Yuk-Ming Dennis Lo arrived in Cambridge, England, in October 1983, on the brink of one of the coldest winters in British history. Traveling with more luggage than he could carry, the 20-year-old took a taxi from the coach station to nearby Emmanuel College, which would be his home during his three undergraduate years at Cambridge University. Within weeks, the spires and towers of the ancient university town were covered in snow. Walking through the bitter, blustery streets to class was a trial for Lo, who was born and raised in sultry Hong Kong. Inside the lecture halls, he faced another challenge. He had been learning English since he was four, but his professors and classmates spoke so fast and with such a dizzying array of accents that they created their own kind of blizzard.
Then there were the tutorials, which happened three to five times a week, each lasting 60 minutes. “That's one hour when you have to face a very clever professor,” said Lo, professor of chemical pathology, Li Ka Shing Professor of Medicine, and director of the Li Ka Shing Institute at the Chinese University of Hong Kong. One day, early on, his professor asked Lo a question. Lo gave a technical answer, drawn from his textbook. His professor shot back: how do you know that? “At the time, I felt that was a strange question, so I told him, ‘The book said that,'” said Lo. “What he meant was, ‘How do you know the book is correct? What is the experimental evidence?'”
That tutorial marked a turning point for Lo. He would take his professor's lesson—doubt dogma, revere data—to heart, nurture it, and develop it into a credo and a passion. In 1987, as a 24-year-old medical student, he had the idea that fetal cells might be mingling in with the mother's blood—an impossibility if one believed the prevailing doctrine that the fetal and maternal circulatory systems are separate. He found the cells and would spend the next 10 years looking for a way to turn his findings into a simple blood test that could be used to noninvasively detect fetal abnormalities such as Down syndrome and β-thalassemia.
In 1997, after an exhaustive and frustrating search, he had another paradigm-shaking inspiration—could the fetus be shedding DNA directly into the maternal plasma? Within weeks, he and his coworkers found the fetal genetic fragments and would spend another 10 years developing this breakthrough into a clinical test. In 2007, he and his colleagues showed that the test could successfully detect trisomy 21—the marker for Down syndrome—in the plasma of pregnant women.
“That is truly the holy grail in our field,” said Cees Oudejans, head of the molecular biology laboratory in the department of clinical chemistry at VU University Medical Center in Amsterdam. When asked about the secret to Lo's success, colleagues cite his creativity and ability to think outside the box. “He's what I call a lateral thinker,” Oudejans said.
“He's very good at combining concepts across fields. He will get an inspiration just by watching movies,” said Rossa Chiu, professor in the department of chemical pathology at the Chinese University of Hong Kong. Recently Lo, working with Chiu, and colleagues, set out to map an entire fetal genome using maternal plasma. It was a hugely challenging undertaking, involving the sequencing and assembling of billions of DNA fragments. Lo had the idea for how to do it while watching the first few minutes of a Harry Potter movie.
His motto is to see the world with one's own eyes, but the truth is Lo sees things that are not apparent to others. It's an ability that hints at a rich interior life. It might be tempting to call it “intuition”—a deep insight into the nature of things. “His way of thinking is very complex. In one sense he does have a lot of insight. But if he just relies on insight, then he cannot make breakthroughs. The reason I believe he makes breakthroughs is because he remains open-minded forever,” said Chiu. Rather than sit and mull over a hypothesis or idea, Lo needs to share it, bounce it around, and challenge it—immediately.
“No matter what time it is, what day of the week it is, he will call and we will discuss it on the phone. He has to think out loud. It's his habit,” said Chiu. “If the evidence doesn't fit the hypothesis, we change the hypothesis completely—a 180 degree change. This process keeps going and going until every single piece of data fits in. This is why we manage to do things that other people don't do. We don't stay within a particular box.”
To the outside world, and even to colleagues, Lo—with his finely drawn features, erect posture, and genteel manner—can appear reserved. Where he truly relaxes and comes to life is in the lab and in lab meetings. “I think science is his core passion,” said Chiu. “When he comes to discuss science, he completely loosens up. He knows whom he can talk to about his ideas and his science. He likes that interaction with those of us he describes as having the same wavelength in thinking.”
Combine all that with his reputation for holding extremely high standards, and he might be confused for one of the brilliant professors he encountered in those 60-minute tutorials years ago in Cambridge.
