Genomics England and their quest to revolutionise the NHS

Genomics England was born on the 65th birthday of the UK’s National Health Service (NHS). The NHS is a peerless service and institution in the world; a nationalised, comprehensive and universal healthcare system and one the greatest social reforms of the post-war era. Initially the brainchild of visionary MP Aneurin Bevan, it was built around 3 core socialist principles: To meet the needs of all citizens, to be based on clinical need not social nor financial standing and to be free at the point of delivery. 

In 2013, then Prime Minister, David Cameron set forth a mandate to place the NHS at the forefront of global healthcare by establishing the world’s first national genome project, the forerunner to the application of genomic medicine universally across every one of the UK’s 65 million residents. To this end, Genomics England was established as a company under the management of the Department of Health.

Cameron had been inspired toward this paradigm shift following the death of his son, Ivan, aged 6, four years earlier. Ivan had been born with cerebral palsy and a form of severe epilepsy called Ohtahara Syndrome both rare, incurable genetic disorders.

Rt. Hon. Jeremy Hunt, Secretary of State for Health and Social Care said at the time: “The NHS has a long track record as a leader in medical science advances and it must continue to push the boundaries by unlocking the power of DNA data. The UK will become the first ever country to introduce this technology in its mainstream health system – leading the global race for better tests, better drugs and above all better, more personalised care to save lives. Genomics England will provide the investment and leadership needed to dramatically increase the use of this technology and drive down costs.”

Genomics England is funded by the Department of Health & Social Care. and any surplus will be invested back into improving healthcare. Initially its focus is the completion of the UK 100, 000 Genome Project (UK100KGP), which seeks to sequence the genomes of patients with cancer and rare disease and their healthy relatives. At its inception it seemed immensely ambitious, the kind of enterprise which had never been attempted before. Five years on, it still does.

Chaired by Sir John Chisholm, former chair of the Medical Research Council, who said: “This project represents a great opportunity to translate our world class genomic science into world leadership in genomic medicine. Genomics England will create a dataset of anonymised whole genome sequences matched with clinical data at a scale unique in the world. Participating patients will have the opportunity to benefit from clinical insights derived from the sequencing of their genome while at the same time contributing to knowledge which will be valuable to the whole patient community. It is from that knowledge that world leading therapeutic products and processes will become available to all patients.”

The Department of Health & Social Care chose to establish Genomics England, which frankly, should be called Genomics Great Britain, as a subsidiary limited company because, to have established it as an agency or a public body, would have required primary legislation such as an act of Parliament.

How & Why?

Genomics England was created with four core aims: to bring benefits to all patients, to create an ethical and transparent programme, and to enable new scientific discovery and medical insights and to kickstart the development of a UK genomics industry.

The 100K Genomes Project is not about sequencing 100,000 different patients but 100,000 different genomes. Specifically, the study looksed at; two genomes from every cancer patient with one coming from them and one coming from their cancer, three genomes from each rare disease family with one from the afflicted individual and two more from close blood relatives such as parents. So the actual numbers are around 75,000 people sequenced of whom around 40,000 are patients.

The number was chosen based on experience from the 2010 Sanger Institute study known as the UK10K which sequenced 4,000 healthy individuals and 6,000 with extreme or undiagnosed health problems. The project succeeded in building the foundations for future genomic studies. It built databases of gene interactions and pathogenicity as well as identifying inumerable variants and giving a clearer understanding of the challenges which would face the world’s first national genomic medicine system. This has gone on to form the blueprint for all subsequent large scale genome studies.

Founded by members of the UK10K, including the Primary Investigator, Prof. Richard Durbin, Congenica developed their clinical genomics decision support platform Sapientia out of that research and work done by Prof. Matt Hurles on the Deciphering Developmental Disorders Project, which identified 80,000 genomic variants from exome sequencing and microarray analysis.

In the intervening years, the cost of sequencing has fallen and knowledge about rare variants has increased, thus 100,000 genomes was selected, as the right balance between cost and benefit for NHS patients, with which to build a clinical and research legacy.

Transformation

The 100,000 Genomes Project is not simply a research project. It is a transformation project using genomic medicine to change how NHS patients are treated.  It is transforming healthcare from the modern model in a paradigm shift as big as the introduction of radiology or penicillin. It is transforming the research and findings of the UK10K into actionable results for the populace. These facts alone will transform the NHS and thusly transform Britain into the world leader for life sciences and healthcare but also the owner of the only socially accountable, universal healthcare system anywhere in the world.

