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Non-Invasive Prenatal Testing

Professor Dennis Yuk Ming Lo –
Bringing revolutionary diagnostic technology to the world inspired by daily life
Using non-invasive prenatal testing to detect genetic and chromosomal disorders in babies

In the past, pregnant women may need to receive amniocentesis (taking amniotic fluid from the womb) to test the risk of fetal Down’s syndrome and other fetal genetic diseasese, which may lead to fetal injury or miscarriages. Professor Dennis Yuk Ming Lo, Associate Dean (Research), Faculty of Medicine of the Chinese University, achieved a breakthrough in prenatal examination technology with his research published in 1997. He found high concentrations of fetal DNA in the plasma of pregnant women and subsequently invented non-invasive prenatal testing (NIPT).

NIPT can examine the possibility of fetal Down syndrome and genetic diseases by analysing blood samples taken from pregnant women. Since its introduction to clinical practice in 2011, NIPT has been adopted by more than 90 countries and helped more than 10 million pregnant women every year.

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Research Journey - University of Oxford

The story of Lo’s research journey began in 1989.

At that time, he was studying medicine at Oxford University and did a clinical rotation in the obstetrics and gynaecology department. As a result, he had a chance to learn about invasive prenatal examination e.g. amniocentesis. Under ultrasound guidance, doctors insert a needle through the abdomen of a pregnant mother to extract amniotic fluid from the uterus for testing. However, this method may cause fetal injury or a miscarriage.

It prompted a question in his mind: Is there a safer way to check whether the fetus is normal?

Do you know what is the typical time when a pregnant women can undergo amniocentesis?

• 8-10 weeks into pregnancy
• 12-14 weeks into pregnancy
• 16-18 weeks into pregnancy
• 20-22 weeks into pregnancy

Check out the answer on the next page!

Typically, amniocentesis is performed during the 16th to 18th week of pregnancy and pregnant women have to wait for the test result for a period of time. Moreover, amniocentesis has a 0.5-1% chance of causing fetal injury or miscarriage. The process causes adverse mental effects on pregnant women and their families.

Lo suddenly hit upon a wild idea: If the fetus is a boy then the blood of pregnant women should contain male chromosomes. If a male chromosome is detected in pregnant women then the chromosome must have come from the fetus.

As a medical student, he discussed the idea with professors and fellow students but many thought it would not succeed. Fortunately, a doctor allowed him to carry out the research in his laboratory. As a result, he detected fetal DNA in the blood cells of pregnant women from which the sex of the baby can be inferred.

Although fetal cells were found in the blood of pregnant women, it was not possible to detect whether the fetus was normal since there were too few fetal cells. Hence, a safe and reliable method to test the fetus was still not available.

After graduating from Oxford University, Lo became a houseman. However, the research was always in his mind. He had a sense of mission that he should complete the study as he had started this. After working as a doctor for a year, he returned to Oxford University to pursue a doctorate and engaged in full-time research. However, the road of scientific research had not been smooth. He spent eight years and countless hours on his research but to no avail.

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Research Journey – Returning to Hong Kong

Many of Lo’s researches were inspired by daily life. Do you know which of the following moments ensured a significant breakthrough to his research?

• Taking a shower
• Photography
• Cooking instant noodles
• Sleeping
Answer will be revealed in the next page!

This long exploration lasted until the summer of 1996. As there was no breakthrough in the research, he nearly gave up and went a different direction.

That summer, however, things took a turn for the better.

At that time, he read two medical articles pointing out that tumour genes could be detected in the plasma of cancer patients. He let his scientific mind ponder on the finding: given how both the fetus and the tumour relied on the nutrition from mother/patient for survival, surely they must share something in common?

He decided to study the plasma. However, how can one extract fetal genes from a pregnant women’s plasma for testing? Given that he did not have research funding, he could only use low-cost methods.

Lo loves Asian food. One day, he cooked instant noodles in his home in England. When he saw the steam, he stumbled upon an idea: what would happen if a pregnant woman’s plasma was boiled and then tested?

The method sounded crude and unscientific but he still gave it a try.

He went back to the laboratory, where the plasma from a pregnant woman was boiled and then a few drops were tested. He couldn’t believe his eyes - more than a tenth of the pregnant women’s plasma was fetal DNA, the concentration of which was 100,000 times stronger than what could be found in blood cells!

When examining blood cells, the first thing one does is to remove and throw away plasma. It turned out that he had been looking in the wrong place for the past eight years.

The result was simply unbelievable.

In early 1997, he returned to Hong Kong and started teaching at The Chinese University of Hong Kong. He also published the research paper, “Presence of fetal DNA in maternal plasma and serum”, and invented non-invasive prenatal testing (NIPT). Only the maternal blood would be required to test the sex of the fetus and it can also help identify whether a given fetus has Down syndrome by testing chromosome 21 of the fetal DNA.

