Profile of Dennis Lo

After 22 years of persistent research, Dennis Lo succeeded in decoding a fetal genetic blueprint found within maternal blood. The advance is already saving lives by allowing pregnant women to be noninvasively screened for genetic abnormalities in fetuses they carry. For this achievement and many others, Lo was elected in 2013 as a Foreign Associate of the National Academy of Sciences. He directs the Li Ka Shing Institute of Health Sciences at the Chinese University of Hong Kong, where he also serves as a professor of medicine and chemical pathology.

Dennis Lo. Image courtesy of Michael Perini.

Childhood in Hong Kong

Lo’s interest in science dates back to his childhood in Kowloon, Hong Kong. His mother, a music teacher, and his father, a successful psychiatrist, introduced Lo to colorfully illustrated books on nature and biology. Lo says, “Those years of reading about science had me excited as an observer and had triggered my desire to become one day involved first hand in scientific discoveries.”

During his sixth year of grammar school, Lo passed a competitive examination and was promoted to the secondary section of the prestigious St. Joseph’s College in Hong Kong. A biology teacher at the school, Stephen Hui, was an early mentor. “He was the one who first taught me about the molecule DNA and about the then-new science of recombinant DNA technology,” Lo says. In Hui’s class, he recalls seeing a biology textbook photograph of scientists James Watson and Francis Crick standing in front of King’s College Chapel at the University of Cambridge. Lo says, “This had planted a seed inside me that would eventually lead to my studying medicine in Cambridge.”

Cambridge and Oxford

Lo followed a fast track at Cambridge, completing his course work in preclinical medicine in two years, instead of the usual three. The third year was devoted to research on genetic cloning. He then transferred to Oxford University to continue his clinical training. During Lo’s first year as a clinical student, he attended a lecture by John Bell, now Regius Professor of Medicine at Oxford. Bell talked about a then-new research technique called PCR. Lo asked Bell to teach him the essentials of PCR, a technology that helps amplify DNA, generating thousands to millions of copies of a desired DNA sequence for further analysis. For months afterward in 1987 and 1988, Lo and fellow medical student Wajahat Mehal performed PCR in the laboratory of pathologist Kenneth Fleming, resulting in Lo’s first published works: “False-positive results and the PCR” (1) and “Rapid production of vector-free biotinylated probes using the polymerase chain reaction” (2).

Mastering PCR enabled Lo to detect rare target DNA sequences. “My clinical curriculum had given me a general idea about the invasive and potentially risky nature of conventional prenatal diagnostic procedures, such as amniocentesis,” he says. “I thought that it would be an interesting idea to use the PCR to detect fetal nucleated cells that might have entered into the maternal circulation.” With this as an early goal, Lo decided to pursue a doctorate at Oxford. During this time, he met his wife, Alice, who was also from Hong Kong and working on her doctorate at Oxford in semiconductor physics.

Advances in Prenatal Testing

Lo and his wife moved back to Hong Kong in early 1997, a historic year for the city because it was returned to Chinese rule after years of British colonial governance. Many professionals left Hong Kong, opening up desirable posts. Lo accepted a position as senior lecturer in the Department of Chemical Pathology at the Chinese University of Hong Kong, the move facilitated by Magnus Hjelm, chairman of the department. Hjelm supported Lo’s efforts to develop quantitative PCR assays for measuring concentrations of fetal DNA in maternal plasma.

Before the move, Lo read two articles in Nature Medicine concerning the detection of tumor-derived genetic alterations in the plasma and serum of patients with cancer (3, 4). “I thought that a cancer growing inside a cancer patient was somewhat similar to a fetus growing inside its mother,” Lo says. “Furthermore, in my clinical experience, I had yet to see a tumor that was as big as an 8-lb baby! Thus, I and my long-time collaborator, James Wainscoat, thought that if tumor DNA could be detected in the plasma of a cancer patient, then there should be a good chance that fetal DNA would be detectable in the plasma of a pregnant woman.”

At first, he and his coworkers puzzled over how best to extract fetal DNA from maternal plasma. “In the end, we had chosen what was possibly the simplest method: boiling the plasma samples,” Lo says. “Surprisingly, even with such a crude sample preparation method, we were able to detect male fetal DNA sequences from just 10 μL of maternal plasma.” This was the first time that cell-free fetal DNA had been detected in maternal plasma (5). The following year, 1998, Lo and others (6) showed that cell-free fetal DNA is present in high concentrations in maternal plasma and serum. Plasma has since become a preferred material for noninvasive prenatal testing.