Rare diseases aren’t as rare as is commonly conceived, affecting, as they do, 1 in 17 worldwide, over 6% of the global population - half a billion people. In 2014, 163, 444 people in the UK died of cancer, in 2015, 359,960 new cases were reported and the UK has a further 3.5million rare disease sufferers. The legacies of UK100KGP will be most acutely felt by some of the youngest and oldest patients on the NHS. This is because, the risks of cancer increase significantly as you get older and as a nation we are living longer with every generation. In the case of the youngest, it is here that genomics has the greatest life saving potential as 80% of rare diseases manifest in children and, tragically, most of them won’t live to see their 5thfifth birthday.

As the UK100KGP draws to a close in the first half of this year and the company prepares to change its focus to a more traditional business model, it will trade on access to the anonymised data held in the Genomics England Secure Data Centre with research organisations and commercial entities. To aid in this shift, they recently announced the appointment of a new CEO. Taking over from former Chairman, Sir John Chisholm, is Prof. John Mattick, previously of the Australian based Garvan institute of Medical Research, is focusing on this next stage in the life cycle of Genomics England.

Innovative Britain

Britain has always led the world in scientific breakthroughs and DNA was no exception. Crick and Watson won the Nobel Prize for discovering the double helix structure of DNA alongside the too-oft ignored Rosaline Franklin. It was a British scientist, Fred Sanger, who discovered how to sequence it, winning two Nobel Prizes in the process. Now there is the very real opportunity to turn these discoveries into a life-saving reality for NHS patients. A pedigree and mentality of innovation and an understanding of the public good overriding the profit motive have long personified British innovation and the genomic revolution is no different.

Within genomics, researchers and clinicians need as much data as possible and there is no shortage of it. Each person’s genome contains 3.2billion individual letters, nucleotides, within which a single change could result in a devastating pathogenicity. The NHS has lots of supporting data too, this data includes test results, scans, medicines administered, the age at which a person developed particular symptoms and so on. They continue to collect it so they can keep monitoring how a condition progresses over time. This information is important because even small differences in symptoms between individuals might be crucial in finding the changes in their genomes and helping to decide the best treatments.
 

Beginning with a Bake-Off

In the Spring of 2014 Genomics England began taking its first steps towards their bold vision with what was branded the, ‘Genomics England Bake-Off’. This initial phase, named in reference to the popular BBC cookery competition, saw 28 companies compete to find the variants within 15 trios. These companies ranged from industry giants such as Illumina to start-ups, then, still in their infancy such as Congenica.

Of these competitors, 10 were selected in October of that year based upon their ability to quickly and accurately identify the variants known to be in the trios. This pool would reduce further as the four most exciting and effective prospects were given a grant to further develop their ground breaking software platforms. They became Genomics England’s Clinical Interpretation Partners, a validation against their peers thatwhich gave enormous credibility to their tools.

Amongst these companies was Cambridge based, Congenica, and their clinical genomics decision support platform Sapientia. Founded by key members of the 10KGP and DDD, Congenica grew quickly drawing expertise from the private and public sectors and spearheading innovation. Previous diagnostic methods had often been phenotype driven discovery of genetic causes in cases of monogenic disorders but now doctors and clinicians were able to demonstrate the power of their unbiased genotype driven approach and were able to apply this further to identify subsets of patients with similar disorders.

Counting 6 of the world’s leading genome scientists amongst their founders, Congenica came into being after they were inspired to attempt to eliminate the arduous diagnostic odyssey experienced by the majority of rare and inherited genetic disease patients. Using traditional testing methods and consulting strategies, it can take 7 cliniciandoctors 5 years to reach a diagnosis but with Sapientia they had found a way to reduce this to 1 clinician doctor and just 5 days on average. A life changing, and often life saving, difference for patients and their families. Sapientia forms part of the front-line services delivering robust and reliable diagnoses in a rapid manner reducing the anxiety of patients, empowering doctors and reducing costs for healthcare providers.

Implementation

Within the Genomics England ecosystem the aim is to analyse and constantly refine the clinical interpretation of the 100,000 genomes dataset. Clinical interpretation is the next step for the data after the whole genome sequencing, annotation and integration of existing phenotypic data is completed. Through data linkage, this dataset will develop into a rich resource of longitudinal life-course data that is continually augmented and refreshed over time. The goal is to create a truly unique resource in its number of subjects and its breadth of variables.

Genomics enables healthcare professionals to collect associated data in the form of secondary and tertiary findings. These findings may not have direct relevance for the health condition under investigation but, may affect:; medication options, reproductive choices or future medical conditions which are yet to manifest. Implicit in this too is the potential impact one person’s data may have on the patient population as a whole as with every bit of data added to our collective knowledgebases, the more powerful the science becomes.