After three years of trials, this ground-breaking technology was introduced to clinical practice in 2011. The accuracy rate of this technology is as high as 99.7%. It can also eliminate the risk of fetal injury or miscarriage.

Lo is now fondly referred as “the father of non-invasive prenatal testing” around the world and is regarded as a scientist from Hong Kong with the potential to win major international prizes in science.

The success of the research did not stop Lo from exploring further . He hoped to take the research to a new level: Would it be possible to draw a complete genome map of the fetal DNA from a pregnant woman’s plasma?

Once again, he was inspired from daily life and managed to successfully solve the problem. Can you guess what inspired him?

• Watching a 3D movie
• Going on an amusement park ride
• Photography
• Scuba diving

Check out the answer on the next page!

In order to further expand the application of the research, Lo hoped to draw a complete genome map of the fetus. He had been trying to come up with a formula to solve the problem but he struggled.

Unexpectedly, a Harry Potter movie helped him capture the magic needed to solve the problem!

In 2009, when Lo and his wife were watching a 3D version of one of the Harry Potter movies, he was struck by the letter H that floated in front of him on the screen, the shape of which looked like a pair of chromosomes. Since the two chromosomes of the fetus came separately from the father and the mother, he realised that two equations should be used to analyse the two chromosomes instead of one equation.

As a result, he achieved another significant breakthrough. In 2010, his team produced the first complete genetic map of a fetus in maternal plasma. By extracting blood from pregnant women, any fetus with a single gene disease can now be detected.

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Non-invasive prenatal testing has brought revolutionary development in the prenatal diagnosis of pregnant women, benefiting the public and has a far-reaching influence. Here are some of the applications and commendations received by this technology.

Click on the following to find out more:

Clinical application

The non-invasive prenatal testing for fetal Down syndrome was successfully introduced for clinical application in 2011, with an accuracy rate of 99.7%. Pregnant women can have a non-invasive, safe and accurate prenatal examination in the early stage of pregnancy (e.g. 10 weeks).

Cancer test

The research team has successfully applied DNA sequencing technology to cancer detection. More than 50 kinds of cancer can be detected with only one blood sample. This technology has been launched in the USA in the middle of 2021.

Widely used

More than 90 countries and regions provide non-invasive prenatal testing services and more than 10 million pregnant women worldwide use this technology every year. This technology has been endorsed by multiple international professional associations.

Market value

The global market for NIPT has been estimated to be approximately US$4 billion in 2019.

Contribution to Hong Kong

In 2019, the research team provided the technology for free to the Hospital Authority so that pregnant women in needs can have unobstructed access to this technology.

Top international awards

Through this work, Professor Dennis Lo has received numerous awards, including his election as a Fellow of the Royal Society (2011), his election as a Foreign Associate of the US National Academy of Sciences (2013), a Thomson-Reuters Citation Laureate in Chemistry (2016) (well-known as a metric for predicting future Nobel Prize winners),and he was awarded the inaugural Future Science Prize (2017) (regarded as the equivalent of a Nobel Prize in China) as well as the Breakthrough Prize in Life Sciences (2021)(known as the “Oscar of Science”). He was named the world’s “Top 20 Translational Researchers” for consecutive years. Furthermore, Professor Lo is the first Chinese Scientist ever to receive the Royal Medal for Outstanding Achievements in biological sciences category. The Royal Medal is one of the most prestigious awards of the Royal Society. Two Royal Medals are awarded annually for the most important contributions to the advancement of "natural knowledge” in the physical and biological sciences, respectively. There are 400-some awardees in history, including Charles Darwin who proposed the theory of evolution and John Dalton who developed the atomic theory.

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The spirit of a scientist

Any scientific research journey is full of obstacles. Scientists take years of persistence to succeed, and the efforts may not be rewarded.
Professor Dennis Lo is not afraid of failure and has fully devoted his time to research. Here are some of his beliefs that support him on the road of research.
Let’s learn about his spirit as a scientist!

LEAVE NO STONE UNTURNED

Professor Dennis Lo looks over every piece of evidence, searching carefully to see if it may point to any solution of problems. He believes scientists should spare no effort to solve the puzzles one by one. Otherwise, we may overlook treasures.

The fascinating scientific research

Science is all about the search for eternal truth and can be just like discovering previously unseen natural beauty for the first time during a trip. The process of research is not necessarily intrinsic rewarding but when you discover or invent something that can help others in the long run, the satisfaction goes beyond conventional clinical work.

Find out what is not obvious

Don’t ignore the “non-obvious” things in the research process. Many people have studied the obvious stuff. For example, people thought genes could only be found in blood cells but the NIPT technology showed that it can also be discovered in other places. In addition, some fields seem unrelated to each other, such as fetal testing and cancer. However, if we can spot the hidden link, knowledge from one area can be applied to another.

Pursue research as a hobby

Professor Dennis Lo once said that scientific research is not a job but a hobby for him. Therefore, success or failure is not the most important thing for him. He simply enjoys the process of research.

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