Focus on Fetal Disorders and SARS

Lo and his team next applied their plasma analysis methods to determining fetal rhesus D (RhD) status. RhD is a blood group protein that can cause Rh disease, which is usually treatable if diagnosed during pregnancy or promptly after childbirth. Lo and his coworkers (7) determined that fetal RhD status can be detected in the plasma of RhD-negative pregnant women. The approach is now in clinical use in many countries, such as the United States, the United Kingdom, Denmark, the Netherlands, and Sweden.

Lo has spent most of the past two decades working in the field of noninvasive prenatal testing. One exception arrived in the form of the severe acute respiratory syndrome (SARS) epidemic of 2003. “One of the first “superspreaders” in Hong Kong was admitted to our hospital and had spread the disease to many staff members, medical students, and the public,” Lo explains. During this period, Lo’s group was among the first to sequence the SARS-coronavirus and to work on the molecular epidemiology of the virus.

Returning to prenatal research, Lo and his team demonstrated that concentrations of cell-free fetal DNA in maternal plasma were increased in the plasma of pregnant women carrying a fetus with Down syndrome. The difference was not always detectable, however, complicating efforts to create a reliable test. For nearly a decade, the researchers tried various ways of improving the process before finally settling on a technique known as massively parallel sequencing (8). Using the technology, Lo and his colleagues tested blood samples from 753 pregnant women and found that 86 carried a fetus with Down syndrome. This large-scale validation of massively parallel sequencing (9) led to a diagnostic blood test for Down syndrome that has since been performed on more than 300,000 pregnant women in more than 15 countries.

Sequencing the Fetal Genome from Maternal Plasma

Lo’s inspiration often comes from surprising sources. In the summer of 2009, he and his wife watched the movie Harry Potter and the Half-Blood Prince in IMAX 3D. For months earlier, he had been trying to find a way to sequence the entire human fetal genome using maternal blood. As the Harry Potter logo flew toward Lo, he experienced an “aha” moment. The “H,” says Lo, reminded him of two homologous chromosomes, and he realized at once that he would need to address the maternal and paternal halves of fetal inheritance separately. The idea and subsequent research led to a widely publicized paper in Science Translational Medicine (10). Lo says, “It describes how one could deduce the fetal genome using a combination of genotype data from the father and haplotype information from the mother.”

More recently, Lo and his colleagues (11) have pushed beyond fetal genome sequencing and into the realm of fetal epigenome analysis. Epigenetics is the study of changes in gene expression or other biological processes caused by mechanisms other than changes in the underlying DNA sequence. Because epigenetic mechanisms are involved in a variety of developmental and pathological processes, the ability to explore them noninvasively via maternal plasma opens up new research and diagnostic applications.

Detecting Cancer in Blood

Lo is currently working on developing a plasma DNA-based test that can be used to detect different types of cancer. In late 2012, his team showed how cancer-associated genetic aberrations and variants could be detected in plasma taken from patients with cancer (12). Lo’s Inaugural Article “Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing” (13) reveals how epigenetic and genetic changes associated with cancer can be detected in plasma. Lo says, “We have demonstrated that this approach would work for multiple types of cancer, including liver cancer, breast cancer, lung cancer, nasopharyngeal cancer, smooth muscle sarcoma, and neuroendocrine cancer. Thus, we are optimistic that this approach can potentially be used for virtually all cancer types.” The method can detect these types of cancer with a sensitivity of 87% and a specificity of 88%.

Although Lo continues to research noninvasive prenatal testing methods, half of his current research efforts are devoted to detecting cancer in blood. He explains, “The ability to detect cancer early would help to save lives. One could also use such an approach to guide therapy and for detecting early tumor relapse.”

Lo credits his long-time collaborators, Rossa Chiu, Allen Chan, as well as teachers, colleagues, mentors, and his wife, for much of his continued success. One lesson learned during his university days, he says, still remains fresh in his mind. Lo recalls an anecdote during a first-year undergraduate tutorial at Cambridge with the physiologist Richard Barnes. “I remember that in one of my first tutorials with him, he asked me a question on cardiac physiology. I gave him a textbook answer, but, surprisingly, he was not satisfied and kept asking me how I knew that answer was true. It eventually became clear that what he was asking was what was the scientific evidence for my answer. That tutorial taught me the importance of going back to the primary scientific evidence about what one perceives as scientific truth.”