technologies are being utilised by the company?HT: Our founding technology of TrueMethyl oxidative bisulfite sequencing, oxBS-Seq, is now the gold standard for the accurate identification of methylation and hydroxymethylation. This enables the chemical changes within DNA to be identified more accurately, identifying and quantifying 5mC and 5hmC.

QW: What does the company’s quality strategy include?HT: As the quality implementation lead, I’ve had the opportunity to design the quality strategy, to work with all employees to build a quality culture, as well as to develop, implement and maintain a quality system to meet the various requirements of in-vitro diagnostic devices.

Our quality strategy for the 2018/19 period is founded on Oakland’s Total Quality Management Model. It is focused on building a framework for quality, the ‘house of quality’, using the four pillars of planning, people, processes and performance. Planning activities have included defining a quality policy,

EPIGENETICS AND PSYCHOLOGY

Studies have demonstrated a link between epigenetic tags and mental illness in humans, according to the American Psychological Association. In a study by Melas et al in 2012, genome-wide and local changes in methylation level were found in white blood cells of individuals with schizophrenia compared with normal controls. Although these results need to be further examined, there is the potential to produce a blood test for schizophrenia and examine the methylation status of an individual’s leukocytes.

"The company has decided to recognise its committment to quality system implementation by undergoing ISO 13485:2016 certification later this year"

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the quality strategy, key partnerships for the supply chain, and the processes and resources required.

Process activities have focused on process mapping and identifying business owners for all our quality critical processes and activities. We have worked to ensure that we have fit-for-purpose staff members, through both the recruitment and training processes. We track performance through the assessment, measurement and monitoring of each strategy pillar through audits, training reviews, ‘voice of the customer’ surveys and good quality behaviours.

QW: What challenges did you face when designing the quality strategy, and how did you overcome them?HT: Working with a team from different backgrounds and with differing levels of knowledge around quality strategy, a key part of my role was to ensure the Cambridge Epigenetix team was aligned around a set of basic quality principles that needed to be communicated using

a simple, systematic and unthreatening approach. The ‘house of quality’ was the ideal mechanism.

Although strategy infrastructure and communication methods were in place, full commitment from all remained a challenge. These challenges were overcome by incorporating the elements of the quality strategy into the 2019 objectives, holding weekly drop-in ‘quality clinics’ to discuss and assist with documentation completion and ensuring quality presence at all planning and laboratory meetings. The quality stigma of policing activities has been removed and quality presence is seen as essential in communicating with suppliers, investigating failures and understanding product regulations. The company has decided to recognise its commitment to quality system implementation by undergoing ISO 13485:2016 – Medical devices certification later this year.

QW: What does the future hold for your organisation?HT: Epigenetic changes are reversible in nature, making them an ideal target for drug therapy. Already, therapies are available that elicit their clinical effects through interactions with the various epigenetic sites.

These drugs are designed to provide targeted approaches that cannot be achieved through traditional medicines. Currently, specialised medicines have provided therapeutic options for many patients with conditions such as lymphoma or myelodysplastic syndrome (MDS).

Collaboration, knowledge sharing, and partnership are key to realising the potential of epigenetic research within the clinical setting for the benefit of the patient. Collaborative approaches with pharmaceutical partners will enable the application of these identified biomarkers across the platforms of companion diagnostics and technologies which support personalised therapies. It is our vision to help make disease optional, not inevitable.

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