Cover Story Knowledge Exchange Books Making Babies How Science, Politics and Social Change Affect Human Reproduction The Labour of Giving Birth Birthing in Hong Kong Raising the Odds of Conception The Limits of Artificial Reproduction and Surrogacy Bringing Hope for Congenital Disorders 01 03 05 07 09 11 Research Teaching and Learning Data Wizard Advances Precision Medicine A Saucy Take on History Fast Track to Healthy Teeth Circulation Problem Learning to Play in the Mud Summertime, and the Living Is Deadly Tissue of Lives Turning Tent to Townhouse? Ulaanbaatar’s Ger Sprawl Wake-up Call for Construction 15 17 19 21 23 25 27 29 31 43 45 47 49 Teaching the Science of Heritage Conservation Clarity Comes with the Click of a Mouse Investigating Human Rights Abuses A 360-Degree Take on a Dynamic Hong Kong Community Nourishing the Middle Ground 33 35 37 39 41 Contents The Business of ‘Best before’ Law Scholars Provide Inspiration for Special Needs Trust Student Visions for Coral Reefs and the Blind A Global Voice on Sustainability Policy 51 53 Chinese Art in the Modern Era Journey of Hope
The University of Hong Kong Bulletin | May 2019 01 | 02 The rapid changes in technology and society over the past 40 years are affecting how and whether couples can conceive. HKU researchers have been studying the impact of social and political transformations in China and Hong Kong, and of non-natural births. They are also producing research to improve the odds of conception and to identify and treat congenital diseases, so more babies have a chance of a healthy life. MAKING BABIES Cover Story
China’s transformation into an economic superpower is often framed in terms of production output, technological advancement and infrastructure. What is often missing is another kind of production – that of workers. Dr Gonçalo Santos has been tracing the transformation of birth in China as it moved from the home to the hospital and became increasingly subject to biomedical interventions. THE LABOUR OF GIVING BIRTH It’s not called labour without reason. The effort of pregnancy and giving birth, and then raising children, has been termed ‘reproductive labour’ by social scientists like Dr Gonçalo Santos of the Department of Sociology and Hong Kong Institute for the Humanities and Social Sciences, who is leading a research group on the technologies of reproductive labour in East Asia with colleagues at the University of Chicago and Smith College. “The work of reproductive care doesn’t get the attention of something like the One Belt One Road project. But workers are the foundations of those projects, and as feminists have long noted, in addition to asking questions about workers, we also have to ask questions about the work that is involved in producing workers,” he said. In China, that work has undergone profound changes in a very short time period. As recently as the 1980s, half of all babies were still born at home. Today, most are born in hospitals – and fully one-third by caesarean section (C-section). Dr Santos has been a witness to the transformation, which has been driven by government policy, technology, and changing moral and social dynamics. His work started in the late 1990s, when he undertook fieldwork in rural areas where most people still delivered at home. He saw villagers grapple with the one-child policy, which was also pushing people towards hospital births where it was easier to keep track of numbers. “Women were giving birth in secret places and relying on village midwives. Birth became heavily politicised and people tried to negotiate with the state at various levels over the right way to give birth, where to give birth, whether to follow state prescriptions,” he said. There’s a sense that they want to escape the natural birth experience,” Dr Santos said, “and there is nothing wrong with that.” From zero to 100 in a generation Women are also giving birth at a later age, sometimes with the help of assisted reproduction technology – factors that increase risk and thus lead doctors to advise C-sections. Families have reason not to oppose C-sections, too. Although they must pay for births even in public hospitals, the government subsidises at least half the cost. Dr Santos believes these subsidies will become unsustainable in the long run and, for this reason, the government is curbing the growth in C-section rates through investment in maternal care and punitive measures against hospitals. A ‘wellness culture’ that favours natural birth is also on the rise among the urban middle classes, although not yet to the extent seen in Japan, where it started much earlier. “In China and some East Asian societies, there has been a compressed modernity – a story of emerging economies that went from zero technology in a biomedical sense to benefitting from all these highly-sophisticated technologies within practically the space of one generation. They have leapfrogged without the middle layer and didn’t form a culture of natural birth in the process,” he said. Such a culture is only now starting to take hold under the influence of global discourses of ‘wellness’ and traditional Chinese medical wisdom. Women should have as much choice and information as possible about giving birth, he added – something that scholars can contribute to through research. █ Not strictly a medical