Dennis Lo’s three-decade journey to science’s greatest prizes

22 September 2020

Innovation does not come easy and for Professor Dennis Lo (Croucher Senior Medical Research Fellow 2006). It involved “going in the wrong direction” for almost a decade.

From the time he was a medical student in Oxford in the late 1980s to his arrival at the Chinese University of Hong Kong as an associate professor in Chemical Pathology in 1997, he was hunting for foetal cells within maternal blood as part of his quest to find a way to conduct non-invasive testing of genetic and chromosomal disorders in unborn children.

He was frustrated to find very few such cells.

Around 1997, he came across a clue from cancer research that it might not be cells he was looking for, but fragments of DNA. If tumours shed cell-free DNA into the host’s blood, might not a growing foetus do the same?

Lo changed tack and made the discovery that has revolutionised clinical practice in prenatal genetic testing across the world, recognised on 10 September 2020 when he became the first Hong Kong-based scientist to win a US$3 million Breakthrough Prize for Life Sciences.

“I wasted quite a few years, from 1989 to 1997, going in the wrong direction, failing to find many foetal cells in maternal blood,” he said. After all, it had been generally assumed that DNA belonged within a cell. Instead, he found it outside, in a pregnant mother’s blood plasma.

“It was like thinking that money is normally kept in the safe inside a bank, when it was in fact left scattered on the floor,” he said.

Lo, Director of the Li Ka Shing Institute of Health Sciences and Associate Dean (Research) of the Faculty of Medicine, Chinese University of Hong Kong, was speaking during the euphoric hours after the prestigious prize was announced, about that discovery, and the even greater prize of using the same principle for the early detection of multiple cancers.

Since 1997, it has taken the best part of two more decades to refine maternal blood tests to identify different genetic and chromosomal conditions in foetuses, which means pregnant women no longer need to make that agonising decision as to whether to have an invasive test that is not only stressful but involves a risk of miscarriage.

After discovering the foetal DNA strands in maternal blood, it took another decade to find how to detect the signature abnormalities associated with Down’s syndrome using such free floating DNA. The fact that the DNA fragments existed randomly outside of cells made it challenging to count chromosomes using conventional methods, such as microscopy-based approaches, needed to find trisomy 21 – a condition characterised by the presence of an extra copy of chromosome 21.

The breakthrough came when he realised he could do this by identifying the ratio of chromosomes, through a technique known as massively parallel sequencing, he said, crediting his 2006 Croucher Senior Medical Fellowship for giving him the time to pursue the methodology. The accuracy of the test was affirmed in a large-scale study that tested blood samples from 753 pregnant women, of whom 86 were found to be carrying a foetus with Down’s syndrome.

“The first lesson is that it is good to start early. When you start young, time is on your side. You can afford to make mistakes and reposition,” Lo said. Perseverance has also been essential. “If you are working on something very innovative, by definition it is difficult, otherwise others would have done it.”

He benefited from a change of environment, from Oxford to CUHK, which helped him look in new research directions.

He also secured the tools he needed. In December 1996, at a Christmas party hosted by Magnus Hjelm, his future department’s chairman at CUHK, Lo asked Hjelm for the funds to buy an expensive instrument for conducting real-time polymerase chain reaction (PCR).

Hjelm agreed, a decision that turned out to be the biggest Christmas present of his life, Lo said. Using the technique he could develop quantitative PCR assays for measuring concentrations of foetal DNA in maternal plasma, published in 1998.

Real-time PCR was invented by US scientist Russell Higuchi. Lo saw the interesting intertwining of careers when he received a second award , the Association for Molecular Pathology (AMP)’s Award for Excellence in Molecular Diagnostics, in the same week as his Breakthrough Prize. Higuchi won that award in 2019.

Today, Lo believes the 1997 discovery came at the right time, in the right place. “If I had solved the problem as a student, I would probably not have been able to back it up, because the resources were minimal,” he said.

In addition, he had started his research more than a decade before the human genome had been sequenced, a development that greatly assisted his subsequent work using DNA sequencing technologies, especially when he decoded the entire foetal genome from maternal blood.

“Without the human genome as a guide, it would be like navigating the ocean without a map. One is constantly being reminded that scientific advances are built on foundations laid by others that have come before.” Lo said

Through this work, CUHK has a number of patents that have been licensed globally. Royalty income is now an important source of funding for his team’s research, he said.

Lo still spends half his research time focused on refining prenatal testing. The other half is devoted to cancer diagnosis, which is at least as exciting. He is close to his next ambition of giving the world the key to identifying multiple cancers – as many as dozens from one blood test that can reveal genetic, chromosomal, epigenetic and virus-associated aberrations manifesting in cancer DNA.

He explained that his team, which includes Professor Rossa Chiu (Croucher Senior Research Fellowship 2016) and Professor Allen Chan, had successfully tested the principle on nasopharyngeal cancer (NPC). This is prevalent among mainly men in the southern provinces of China, such as Guangdong, with 75 per cent of cases traditionally found at a late stage, and a five-year mortality as high as 40 per cent.

From a study of more than 20,000 men, completed in 2017, the team identified 34 cases, of which 70 per cent were in the early stage. As a result, the five-year survival rate has greatly improved, with just one fatality among that group.

Current blood tests for NPC that rely on antibodies have high false positive results, he said. His innovation should be much more specific, facilitating early treatment and greatly improved chances of surviving cancer.

Lo does not just do the research, but has been highly successful in its translation. Along with Chiu and Chan, he co-founded startups Cirina and Xcelom. The latter has become a leader of non-invasive prenatal testing in Hong Kong. Cirina focused on the development of cell-free DNA-based screening tests for cancer, merging in 2017 with Grail, a US-based life sciences company now preparing for a Nasdaq listing and also focused on early detection of cancer. In 2017, Lo and Chiu were also awarded a Leader of the Year award in commerce to recognise their efforts in driving biotechnology development in Hong Kong.

With the principle of cell-free DNA testing for cancer already affirmed, Lo’s Breakthrough award is unlikely to be his last.

Professor Dennis Lo Yuk-ming received his Bachelor of Arts degree from the University of Cambridge and Doctor of Medicine and Doctor of Philosophy degrees from the University of Oxford, where he was subsequently appointed University Lecturer in Clinical Biochemistry and Honorary Consultant Chemical Pathologist at the John Radcliffe Hospital. He joined the Chinese University of Hong Kong (CUHK) in 1997, where he is now Director of the Li Ka Shing Institute of Health Sciences, Li Ka Shing Professor of Medicine, and Professor of Chemical Pathology. He is also Associate Dean (Research) of the Faculty of Medicine at CUHK. He received his Croucher Senior Medical Research Fellowship in 2006.

To view Professor Lo’s Croucher profile, please click here