The raw sequence data from one genome is about 200GB. This mountain of data needs to be interrogated, annotated and presented in a way that is helpful to doctors and clinicians. Here lie Sapientia’s greatest strengths, as this mass of genomic data is uploaded into the system’s ISO-certified, secure, cloud based environment and the variants within it automatically presented in an intuitive integrated genome browser with pedigrees, pathogenicities and known HPO terms all displayed alongside them. From here specialists can further annotate or interrogate the genes in question, can seamlessly search for supporting publications and hold asynchronous multi-disciplinary meetings.

Field programmable gate arrays and automated secondary and tertiary bioinformatics pipelines ensure that the process is a fast as possible and Sapientia is currently the only platform available able to return results against both the established GRCh37 and the most recent GRCh38 reference genomes.

To make genomics a reality for the NHS it has to be of high quality, fast and affordable with results that are readily understood and these values are encapsulated in the Sapientia platform.

Deployment

Now, two years on, Congenica are involved in a number of ground breaking research projects, including…  with major organisations such as Science Foundation Ireland and their joint effort to add the diagnosis of somatic epilepsy to their list of abilities. Sapientia is deployed across Europe, in the United States with such high profile clients as the New York Genome Center and in China through the partnership with Chinese sequencing giant, Beijing Genomics Institute.

In the UK, it was at Manchester’s Centre for Genomic Medicine that Sapientia saw its first live deployment within the NHS. In their Ophthalmology lab in particular they were able to go from offering genetic testing in around 10% of cases to offering it universally.

Now, as the UK100,000K GP enters its final stages, Sapientia is deployed and routinely used in the majority of  6 of the NHS’s 13 Genomic Medicine Centres, where it has been simple to integrate into existing systems, has returned thousands of actionable clinical results and made a tangible difference in treatment or diagnosis to over 450 individual patients. whose cases would have seen little or no progress otherwise.

Legacy

This common approach ensures consistency and coherence across the NHS to gain maximum benefits from the application of genomic technologies, curation of knowledge, and is laying the foundations for the future. The UK is increasingly recognised worldwide as a leader in genomics and the unique structure of the NHS is allowing for these advances to be delivered at scale and pace for patient benefit. The 100,000 Genomes Project is cementing the NHS’s position as one of the most advanced healthcare systems in the world, and is providing the foundation for a new era of personalised medicine, and this in turn will contribute towards the delivery of high quality care for all, now and for future generations.

The list of additional findings for will also change over time asbecause new evidence becomes available about the role of genes in disease. Any findings will be fed back to the NHS, to confirm the result. The structure of the NHS makes it much easier to know much more about the patient in question; details like their symptoms and when they first started, along with physiological measurements, such as heart rate or blood pressure.  Another set of information which may be important in interpreting genomic data comes from their past medical records. The way in which the NHS is able to link a whole lifetime of medical records with a person’s genome data on a large scale is unique.

It is not just patients and the NHS that stand to benefit from the 100,000 Genomes Project. There will be numerous knock-on advantages for the country. Benefits such as new medicines and diagnostic tests some of the companies that may develop will be unexpected, built on new, as yet undiscovered technologies that will emerge over the next five years. The UK, which not only leads the world in life sciences but has the unique benefit of the NHS, is the best place in the world to initiate the practical use of genome sequencing and interpretation for patient benefit. Their vision was one where Britain is the leader in a new industry where genomics is used to help patients get better, more personalised care and treatment.

Genomic England’s legacy will be a genomics service ready for adoption by the NHS, high ethical standards and public support for genomics, new medicines, treatments and diagnostics and a country which hosts the world’s leading genomic companies. It is a bold ambition with benefits for all.

A New Method for Neonatal and Prenatal Diagnosis

There are over half a billion people living with rare diseases - one in every 17 people , or 7% of the world’s population. It feels counter-intuitive, half a billion of anything being rare, but there are more than 7,000 rare diseases classified worldwide, 80% of them with a genetic basis that can be attributed to changes (mutations) in one or more genes.

Rare diseases can manifest in adulthood, but the majority of them present in childhood, particularly in newborns. Twenty percent of infant deaths are a result of such conditions, so the work performed in Neonatal Intensive Care Units (NICUs) and Pediatric Intensive Care Units (PICUs) is some of the most urgent and vital that takes place.

The NICU is a specialized care environment for premature babies or those presenting symptoms. Here they have access to cutting edge diagnostic tools; from MRI and CAT scans to whole genome sequencing, which is used in the rarest and most severe cases, where time is of the essence or no other diagnostic methods are possible. The PICU offers a similar care environment to children over 6 months of age and also offers complex operations and post-operative care.

