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Professor LO Yuk Ming Dennis

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Honorary Fellow Professor LO Yuk Ming Dennis (2013)

Professor Yuk Ming Dennis LO is currently the Director of the Li Ka Shing Institute of Health Sciences, Associate Dean (Research), Faculty of Medicine, Li Ka Shing Professor of Medicine and Professor of Chemical Pathology at The Chinese University of Hong Kong. Professor LO is recognized today around the world as an authority who made non-invasive prenatal diagnostics a reality. To date, he had contributed over 300 publications with total citations of 13,520 and an h-index of 63.

Reflecting upon his childhood, it seems that Professor LO was destined to be a scientist since his youngest days. Some of his earliest experiments involved insects and small animals found wondering around his Kowloon home which became his research subjects and were recruited without informed consent. As a school boy, Scientific American, National Geographic and Discover were among the journals on his regular subscription list. It was through these readings that he learned of the great works of the scientific giants. He read about Charles DARWIN’s theory of natural selection, pondered upon the garden pea experiments conducted by Gregor MENDEL that revealed the laws of inheritance, and gazed at the black and white photograph where James WATSON and Francis CRICK posed with a model of the DNA double helix. These iconic stories captivated the young Dennis, who then was determined to enter into medical school to learn the wonders of human biology. In 1983, he was accepted into the University of Cambridge where lecture hours were few. Instead, students spent most of their time engaged in open-ended conversations with professors while being nurtured in the academic atmosphere. After completing a student thesis on gene cloning, Professor LO moved to the University of Oxford for the remainder of his medical studies.

It was here at Oxford that Professor LO had his first taste of academic research. While attending an outpatient clinic session as a medical student, he made an observation where there was no explanation in the textbooks. He developed his query into a hypothesis and proposed it to his clinical tutor who replied with skepticism saying, “Dennis, if you could think of this, I’m sure that others would have thought of this already? Driven by curiosity, Professor LO spent hours turning the pages of volumes of index medicus (the hard copy version of what is known as Medline now) and found that there were only four earlier case reports, confirming that his observations were indeed correct though rare. His manuscript reporting these observations were later published in the Journal of Clinical Gastroenterology.

The hobby of scientific pursuit soon became a vocation. Even years before Professor LO’s graduation from Bachelor of Medicine and Bachelor of Surgery in 1989, he was already heavily involved in laboratory research. Polymerase chain reaction (PCR) had just been invented around this time and Professor LO learned this art first hand from the pioneers, namely Sir John BELL, the current Regius Chair of Medicine at Oxford University. Not only did Professor LO master the art, he was the first to report the problem of PCR contamination which all laboratories nowadays have to safeguard against.

After graduation, Professor LO pursued Doctor of Philosophy training under the supervision of Professor James WAINSCOAT. He was awarded the highly competitive Wellcome Medical Graduate Fellowship. Motivated by reports on the presence of fetal cells in the circulation of pregnant women, in 1989, Professor LO used a PCR assay to target DNA on the Y chromosome to provide the first molecular proof of the presence of fetal cells in maternal whole blood. This was his first experience with non-invasive prenatal diagnostic research. However, due to the scarcity of intact fetal cells in maternal blood, researchers spent decades of efforts without much progress and have coined the pursuit of non-invasive prenatal diagnosis of Down syndrome as the Holy Grail of the field.

In the mid-1990s, publications emerged showing that cancer-specific genetic changes can be detected among cell-free DNA found floating in the plasma of cancer patients. Being a lecturer at the Nuffield Department of Clinical Biochemistry at Oxford at the time, Professor LO took a note of those intriguing studies. He started to draw analogies between a growing cancer and a growing fetus. Both are parasitic on its hosts, both enjoy high growth rates and the placenta is an invasive organ. Professor LO hypothesised whether cell-free fetal DNA existed in the plasma of pregnant women. It was between his transfer from Oxford to The Chinese University of Hong Kong to become a senior lecturer at the Department of Chemical Pathology, when he began his experiments. He collected peripheral blood from pregnant women, removed the blood cells by centrifugation to obtain plasma. He then extracted DNA by simply boiling the plasma samples, what he described as like cooking instant noodles, and applied the PCR assay for detecting chromosome Y DNA sequences. To much of his surprise, positive signals were revealed in front of his eyes. In a state of disbelief, he worried if the positive signals of male DNA were from himself due to the phenomenon of PCR contamination which he first reported as a medical student. Only after the same results were shown after the experiments were repeated by a female student, then he realised the vast implications of his novel finding. The data of these earliest experiments were reported as an article titled, Presence of fetal DNA in maternal plasma and serum, in the Lancet in 1997 which has been cited over 700 times to date.

