While the term “Precision Medicine” is of fairly recent origin, the desire to provide accurate and unerring care for patients is a fundamental principle in the practice of medicine. It is the basis, for example, in the deliberate care taken to make sure patients in need of blood transfusions are matched with the correct blood type. In this new series, Dr Khor Ing Wei, Dean’s Office, explains how precision medicine is using additional pieces of information such as genetic data to open an exciting new window of possibilities.
Firstly, what is precision medicine?
As opposed to a “one size fits all” approach, precision medicine uses relevant biological, medical, behavioural and environmental information about a person to tailor their healthcare.
What does it mean for your health?
Various types of information helps doctors to better predict patients’ disease risk, allows doctors to make more accurate diagnoses and select therapies that are more likely to work for a particular patient or group of patients. Researchers can also mine the data to develop new, more effective therapies.
How is it different from today’s medicine?
Doctors already use information about us when deciding how to treat us. Currently, this information mostly consists of characteristics such as gender, body weight and ethnic group, as well as simple measurements such as blood sugar, cholesterol, and blood pressure.
One of the big advantages of precision medicine is that it also considers genetic factors, which explain up to 30% of health, such as how long one lives and which diseases may affect a person. Now, technology has advanced to the point where genetic sequencing of people is much more affordable, allowing us to study and understand the genetic contribution to disease better than ever before.
A quick refresher about genes and genetic variants
Genes contain the basic information needed to code for the proteins, cells and tissues that make up all living things. They play a role in determining our physical characteristics. More importantly, genes determine how individual organs and cells work in our body.
Our genes are coded as sequences of 4 letters, C, G, A and T. Differences in one or more of these letters are called genetic variants. Genetic variants are part of what make us unique. They determine how vulnerable we are to certain diseases and how we respond to foods, medications, exercise and toxins. Genetic variants can be passed down from parents to children.
Using genomics to uncover the secrets behind inherited diseases
In 2001, the first sequencing of the human genome (all of the genes in our body, plus non-coding DNA) was completed, taking 13 years and costing US$3 billion.1 Now, two decades later, it takes less than a day and under US$1,000 to sequence a person’s genome. In a few years’ time, this may fall to as little as $100 to $200.2 The implications for healthcare are nothing short of revolutionary, with the genomic sequencing of populations changing how scientists understand disease and the way that doctors care for patients.
Against this exciting possibility, researchers held the first Human Genomics Symposium in Singapore, which took place on 14 and 15 October 2019 at the National University of Singapore. Sponsored by the National University Health System, A*STAR and the genetic sequencing company NovogeneAIT, this conference featured a wide range of speakers who are applying genomics in research and clinical care.
Dr Richard Scott
THE GREAT ENGLISH
GENOME HUNT
One of the invited speakers was Dr Richard Scott, who is the Clinical Lead for Rare Diseases at Genomics England (GeL), the national programme in the UK for incorporating genomic data in clinical care and research. The work that GeL has done, especially their landmark 100,000 Genomes Project, is helping to improving health in the UK. It presents a tantalizing vision of what this might mean for the genomics-based work that Singaporean clinicians and researchers are doing.
The 100,000 Genomes Project team has now sequenced all their targeted 100,000 genomes from individuals with cancer or rare inherited diseases, including family members recruited through a network of National Health Service (NHS) Genomic Medicine Centres. Genomics England is currently engaged in analysing the genomic data and returning the primary findings to NHS laboratories to review and report to participants who had consented to receive them.
They have already chalked up some early successes. Dr Scott described a case involving a young boy who had various problems in growth and learning. Over five years, the boy and his parents consulted multiple doctors, but did not receive a definitive diagnosis. Finally, scientists at the 100,000 Genomes Project sequenced the boy’s genome and found a change in one of his genes, or a genetic variant. This genetic variant causes the DNA repair disorder called Cockayne syndrome in just three out of every million live births.3 Although there is no cure at present, aspects of the condition may be managed to maximise the patient’s quality of life.
For example, the boy’s doctors could avoid metronidazole, a commonly prescribed antibiotic that can cause fatal liver failure in people with Cockayne syndrome. His parents were also able to receive genetic counselling about the risks that any future children of theirs may face.
By collecting genomic data from this young boy and other people with Cockayne syndrome, and allowing authorised researchers to access the data, the 100,000 Genomes Project is increasing the chances that other children with the condition will be able to receive a diagnosis, and that new treatments for the devastating disease will be found. At the same time, the project is collecting and sharing data from people with many other diseases, which may stimulate the discovery of new and better treatments. As of now, 4,000 researchers at over 200 institutions around the world are authorised to access and view the data in a secure environment via virtual desktop, allowing it to be accessed remotely.
To ensure that the data is secure and that the participants’ privacy is protected, a governance committee oversees the usage and sharing of data in the programme. Importantly, the committee includes several participants, who often surprise healthcare professionals with their progressive views about data sharing.