The fact is, the lessons he learned there were taking root years before in the subtropical peninsula of Kowloon, where Lo was raised. His father came to Hong Kong in 1946, and rose to become a successful psychiatrist. Like many Chinese fathers, he was strict, and his work kept him busy. But he nurtured talents in Lo and his younger brother. He encouraged Lo to draw, which he saw as good preparation for a medical career. “He always would say that a picture is worth a thousand words,” Lo said. He would practice scientific talks in front of his sons, and even asked Lo, who had developed an avid interest in photography, to help him prepare slides. “I had to type out each slide and photograph it,” Lo said.
His mother was the softer of the two. An accomplished pianist and singer, she taught music in school. She taught her sons piano, though Lo's brother was the more willing, and better, musician. Lo's musical ambivalence was the flip side of what would later attract him to science. “I like to solve problems my own way,” he said. “Learning piano, I was actually quite bored. If you asked me to devise a style to play, then maybe I'd be more interested.”
Hugely curious as a kid, and with an insatiable appetite for information, he loved reading magazines. National Geographic, Scientific American, Discover—he would pore through them, finding outstanding problems in such fields as computer science and devising his own solutions that, to his delight, sometimes matched those of the experts. It was not something he shared with his teachers—it was the late 70s, early 80s, before desktop computers became popular, so not many would've been able to recognize his accomplishment. “It was something I did alone, for fun,” he said.
Lo came to the attention of his teachers for other reasons. Active as a very young boy, and schooled under a British system that did not “spare the rod,” he remembers a couple of situations where he was on the “wrong end of the stick.” By his fifth year, he had turned things around. He passed a highly competitive exam and was promoted to the secondary section of a highly competitive all-boy's school, St. Joseph's College. One day, while reading his biology textbook, he came across a picture of James Watson and Francis Crick, standing in front of King's College Chapel, Cambridge. He was captivated by Cambridge, as well as by the scientists.
At Cambridge, he would follow a fast track, completing his course work in preclinical medicine in two years, and devoting the third to research on genetic cloning. For his clinical training, Lo chose Oxford where, in his spare time, he began working in two professors' laboratories. He heard about the work of a young researcher, John Bell, who was giving a talk on a new technique, polymerase chain reaction (PCR). “In his lecture he said this was going to change the world,” said Lo. “I asked him to teach me PCR.” Lo would be among the first to learn the new technique.
It was 1987. PCR was starting to generate a buzz, but it was relatively untested. Indeed, Lo and a classmate were finding lots of false positives, due to contamination. They published their results in a letter to The Lancet. “Many senior people laughed at us. They thought we weren't skillful,” he said. It turned out, the problems were real—lots of people were having them.
Lo would soon come up with another “laughable” proposition: that fetal cells might be detected in the mother's blood. He was casting around for a way to test his hypothesis when, one evening, he had dinner with a friend. The pair were talking about having children—the pros and cons of girls versus boys. Suddenly, Lo had an idea: if a woman is carrying a male fetus, she should have Y-chromosome–bearing cells in her blood. He decided to use PCR to detect the cells. It worked. Lo published the results in The Lancet in 1989.
In 1990, excited by his research and its potential, and with his clinical training complete, Lo decided to do a DPhil, Oxford's equivalent of a PhD. He wanted to develop the fetal cell work into a clinical test but was thwarted by a vexing combination—too few fetal cells, too many false positives. “We couldn't do it reliably. Many others tried and they couldn't do it,” he said. “It was very frustrating.”
As he was finishing up his thesis, a friend introduced him to a young woman from Hong Kong named Alice. She was working on her doctorate at Oxford in the male-dominated field of semiconductor physics. “That caught my eye,” Lo said. The friend would be best man at Lo and Alice's wedding. In fact, the three of them would publish a scientific article together. To this day, Lo shares his work with his wife. “I find that talking with her will bring a new perspective, a new clarity,” said Lo.
They shared another thing, back then in Oxford. “Our hearts were in Hong Kong—we wanted to go back,” said Lo. In 1997, Hong Kong was going to be returned to Chinese rule. Skilled professionals, including academics, were leaving, and desirable posts were opening up. Swimming against the tide, Lo and Alice accepted positions back home. Lo's job as senior lecturer in the department of chemical pathology at the Chinese University of Hong Kong was to begin in January of 1997.