In many of these cases the genetic variant responsible is so rare and undocumented that doctors might be seeing it for the very first time. These disorders can be difficult to diagnose, as they have many symptoms that are shared by other conditions. These may be phenocopies, in which patients manifest the same clinical symptoms but the underlying genetic causes are different, or they may simply be unique cases in which doctors or clinicians are faced with a variant that has never been seen or documented before. Take, for example, cases of epilepsy caused by different mutations in the SCN1A gene, in which the phenotypes and seizures on the surface appear identical, but can have drastically diverse consequences for prognosis, medication and future pregnancies.

With traditional methods, this could set the child on a diagnostic odyssey of many years as each suspected condition was methodically eliminated, but with clinical genomics, answers can be received, and treatment delivered, in a matter of days.

Clinical genomics is the act of taking an individual’s entire DNA code, all 3.2 billion letters of it, sequencing it (converting it into electronic data) and comparing it to a human reference genome, in order to identify variants and mutations that may be causing a disease or condition. This sequence data is a huge amount of information for doctors and clinicians to work through, and this is where interpretation software platforms such as SapientiaTM, from Cambridge based Congenica, are proving invaluable.

Sapientia takes this sequence and displays it to the doctors and clinicians in an intuitive graphical browser. Here, the whole sequence, or specific genes, can be examined and the potential effects of any variants scrutinised. By placing a huge amount of computing power at the doctors’ and clinicians’ backs and a vast array of medical insight at their fingertips, Sapientia empowers them to make actionable, clinically relevant decisions quickly and confidently.

With a diagnosis the family will have realistic prognostic expectations, clear information on reproductive options and definite focus for management of the condition. In cases where treatment is possible, the more timely the intervention, the more likely it will be that doctors will be able to alleviate symptoms, halt further damage to the child’s health or at the very least direct care towards palliative options.

Bringing the Right People to the Right Information

All parents are offered a screening test on the birth of their child, using a drop of blood taken from the newborn’s heel moments after birth. For some conditions, doctors know that an early intervention can drastically change potential prognosis for the newborn, and in these cases the blood sample will be used for whole genome sequencing (WGS). This sample is then sequenced, processed and introduced into Sapientia. Sapientia enables easy viewing the child’s individual genomic data, including the genes, phenotypes and pedigrees, as well as those of their parents or other family members who have submitted samples.

The presented data is then carefully examined by registered Clinical Scientists who identify variants and assign pathogenicity (their likelihood to cause or affect a known disease or disorder) using the worldwide standardised Human Phenotype Ontology (HPO) terms. These assignments are backed up by expert annotation and supported by literature from the world’s leading academic journals and periodicals.

This information is then displayed graphically in a genome browser for members of the healthcare team. The system then enables leading specialists from around the world to consult on the case. This enormously expands the catchment of experts who are able to share their findings and results, making it easy for the multi-disciplinary teams to add or review annotations, cross reference findings, view pedigrees and trios and form the most effective actionable clinical reports.

Multi-disciplinary teams such as these are integral to synergistic healthcare. In addition to the expected doctors and specialists, you also find physiotherapists, psychologists, dieticians and even play specialists.

Then there are the parents themselves who have a crucial part to play in the form of caregivers. Even if the child is sedated, parental contact is incredibly important; the familiar heartbeat of a mother, skin to skin contact, the recognisable tones of voice or innate scent of their skin are all proven to aid bonding and reduce stress in the child.

A matter of time

In NICU or PICU the child’s condition can deteriorate very quickly. In many cases the illness could have already progressed under the surface and only recently started showing symptoms, meaning the risks from the condition may already have matured and become more dangerous.

The application of genomics into clinical practice allows faster and more accurate diagnoses leading to the most targeted and effective medical treatments to be applied, management steps to be taken, and irreversible neurological and developmental problems potentially averted.

Using traditional medical methods, investigative testing and systematic elimination of potential diseases, the average diagnostic odyssey faced by any patient, adult or child, consists of an average of 7.3 clinicians taking 4.8 years of tests to deliver an actionable, clinical diagnosis. It is a tragic truth that the multitude of these children will not see their fifth birthday. Sapientia has the power to greatly curtail that diagnostic odyssey to an average of only one clinician and just five days. The impact is unequivocal.

Sapientia is helping to save the most vulnerable of lives by providing clinically actionable information, which can be carried out within the critically tight window available to these doctors and clinicians on the NICU and PICU wards.

Congenica was founded, and Sapientia developed, with the aim of integrating genomics into healthcare in a way that would provide tangible benefits where patients need them most. Genomics is giving doctors the greatest insight into the patient that they have ever had. It may not be perfect quite yet, but the future may see a form of medical ability unlike anything previously seen outside of science fiction.