“Patients with rare diseases are often very keen on the data [about them] being made available to researchers,” observed Dr Scott.
Other countries have established similar databases and are also applying the data in clinical care and research. Examples include the All of Us programme in the United States, as well as BioBank Japan and the TOP-GEAR and MASTER KEY cancer genetic testing programmes in that country.
A SURE HELP FOR KIDS
Here, the Singapore Undiagnosed Diseases Research for Kids (SUREKids) programme at the National University Hospital (NUH) and KK Women’s and Children’s Hospital involves genomic sequencing and genetic testing (sequencing of a suspected gene or genes) of children to identify rare inherited diseases. The leaders of the 100,000 Genomes Project and SUREKids occasionally interact and share best practices, helping to advance both programmes.
One of the researchers involved in SUREKids, Associate Professor Denise Goh, is a paediatric geneticist at NUH. She uses genetic testing to help diagnose, assess prognosis and guide treatment for rare genetic diseases in children.
In some of the cases that A/Prof Goh has seen, the genetic information led her and other doctors to select a treatment that they might not otherwise have considered. One case involved a 1-year-old child with epilepsy that had not abated, despite treatment with anti-epileptic medications. A/Prof Goh noticed that the child also had delayed physical and cognitive development, slight abnormalities in movements and light-coloured hair, which suggested that another condition was causing the seizures. She ordered genetic testing, which revealed that the child had a rare genetic metabolic disorder. Based on this information, she selected another treatment for the child, who responded well. Having the diagnosis gave closure to the child’s parents, and allowed A/Prof Goh to talk to them about their risk of having another child with the same disorder.
AND HELP FOR ADULTS TOO
The principal investigator of the original research project that grew into the SUREKids programme is Professor Roger Foo, who is a cardiovascular geneticist at NUH. He uses genomic data to track down diagnoses in difficult adult cases.
For example, genomic data helped find the real cause of the heart condition affecting a woman in her 70s. She had previously received a diagnosis of hypertrophic cardiomyopathy, but this diagnosis encompassed too broad a range of conditions to be very helpful. The patient had her genome sequenced as part of a research project and, by comparing her genetic variants against databases that included data from Asians, the researchers found a genetic variant linked to a rare condition called Fabry disease.
Fabry disease is an X-linked enzyme defect that causes a certain type of fat to accumulate, increasing the risk of heart attack, stroke and kidney disease. Some people, such as this elderly patient, also present with skin symptoms. Women tend to have a milder version of Fabry disease since it is an X-linked condition (transmitted on the X chromosome, of which women have 2 copies). Establishing the suspicion of a Fabry disease diagnosis meant that the woman could be referred to a doctor who was familiar with Fabry disease, who could evaluate whether she would benefit from enzyme replacement therapy. It also meant that her family could come forward for screening and be investigated for the condition.
Since the genetic variants linked to disease are often different among ethnic groups, consulting Western databases such as that of the 100,000 Genomes Project may not be optimal for Singaporean patients.
“Our interaction with Dr Richard Scott of Genomics England emphasises to us in Singapore how important it is to have our own database to reference,” notes Prof Foo. “An English normal cannot be taken as a Singaporean normal.”
The continued efforts of Prof Foo and other geneticists, as well as the recent genomic sequencing of 5,000 Singaporeans by the Genome Institute of Singapore4,5, are moving us closer to the goal of a comprehensive Singaporean genomic database and its promise of improved health for our population.
Why do we need Asian databases containing genomic and medical data?
- Aid doctors in establishing diagnoses for genetic diseases in Asians because some genetic variants are Asian-specific
- Help researchers identify novel Asian genetic variants linked to disease
- Help researchers discover new treatments that target Asian genetic variants
- Add to disease understanding by revealing new insights into Asian aspects of diseases
References
1. Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of the human genome. Nature. 2001;409:860- 892.
2. CNBC. 23andMe competitor Veritas Genetics slashes price of whole genome sequencing 40% to $600. https://www.cnbc.com/2019/07/01/for-600-veritas-genetics-sequences-6point4-billion-letters-of-your-dna.html. Published July 1, 2019. Accessed November 21, 2019.
3. Wilson BT, Stark Z, Sutton RE, et al.
The Cockayne Syndrome Natural History (CoSyNH) study: clinical findings in 102 individuals and recommendations for care. Genet Med. 2016;18:483-493.
4. Wu D, Dou J, Cai X, et al; on behalf of the SG10K Consortium. Large-scale whole-genome sequencing of three diverse Asian populations in Singapore. Cell. 2019;179:736-749
5. Channel NewsAsia. Singapore Tonight interview with Professor Patrick Tan. Sequencing The Singapore DNA – First Genetic Databank in Singapore set up to help in clinical research.