The summer before was an uneasy one. Lo had continued his search for a fetal cell assay but it had not been going well. “I knew most likely I'd have to start a new research direction,” he said. Then, in September, he came across two papers describing the presence of tumor DNA in the blood plasma of cancer patients. “I thought, a tumor living inside a patient is a little bit similar to a fetus living inside a mother. If cancer can release enough DNA in the blood plasma for the DNA to be detected then surely an eight pound fetus could release enough DNA for it to be detected,” Lo said.
Knowing that such a radical proposition would need to be easily replicated, Lo hit upon a distinctly low-tech method to test his hypothesis. To purify the DNA—he simply boiled the plasma of women with male fetuses. He then used PCR to identify fragments of the Y chromosome. In a matter of weeks, he had results. “I saw the gel close to midnight. I almost could not believe my eyes—the signal was so convincing. I could not believe that those things which we'd been looking for all those years were actually there in the cell free faction,” he said.
Lo and his wife moved back to Hong Kong in January of 1997. Meanwhile, news of his accomplishment was spreading. “A lot of people were excited but they didn't think it could be used for Down's syndrome,” said Lo. He would pursue the Down's grail relentlessly for nearly 10 years, among other projects, including cancer research. Their work was interrupted only in March 2003 when severe acute respiratory syndrome (SARS) hit China. Lo and his team dropped everything and worked around the clock to sequence the SARS virus. It took 13 days.
Dogged pursuit is one of Lo's defining characteristics. “If he identifies a problem, no matter if it's a big problem or a minor hitch in our data or experiment, he will not let it go. In this regard he's very stubborn. He needs to hold on to that problem and repeatedly think about why that problem occurred and how we can solve that problem,” Chiu said.
Lo's mind is constantly working, always seeking—which could help explain his most recent imaginative leap. In 2008, he had the idea to sequence the entire human fetal genome—a task that he compares to solving two jigsaw puzzles mixed together, one comprising the fetus's genome and the other the mother's, each with millions of pieces—but struggled to find a way to do it. One day, during the summer of 2009, he and Alice went to see Harry Potter and the Half-Blood Prince in 3D. As they donned their glasses, Lo saw the Harry Potter logo flying towards them. “Suddenly, in 3D the H looked to me like two homologous chromosomes,” Lo said. He realized that to solve the fetal genome problem, he and his colleagues needed to tackle the paternal and maternal halves of the fetal inheritance separately. For the paternal half, they needed to look for snippets of DNA found only in the father, and not the mother. For the maternal half, they needed to very precisely count the bits of DNA from the mother. Those that had been inherited by the fetus would be present in excess in maternal plasma. “I still don't know what would've happened if I didn't see that movie,” he said.
The chance of that was low. Lo loves movies and manages to see many new releases. He has a 3D movie projector in his apartment, which is located in the bustling city of Kowloon, across from a green cricket field. He wakes at 8 am and grabs a bowl of corn flakes, and is out the door 15 minutes later. He makes his way to his office that, with its overflowing piles of articles and books, looks as though it were hit by a tidal wave of paper. “I'm the sort of scientist who has a messy desk. It's my style of working,” he said.
After a day of meetings and brainstorming sessions, he is home by 7 pm for dinner with Alice. He is back to work a few hours later. Lo needs to be in a particular mood to write and do other serious work, and the mood is most likely to strike in the hours before and just after midnight. On weekends he likes to golf, often with his wife. In Alice, Lo seems to have met a perfect match. “They stick to each other like glue,” Chiu said. Vivacious and warm in demeanor, she shares Lo's passion for science, his sense of adventure, and love of travel. “Even on their holidays they do the things that somebody else normally doesn't do,” said Oudejans, who has received photos of them diving and snorkeling in the Great Barrier Reef and air ballooning in Turkey.
Lo recently traveled to England, where he was made a Fellow of the Royal Society. The proceedings lasted three days during which each new fellow had to give a talk. On the final day, a huge charter book, dating back to the 1660s, was ceremoniously brought out. “All the previous fellows, like Darwin, Newton, Einstein—they all had their signatures in there. We had to sign in this historical text with a quill pen. A quill pen is exceedingly difficult to use. I wanted to sign my name in both Chinese and English. The quill pen obviously wasn't designed for Chinese,” he said. Apparently, he was not the only eminent scientist to be stymied. “I could see some of my other fellows actually had drops of ink by their names,” he said.
Sponsored by the Department of Laboratory Medicine, Children's Hospital Boston
- © 2012 The American Association for Clinical Chemistry