Exomiser - Using model organisms for deeper genomic insights

Every one of us possesses variants throughout our genetic code. Millions of them. Most are harmless, some may even be beneficial, but a tragic fraction carry the devastating consequences of rare and potentially deadly diseases. It is the identification of these dangerous, pathogenic variants that is the basis for genomic medicine.

Whereas as a genome contains all of the genetic material of an organism - 3.2 billion letters, or ‘base pairs’, in a human - an exome is the part formed by exons. These are the parts of the genome that are actually transcribed into RNA, and thus proteins. The typical exome sequence of any individual is just 2% of the genome and commonly contains more than 30,000 variants. When an exome is sequenced and analysed we identify thousands of exomic variants relative to the human reference (or ‘normal’) genome.

The challenge therefore becomes sorting through them and deciding which variant is a harmless one, and which one is causing the disease.

SIFTing for a solution

One solution for this has come in the form of the Java based, open-source tool, Exomiser, which uses algorithms to annotate and prioritise variants from whole-exome sequencing. The program was developed in 2014 by the Monarch Initiative, a cross institutional collaboration between the UK’s Wellcome Trust Sanger Institute, Berlin’s Charite Universitatsmedizin and a number of leading American and British Universities.

Exomiser compares genetic variants with Human Phenotype Ontology (HPO) terms. HPO terms are standardised descriptions of how genetic variants may manifest in a patient, as well as those of common model organisms, such as mice or zebrafish. For example, the HPO term HP0004925 codes for Chronic Lactic Acidosis, or chronic build up of lactic acid in the muscles. By using these standardised terms, symptoms between patients, and even between model organisms can be compared.

Genetic research has highlighted a huge number of associations between specific genes and their phenotypic symptoms. For example, the BBS5 gene, which is required for the healthy development of cilia, and its role in Bardet-Biedl Syndrome. By using model organisms alongside humans, we can add almost 30,000 more genes with known phenotype associations to the dataset, allowing for faster and more accurate identification of causative genes.

Exomiser also uses ‘semantic comparison methodology’, which compares genes based on the similarity of their function rather than their position in the genome sequence. Exomiser uses two pre-computed scores taken from the Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping version 2 (PolyPhen-2) databases, which both predict how amino acid substitution affects protein function.

Exomiser then assigns a Phenotypic Relevance Score by cross referencing any variants found in the patient against the effects of that gene in model organisms, as well as other humans. Based upon the variant’s known pathogenicity and the likelihood of it being linked to the patients’ recorded phenotypes. Together these form the basis of Exomiser’s final hiPHIVE Score in which it designates the variant’s potential pathogenicity.

The Exomiser suite assigns further scores to support its final hiPHIVE score. The first of these is the ‘variant score’, which is based on allele frequency - the frequency that a variant is seen in the population. Next comes a ‘gene phenotype score’ that decides how critical the gene in question is to the patient’s recorded HPO terms, for example if an individual carries a mutation in both the BRCA1 and BRCA2 genes, the risk of breast cancer leaps up to as much as 90% in later life. Finally, a ‘gene variant score’ is applied to the most potentially dangerous possible genes. The various scores are brought together to form a gene combined score upon which it is ultimately ranked.

This score and its related phenotypic information is then checked against the Online Mendelian Inheritance of Man (OMIM) and Orphanet databases, which catalogue human genes linked to disorders and disease.

The Challenge of Genomic Data

Despite the great strides that scientists have been making in recent years, only around 35% of the human coding genes have been sequenced and identified. Exomiser adds tens of thousands of genes from model organisms used throughout research, and uses HPO terms to bring uniformity to their descriptions. It then uses this data to boost the identification rates of various phenotypes and their causative genes.

The technology can work across exome sequences, gene panels and even be used on the vastly larger and less widely understood whole genome sequences, though it may still struggle with elements such as structural or copy number variants. Exomiser is more than capable of supporting a clinical scientist to drill swiftly down through the millions of possibilities to find the variant that is causing a disease.

Exomiser performs best in situations where a patient’s phenotypes (or ‘symptoms’) have been well defined throughout their health record. Whilst Exomiser can be run in isolation on any computer, it is at its most streamlined when optimised into a wider suite of tools, ideally integrated into a comprehensive clinical genomics analysis platform such as SapientiaTM, from Cambridge based Sanger spin out Congenica.

Such platforms enable clinicians to apply Exomiser alongside numerous other open source and proprietary solutions to their clinical or research investigations. Bringing with it, in the case of Sapientia, the platform’s own extensive knowledge base on top of sources such as OMIM or Orphanet integrations, putting more diagnostic power at the clinician’s fingertips than any other solution.