issue The state prevailed, marking a dramatic shift in how babies were born and who was involved in the process. Birth was no longer managed by local networks of midwives and female relatives, but shifted to hospitals and biomedical professionals, including obstetricians who, until the past decade or so, were mostly men. “However, birth is not strictly a technical, medical issue. It should be seen from a holistic perspective that allows for the social and cultural dimensions to be taken into consideration, too,” Dr Santos said. These dimensions are evident in China’s high caesarean rate of at least 35 per cent of all births, one of the highest in the world. Doctors and hospitals, pregnant women and their families each have their own reasons for favouring C-sections. (And note: all three are involved in providing informed consent for birthing procedures in China – it is not just a matter between a woman and her doctor.) Hospitals are more likely to favour C-sections because they are more profitable and can be planned – an important consideration given many hospitals are understaffed. Doctors are more likely to favour them because their training is in handling complications and applying the techniques they learn, rather than waiting out the unpredictability of a natural birth. Many women regard C-sections as easier than natural delivery. Their mothers and grandmothers were better prepared for the physical trials of labour because they often engaged in hard physical work, but people today live more sedentary lives, particularly in urban areas. “For most women working in the new China, reproduction is a chore and it’s often perceived as a burden – as something to be afraid of. For most women working in the new China, reproduction is a chore and it’s often perceived as a burden – as something to be afraid of. Dr Gonçalo Santos The University of Hong Kong Bulletin | May 2019 Cover Story 03 | 04
The more things change, the more they remain the same, as Dr Carol Tsang of the Department of History has discovered. Her area of research is women’s health and reproduction in Hong Kong and China, and her female students and acquaintances keep reminding her that while they have plenty of opportunities in career and education, in the home, not much has changed. “I have met a lot of women from different walks of life who feel the social expectations of marriage and motherhood limit their capacity. They feel pressured to get married by a certain age and to have children, especially a male heir. And after having children and marriage, they feel their careers stall. These social expectations haven’t changed much over the decades,” she said, as her 15 years of research has shown. Dr Tsang’s first major project was a history of the Family Planning Association of Hong Kong (FPAHK), an organisation founded in 1950 to promote birth control to ordinary Chinese families in the context of traditional values. The Government wanted to contain population growth and the FPAHK supported that goal through promotions such as the ‘Two is Enough’ campaign featuring a smiling family with just two children – the message being that birth control was a path to a cordial family life. “What interested me was how the FPAHK and the Government used Chinese family values to promote birth control. This was totally different from Europe and America where birth control was tied closely with the women’s movement and sexual liberation. In Hong Kong, it was about Chinese values and being an ideal Chinese nuclear family,” she said. Colourful debate Birth control was a more contentious topic in the pre-war era. American Margaret Sanger, an activist for birth control who was popular in China, was invited to Hong Kong in 1936, where she gave a talk on such methods as sterilisation Colonialism and modernisation have both brought changes to reproduction and birth control practices in Hong Kong. But some attitudes are proving to be immutable. What interested me was how the Family Planning Association of Hong Kong and the Government used Chinese family values to promote birth control. This was totally different from Europe and America where birth control was tied closely with the women’s movement and sexual liberation. Dr Carol Tsang An advertorial portraying a happy family in which the wife gave birth to a son after taking a patented medicine published on Wah Kiu Yat Po in March 1926. and the diaphragm. Non-Catholic Christians welcomed her message because they thought birth control could help ordinary people and deter abortion, but there was strong opposition from Catholics. “It was a very colourful debate. Hong Kong people were pretty split in terms of accepting or rejecting artificial birth control, but at the same time, many were already practising it by taking different patented medicines or visiting Chinese abortionists,” Dr Tsang said. The talk had a lasting effect, though: the FPAHK links its heritage to Sanger’s visit because she inspired the establishment of FPAHK’s predecessor, the Hong Kong Eugenics League. Abortion was an accepted form of birth control within Chinese society, especially in the chaotic period before the Second World War but, as today, it exposed rifts in society. The Government was keen to curtail abortionists, many of whom came from Mainland China and were regarded as