With his newly established laboratory in Hong Kong, he was ready to fully explore the new field that he had founded. He reported that cell-free fetal DNA was present at a surprisingly high amount of some 10% of all DNA in maternal plasma. He showed that fetal DNA was rapidly cleared from maternal plasma after delivery and that fetal DNA circulated in a highly fragmented form. The fetal DNA concentration increased with pregnancy associated complications such as preeclampsia and preterm labour. He was the first to show the existence of fetal RNA and fetal epigenetic markers in maternal plasma.

Determined to reach the Holy Grail in non-invasive prenatal diagnosis, Professor LO and his team set an ambitious goal to develop approaches for the direct detection of fetal Down syndrome through maternal plasma DNA analysis that could be applied to all pregnancies. In 2007, Professor LO was the first to use single molecule counting techniques to measure the increase in maternal plasma chromosome 21 content that is associated with fetal Down syndrome. In 2008, the team adopted the use of next-generation sequencing for the non-invasive detection of Down syndrome. This protocol was subsequently confirmed by large-scale validation studies from multiple research groups that it offered 99% sensitivity and specificity for Down syndrome detection. The team further refined the protocol to also achieve accurate detection of trisomy 18 and trisomy 13. Due to the high accuracy and robustness of the protocol, the test became available as a clinical service in end of 2011. The launch of the service was shortly met by a rapid surge in clinical demand. In December 2012, the American College of Obstetricians and Gynecologists published a set of recommendations supporting the use of the cell-free fetal DNA non-invasive test as a screening test for trisomy 21, trisomy 18 and trisomy 13 among pregnancies deemed to be at high risk for these aneuploidies. Similar recommendations have since been issued by the American College of Medical Geneticists and the International Society of Prenatal Diagnosis.

To date, the cell-free fetal DNA non-invasive prenatal screening test is available in more than 15 countries around the world. Because the test has a false-positive rate < 0.5%, which is 10 times lower than the conventional aneuploidy screening tests, the number of pregnancies undergoing invasive prenatal diagnostic procedures is predicted to reduce substantially. A paradigm shift in the practice of prenatal diagnosis has been set. Yet, one is just witnessing the beginning of an era of non-invasive prenatal diagnostics. The profile of non-invasive prenatal diagnostic tests is destined to expand because more recently, Professor LO’s team has achieved the direct assessment of the fetal molecular karyotype, the assembly of the fetal genome, the detection of single gene diseases and the determination of twin zygosity; all through the analysis of cell-free DNA in maternal plasma.

For these seminal discoveries, Professor LO was awarded the 2002 Avadesh Saran Memorial Oration Award; 2005 State Natural Science Award of the People’s Republic of China in 2005; 2006 International Federation of Clinical Chemistry and Laboratory Medicine Abbott Award for Outstanding Contribution to Molecular Diagnostics; 2006 U.S. National Academy of Clinical Biochemistry, Distinguished Scientist Award; 2006 Cheung Kong Scholars Achievement Award, Ministry of Education, China; 2009 Fulbright Distinguished Scholar Award; 2012 American Association of Clinical Chemistry Outstanding Contributions to Clinical Chemistry in a Selected Area of Research and 2013 World Academy of Sciences Ernesto Illy Trieste Science Prize award.

Professor LO is a Fellow of the Royal College of Physicians (Edinburgh), Royal College of Physicians (London), Royal College of Pathologists and Honorary Fellow of the Hong Kong College of Pathologists. To top this list of distinguished accolades, in 2012 Professor LO was made a Fellow of the Royal Society, the world’s oldest learned society dating from 1660; and just two months ago, Professor Lo became a Fellow of the National Academy of Sciences of the USA. Fellow and guests, I hereby present to you our Honorary Fellow of the Hong Kong College of Obstetricians and Gynaecologists, Professor Yuk Ming Dennis LO.

Profess LEUNG Tak Yeung
at the conferment ceremony in 2013