Ever since the first successful identification of a disease causing variant from Whole Exome Sequencing (WES) in 2010 the industry as a whole has made impressive advances. The extra diagnostic power that Exomiser can bring to a clinician can be the critical element by essentially doubling the number of gene associations available. It can save time and money for institutes and experts and provide the diagnoses and treatment possibilities for which rare disease patients are so desperate, and in the long-run, save lives.

The rise of life science in China

From BRIC to broke

For many, if not all, national governments the health and wellbeing of the population is paramount to maintaining a successful nation. Nowhere is this truer than in the cases of emergent and second world economies. On the modern planet the focus has shifted in recent years away from established first world healthcare systems such as are found in America or Europe to look at those of the fastest growing emergent economies; Brazil, Russia, India and China.

Widely known as ‘BRIC’, a name coined by Goldman Sachs Asset Management Chairman Jim O’Neil in 2001, these four states have either outpaced or were expected to outpace normal growth patterns and break through the glass ceiling between first and second world nations. Unfortunately, the road wasn’t without its pitfalls; Brazil fell to corruption and overspending on the 2014 World Cup and 2016 Olympics which were held in the country, Russia has suffered a number of international sanctions since its aggressive actions concerning the Crimea and the Ukraine and India struggled to modernise and stabilise its economy. Investment assets in these countries have now lost 88% of their 2010 value. Only China remains.

Reforms in the far eastern state started in earnest in 1976 following the death of brutal communist dictator Mao Zedong. China of the 80’s and 90’s was built by Deng XiaoPing who understood the importance of infrastructure on the nation. It was this era that saw the birth of the China we know today and that made the ‘Chinese economic miracle’ possible at all. The next key date was the 2008 Olympic games. The ruling Communist party used this as an opportunity to bulldoze and modernise massive swathes of the country in the name of progress and solidify China’s place on the world stage.

Rise of the middle-class

The core demographic group in any such transition and the metric to measure its success is by the growth and expansion of the middle class. They are the indicator of true global economic progress. The middle class is defined by the Organisation for Economic Co-operation and Development (OECD) as those earning between 75% and 125% of the median income in that country. This could however mean that almost $20,000 in Norway and $120 in Liberia would, in both cases place you in the middle class, but everything is relative.

The middle class underpin the growing economy by providing stable demand and stable growth. However, with this comes increasing expectations of provision and opportunities domestically. In China there has been an overt trade-off between the populace and the party which centres on the exchange of economic growth at the cost of political and human rights. Whilst this group may accept that, they expect a higher level of services such as healthcare and education now.

Twenty years ago China lacked any kind of effective primary care system. Mao’s chaotic and brutal reign had driven the nation back into a primitive agrarian state. Now, as demand and a sense of entitlement to such services increases, the Party has promised healthcare for all by 2020. Whilst building structures and upgrading facilities are very much within the Chinese comfort zone they also have a drastic shortage of GP’s and those they do have differ wildly in their levels of education as only two universities in China offer training comparable to that of western countries.

There is also the problem of scale. China is a vast country containing 1/6th of the global population. To be able to implement a western style, patient centric healthcare system they will need to be training or retraining around 50,000 GP’s per year for the indefinite future.

This is why China is turning its attention to precision medicine and genomic technologies.

Genomic China

The spring of 2015 saw China’s central government announced 60 billion Yuan (£6 billion) budget to be spent over the next 15 years with the goal of creating a functioning precision medicine system that will sequence genomes, develop new and generic drugs and gather variant and other clinical data.

Precision medicine harnesses these huge amounts of clinical data to tailor bespoke medical solutions for each patient. Some of this money is also being driven into education and research with the nation's leading universities, Fudan in Shanghai and Tsinghua in Beijing setting up their own precision medical centres. Nationally they are also engaging in their own mass sequencing effort in the form of the 100K Wellness Project. Most trial and discovery efforts are focused on a number of cancers, in particular lung cancer, with confidence based on the large population to drive mutation and variant identification and lead breakthroughs.

“Life sciences are coveted areas for nation-states. The jobs created in these sectors tend to be high wage and knowledge intensive. Countries with vibrant domestic life science players often have analog industries, such as; agricultural science, engineered materials or food production that are equally advanced. These applications and other respective technologies represent major progress in quality of life.” Said Benjamin Shobert, Senior Associate for the National Bureau of Asian Research.

Massive challenge, mammoth market

Despite the multifarious challenges of doing business in a state such as China with its; authoritarian government, planned economy, manipulated currency and utter disregard for international intellectual property rights, is the potential size of the market. London based consultancy, Global Data predicted a market worth as much $315 billion a year. A figure too compelling to allow the possible negatives to discourage most companies.

