Decoding precision medicine | MEDICUS 2024 Issue 4

Decoding precision medicine: Tailored care based on your genetic blueprint
By Dr Chua Li Min

Precision medicine is not just about combating existing diseases but also pre-emptively battling risks embedded in our genes, long before they manifest, explained Prof Patrick Tan // Credit: Duke-NUS

The first visit to a doctor's office often unfolds like a comprehensive audit of your personal history, where every detail of your life and lineage is scrutinised—not just your habits and health, but the medical histories of your parents, grandparents and even relatives you’ve never met.

This isn’t mere curiosity.

Understanding your family history is essential for doctors as they build a picture of more than your current health, but also the likelihood of you living with inherited risk factors—which may otherwise remain hidden in your genes.

“Genetic testing has the potential to allow us to do even better.”
Prof David Matchar

While doctors used to rely on patient histories to determine an individual’s risk of having an inherited condition, it is now possible to find out more by analysing an individual’s genetic data using enhanced technology and cutting-edge tools.

Explained Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS: “This enables doctors to deliver more tailored care through precision medicine, which is not just about combating existing diseases but also pre-emptively battling risks embedded in our genes, long before they manifest.”

Doing even better than we're doing now

Though seemingly new, precision medicine has long been the medical profession’s aspiration, stressed Professor David Matchar, who has been an internist for more than 40 years.

“We have always aimed to treat patients by providing healthcare in a way that directly applies to them. Traditionally we have done this using standard clinical information and tacit knowledge that comes from a personal relationship,” said Matchar, who is with the Duke-NUS Health Services and Systems Research Programme, and head of the health system design lab at the Programme.

“Genetic testing has the potential to allow us to do even better,” he added.

While it took 13 years to sequence the entire human genome, it is now possible to do so in a couple of days with advanced genetic testing.

Today, researchers like Lim Weng Khong use tests such as whole exome sequencing to zoom in on parts of an individual’s DNA containing specific instructions that affect processes in the body.

Despite being only a small part of a person’s entire DNA, this “small fraction allows us to sequence more deeply and at a lower cost”, explained Lim, who is an assistant professor at Duke-NUS’ Cancer and Stem Cell Biology programme. “So it offers a bird’s eye view of the genes in an individual, which enables us to zoom in on variants that may be present.”

Through this approach, the bioinformatician hopes to identify disease-causing genes in young patients with rare genetic disorders that not only help with diagnosing their disease but may also offer hope of an effective treatment one day.“

It all starts with understanding the genetic makeup of the patient. Once you find out what’s causing the patient's disease, you can ask whether there is a targeted drug for it, or find out which medication works best,” added Lim.

Asst Prof Lim Weng Khong

Asst Prof Lim Weng Khong hopes that with more advances in technology, there will come a day where no one goes undiagnosed // Credit: Courtesy of Lim Weng Khong

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Giving patients a fighting chance

Oncologist Ong Sin Tiong is also leveraging the distinct information in our genes to help doctors recommend the most effective treatment for patients with chronic myeloid leukaemia.

This is particularly important for patients at high risk of developing an aggressive form of cancer, called blast crisis chronic myeloid leukaemia, that is resistant to standard therapy.

Even with the best efforts, the survival rate for patients in this group is dismal, a statistic that Ong is determined to improve.

To understand what differentiates these high-risk patients from patients who respond well, Ong, who’s a professor at the Duke-NUS Cancer and Stem Cell Biology Programme, turned to his long-term collaborator haematologist Associate Professor Charles Chuah for patient samples.

Working in collaboration with Dr Shyam Prabhakar at A*STAR’s GIS, the team discovered that features in a patient’s bone marrow at diagnosis prior to treatment could predict future blast crisis.

Assoc Prof Charles Chuah (right) with Prof Ong (second from right) and his team in the lab // Credit: Norfaezah Binte Abdullah, Duke-NUS

“In cancer biology, one often thinks of mutations that are acquired after you start treatment,” said Ong. “But what we found was: even before you start treatment, we could already tell whether a patient could develop blast crisis and drug resistance or not.”

Ong hopes to translate these findings into a new test that can be used by doctors in the clinic to identify patients at high risk of developing blast crisis. It would offer doctors a significant step up from the current guidelines which categorise patients based on the results of a physical examination and their blood count.

“If we can get this test up and running to identify patients in the high-risk group, we can treat their cancer early and more aggressively when it matters most,” said Ong. “Such as recommending them for a stem cell transplant which is potentially curative,” he added.

“You don’t have to invent a new treatment. With this approach, we can triple the patient’s chances of survival with existing treatment. This is precision medicine in practice,” he stressed.

Giving population and preventive health a boost

Precision medicine isn’t just a game-changer for patients with cancers and rare diseases. Its effects could have implications across an entire population, said Tan, who also leads Singapore’s national precision health programme, Precision Health Research, Singapore (PRECISE).