That figure looks at the sector as a whole though it may be prudent to break the market down somewhat. China already has some large sequencing companies with the Beijing Genomics Institute being the biggest. For them and other Chinese companies their first outlay will be the sequencing machines themselves. As is the case across the industry, these came from California based Illumina who hold the biggest market share globally. This, however, is a single purchase transaction and not a scalable or sustainable revenue stream.

These sequencers will inundate the budding sector with data and processing that will be the next stage of the challenge. Companies such as, Cambridge based, Congenica, who have developed advanced software called Sapientia, to interrogate, classify and annotate clinical genomic data for either diagnosis or research, are able to empower Chinese clinics here. Also, the constant stream of data means that this revenue stream is strong and sustainable. Even more so if robust contracts and partnerships can be signed.

The last aspect of the market is in drug discovery and trials. This is where the biggest windfalls are and the biggest threats. The windfalls are obvious, in the world’s most populous nation, trials and development are much more straightforward than in heavily regulated western countries and the numbers mean any marketable drug will quickly become a high earner. However, at the same time the state is under pressure to fight the rising cost of healthcare in a relatively impoverished country. To this end the government dictates five drugs for major ailments each year which they then demand the price is reduced by 50% and in some cases, patents are not renewed or respected and the drugs given to Chinese companies to make their own generic versions to sell at a fraction of the cost.

“China is the next big wave, it's only a matter of time before it will certainly be the world’s number one pharma market and probably the world’s biggest data producer. You can dip your toe in via partnerships but sophisticated companies need true collaborations where they can build their own R&D facilities and build a true presence.” Advised Greg B Scott, President and Founder of ChinaBio.

The future

Moving forward companies may find themselves attracted by the huge potential market and data set but must be careful of the various Sino-centric business considerations which they will not have faced in other territories.

The state-planned forms of capitalism mean heavy regulation, frequent intervention, a high level of interference and the constant threat of widespread prying into normally confidential aspects of a company.

“What China needs is innovation. It is happening slowly but it it is driven by returnees or through technology brought into the country and then either directly copied or reverse engineered. There is no conceptual reality or legal reality for intellectual property and Chinese enterprises have increasingly turned to buying out competitors to move away from their predatory reputation. There is also the problem of corruption in the country. President Xi is outwardly appearing to address the issue but in fact it is still deeply entrenched in all aspects of the society. Corruption is not unique to China but its level of general practice is high.” Said Greg B Scott, President of ChinaBio.

The biggest threat to most experts is that of stability. Whilst the middle class is growing and China’s population are enjoying more opportunities and income than ever before, a number of spectres sit on the horizon. The housing crisis driven by unsustainable building and pricing alongside rising food and fuel prices threaten to disenfranchise many, shrinking western markets undermine the manufacturing sector and restrictive uncreative teaching methods leave most graduates without the entrepreneurial skills to start their own enterprises and those same graduates are facing a job market with fewer and fewer opportunities every year.

The Eurasia Group, a consultancy which works to aid investors and business decision makers in understanding the impact of political changes on opportunities in foreign markets wrote: “China’s rebalancing agenda is not merely about economics but, ultimately, the political viability of the Chinese system. Beijing has delivered economic prosperity to many Chinese but those very successes have yielded numerous problems for example; the income gap and the accountability gap are both unsustainable, or, disenchanted graduates working long hours and earning low wages and not being able to get on the housing ladder, marry or start a family. All of which are markedly significant milestones to the Chinese.”

These problems may seem familiar to readers in the UK or US, student debts are extremely high, house prices are unattainable, wages are depressed and jobs at a shortage. Yet China remains stable, more stable than a number of European democracies, but dissent and protest are increasing. There are growing demands for political transparency and engagement. Sadly, government repression is increasing too, censorship is an enormous industry and violence is increasingly used to break up grassroots movements.

China is an autocratic state and a frequent and severe human rights abuser yet it is still relatively open, free and stable for an autocracy. If it is going to stay that way or even improve the Party needs to make careful, considered but significant changes to the way the country works but most importantly, they need to keep investing and keep progressing. The market isn’t getting smaller and it needs to be served, as the expectations of the Chinese increase so do the business opportunities.

What is Clinical Genomics?

Clinical Genomics is a modern approach to practising medicine in which healthcare professionals use information on the genetic makeup of a patient to diagnose, treat and prevent disease.

Diseases can be caused by a single DNA mutation, for example, cystic fibrosis, or by much larger chromosomal changes, such as in cases of Down’s syndrome. Genetic data can also help us to understand the causes of more complex diseases, such as Alzheimer’s disease or rheumatoid arthritis. Complex diseases are caused by a combination of multiple genetic changes within the patient but are also influenced by their environmental and lifestyle factors.