The programme which aims to transform health in Singapore through precision medicine kickstarted its first phase by mapping the genetic data from three major ethnic groups in the nation: Chinese, Malays and Indians.

In his plenary talk at the 2024 PRECISE-IHCC Conference held from 21 to 23 August, Prof Patrick Tan shares how the National Precision Medicine Programme creates value for health and the economy // Credit: Chua Li Min

“In doing that, we could potentially contribute towards the application of precision medicine in other Asian countries where these populations are prevalent as well,” wrote Tan in an editorial about the programme.

After collecting the genetic sequences of 10,000 individuals during its first phase, the programme is on track to complete sequencing the genes of 100,000 individuals by early 2025.

“Large-scale population cohorts are the best way to distinguish between cause and effect and understand early cues of disease. And for the next five to ten years, we will continue to build on this goal.”
Prof Patrick Tan

Harnessing the insights from this amassed genetic data will help shape and inform public health policies and efforts, emphasised Tan.

Lim, whose genome analytics platform at the SingHealth Duke-NUS Institute of Precision Medicine was used to analyse the data, described the patterns that emerged from the analysis: “We were able to show that our diverse Asian populations are at increased genetic risks of different conditions.”

One of the conditions that stood out to the researchers was familial hypercholesterolaemia.

They found that one in 140 Singaporeans carries a gene mutation that affects the way they process cholesterol, putting them at an unusually high risk of developing very high cholesterol.

It is a condition not unfamiliar to Matchar.

“It affects people from a very young age because it’s genetic,” he explained. “So they can develop vascular disease fairly early. And these are the people who end up with heart attacks and other vascular problems like strokes in their forties or even earlier, in childhood.”

If caught early, it is a scenario that can be prevented with drugs, giving individuals a better quality of life and reducing long-term healthcare costs by helping patients avoid hefty hospitalisation bills years down the road.

This discovery has paved the way for a national genetic testing programme for familial hypercholesterolemia that will be launched by mid-2025 as the nation readies to systematically test and treat individuals with the disease at the population level.

“If an individual tests positive for familial hypercholesterolaemia, their parents, siblings and children will be encouraged to undergo the same test,” said Minster for Health Ong Ye Kung in his keynote address at the Singapore Health & Biomedical Congress 2024 where he announced the launch of the programme.

He added: “By repeating this process, we can pick up as many people in Singapore with the genetic disorder early. We will then advise them to adopt healthier lifestyles as early as possible and start cholesterol-lowering therapies, if necessary, to reduce their risk of premature heart diseases.”

More tests down the road?

Beyond affecting the body’s cholesterol levels, variations in genes can also affect an individual’s risk of developing an array of health issues, from kidney disease to how the body reacts to different medications, as researchers have found from analysing the samples in the PRECISE database.

“Large-scale population cohorts are the best way to distinguish between cause and effect and understand early cues of disease. And for the next five to ten years, we will continue to build on this goal,” added Tan.

As exciting as it may be to start rolling out more genetic tests, a deliberate and methodical approach is necessary, stressed Matchar, who is also the lead economic and policy analyst at PRECISE:

“Knowledge can be power. But there is a danger to knowing things that you aren’t prepared to address in a way that helps and does not hurt. We want to avoid inducing confusion, unnecessary anxiety and limit potentially unhelpful and expensive further tests and treatments. This is why much of the work that we’re doing now, especially within the public sector, is aimed at asking the question: ‘Which of these tests are useful in which practical use cases’.”

Prof David Matchar

In addition to running the health system design lab at Duke-NUS, Prof David Matchar is also the lead economic and policy analyst at PRECISE // Credit: Norfaezah Binte Abdullah, Duke-NUS

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“It’s not just ‘Oh we are going to do genetic testing.’ And then magic happens. It’s just not the way it works,” he added. “We have to do it thoughtfully, so that it fits into the health system in a coherent process.”

That includes ensuring that there is an infrastructure and system in place that will be able to handle the results.

Considerations like whether it might be more cost-effective compared to usual decision-making or practices will also come in the mix.

As the future of genetic testing unfolds, Matchar is optimistic about the next chapter in the precision medicine story: “I think we can get faster and more efficient about incorporating genetic tests in clinical care in Singapore as we learn how to do this in a way that makes sense in our context; we don’t want the evaluation process to be a bottleneck to progress.”

So in a reality not too far from now, all this personal genetic information could be linked to health data, leading not just to quicker diagnoses but also effective treatments that enable us to live longer and healthier lives. And perhaps even to train the diagnostic systems of the future, where complex medical conditions can be diagnosed with a sweep of a tricorder just like in Star Trek’s universe or a finger prick of blood.