Identifying the genetic changes that occur in a wide-range of diseases offers opportunities to develop new treatments which are targeted at specific mutations. Genetic data can also be used to facilitate the provision of medication which avoids unwanted side effects and increases the chances of success.

The term ‘Precision Medicine’ has been coined to represent the need to gain better insights into the biological, environmental, and behavioural influences upon these diseases and to better serve patients.

Background and Driving Forces

The use of genetics in the clinic dates back to the early 1960s with the introduction of screening tests for newborn babies. Prenatal screening for cystic fibrosis and Down’s syndrome has since become a matter of course. In the UK, and increasingly around the world, clinical genetics is a recognised medical speciality with formalised training and a clear career pathway for doctors who diagnose and manage families with genetic disorders.

In recent years, technology has evolved to the point where it is no longer limited to detecting single mutations. DNA sequencing is a technology that enables us to identify all potential variations in a person’s genetic makeup, this is important when studying complex diseases in which there may be many genetic changes that preside over the risk of developing a disease.

The cost of DNA sequencing has been rapidly decreasing, this combined with innovative advances in software and storage solutions for genetic data have increased the accessibility of DNA sequencing for use in clinical settings.

Now that genetic data can be readily generated, clinical scientists need to accurately identify the genetic mutation or mutations that cause disease and to understand the consequences of those mutations upon the human body. Understanding which biological processes are disrupted by genetic mutations is vital to establishing new treatments, clinical trials or drug development thus ensuring the benefits are felt by patients and society as a whole.

Current State

Today, the potential benefits of using genetic data are widely acknowledged by scientists, clinicians, healthcare professionals and even politicians. There are numerous centres, from small private clinics to nationwide initiatives, intent on developing new processes to accelerate the implementation of clinical genomics in the healthcare, research and pharmaceutical sectors.

One particularly prominent example has been Genomics England and their 100K Genome Project, which aims to gather 100,000 genomic sequences from National Health Services (NHS) patients in the UK, providing genetic insights into diseases and their diagnoses. In some cases the diseases in question are so rare that no diagnosis was previously available or, even, possible as they were only recorded in an individual or single family.

Integration of clinical genomics into healthcare comes with challenges, particularly in understanding the vast and complex data that clinicians must now interpret and understand. However, there are new technologies being developed to help with this challenge, and this is where companies such as Congenica are leading the way.

Congenica have developed Sapientia™, a software platform that integrates human DNA data with clinical information and symptoms, and references them against vast private and public databases of genetics, helping clinicians understand the mass of data provided, and helping them to provide actionable interpretations of inherited diseases.

Previously, it took 7.3 clinicians working over a period of 4.8 years to reach a clear diagnosis for a patient with a rare disease in the UK. With Sapientia, however, it can be as little as 1 clinician and just 5 days to reach the same conclusion. A seismic shift in patient experience.

Challenges currently facing Genomic Data Interpretation

The cost and time required for sequencing a whole genome has plummeted in recent years, giving clinicians access to vast amounts of genetic information. Accurately identifying which are the disease-causing mutations within this data can be extremely challenging, but is of the utmost importance for diagnoses and the development of new treatments. Software advances have been helping clinicians by integrating multiple sources of information, including clinical traits and symptoms. Sapientia, for example, provides an actionable list of all the mutations that are likely to cause disease from any mass of data.

As more genomic data becomes available and the ability to interpret it is made possible by such software platforms, it is imperative to ensure data privacy when sharing and collaborating. Data must be anonymised to ensure that it does not contain any personal patient information, and data transfer and storage must adhere to the highest levels of security.

At the same time, it is important for clinicians and scientists to be able to share their discoveries and insights, so that they can make the best decisions based on all the knowledge available. Sapientia, for example, provides a collaborative software environment, where clinical geneticists can share DNA mutations and literature insights. This allows clinicians, across multiple organizations in different parts of the world to, more quickly, identify disease-causing mutations in patients and administer effective therapies.

Looking to the Future

As knowledge in genomics keeps expanding and healthcare practitioners continue to adopt new technologies, the medical community is working towards a future where diagnosing, managing and treating inherited disorders and complex diseases becomes the norm. To achieve this clinicians, doctors, private businesses and even politicians across all medical sectors from primary care to commercial drug discovery need to keep driving forward to push the boundaries of genomic medicine.

The world that Congenica envisions is one where the sequencing of an individual’s genome is part of routine medical practice and where the highest level of healthcare is available to all. A world where having a genome sequenced is as routine as MRI or CT scans. A world in which we understand diseases which, currently, we can’t even name. Genomics is the key to unlocking a world previously thought impossible and in understanding the very building blocks are lives are built upon. It is the medical revolution of our time.