charlatans by officials, and it wanted to establish the legitimacy of Western midwifery. “A lot of hidden stories in reproduction show clashes between Western and Chinese practitioners,” Dr Tsang said. Women’s voices in these debates were often muted. In the first half of the 20th century, for instance, there were numerous newspaper articles and advertisements on women’s fertility, but they were written with male readers in mind as most women were illiterate. Same discourses today “Some of the advertisements were presented as stories. There was one that featured a man who didn’t have a male heir, but after buying a patented medicine for his wife, she gave birth to a son. Their success and happiness were said to be due to this medicine,” she said. She sees echoes of that thinking today in television commercials for medicines to restore health that are set against images of a happy family. “It surprises me that 100 years on, we still use the same discourses to market these things. It may be repackaged as modern science today, but in the early 20th century it was also packaged as science.” Dr Tsang brings these insights to the classroom, too, where she teaches the global history of reproduction and birth control and Common Core courses on women’s roles across time and culture, motherhood in China, and masculinity studies. The latter includes discussions on the role of men in the history of gender, reproduction and birth, an area that has been neglected in much scholarship and which will be a focus of her research moving forward. In the meantime, Dr Tsang has a more pressing and pertinent task, having recently given birth to her first child, a girl. “People ask me if it’s a first child and when I tell them it’s a girl, they ask, so do you want a boy for the second child? It’s affirming what I read in history,” she said. █ BIRTHING IN HONG KONG Cover Story 05 | 06 05 | 06 Posters promoting birth control and family planning by the Family Planning Association of Hong Kong from the 1950s to 2010s. The University of Hong Kong Bulletin | May 2019
Moment of conception This work led to Professor Liu identifying signalling pathways involved in activating primordial follicles and developing a new treatment for female infertility called in vitro activation (IVA). So far, the method has resulted in 27 babies being born to infertile women but he said the success rate is still low – one study in Tokyo resulted in two babies from 36 women. Other trials are underway in China, Spain and the US. “Theoretically we are targeting the correct pathway but I believe the right drug has not been found yet. I hope we can do this within the next 10 to 15 years,” he said. Professor Liu recently joined HKU from Umeå University in contraceptive that would block the binding of SLeX on the human egg surface with the sperm,” he said. Services in demand He is also working with large IVF centres in China to collect a large number of semen samples, both normal and pathological, to identify markers that can predict the fertilising ability of sperm before they are used for IVF. This work could potentially also identify the quality of the sperm in terms producing healthy babies. The research on forensic evidence collection has come from an independent study at Stanford University that used Dr Chiu’s finding on SLeX to drastically reduce the time needed to collect sperm for sexual assault cases from eight hours to 80 minutes. The sperm can provide the DNA of male attackers but it must be of very high Sweden and finding the right drug will be the major focus of his research here. Dr Chiu has been studying sperm quality and the actions of the sperm at the moment of conception. For sperm to successfully fertilise an egg, they must bind with the matrix that surrounds the egg which is made up of carbohydrates and proteins. Dr Chiu was the first to identify the carbohydrate chain that mediates the interaction between the sperm and egg, called the sialyl-Lewix X (SLeX) – a finding that has spurred research on male contraception, sperm quality and forensic evidence collection for sexual assault cases. On male contraception, Dr Chiu has collaborated with the University of Georgia in the US to synthesise a glycan that can carry SLeX and bind with sperm. “This molecule has very high affinity with the sperm and we are now looking at whether we can develop it into a male “Better have your baby before you’re 37” is advice that Professor Kui Liu of the Department of Obstetrics and Gynaecology likes to give his students in a light-hearted manner. The line draws a laugh but everyone in the room knows that this statement is no joke. A woman’s eggs start to deteriorate in both quantity and quality at age 37, regardless of her ethnicity. Sperm quality also deteriorates as men age, particularly the quality of the DNA they pass to their offspring, although this process has not been pinned to a particular age. Professor Liu and his colleague, Dr Philip Chiu Chi-ngong, have been researching the problem of egg and sperm quality in human reproduction and their findings offer new insights that point to paths of artificial insemination and other benefits. Professor Liu’s work is focussed on egg quality. He has been looking at the cell-cycle regulation of eggs, in particular the primordial follicles that produce eggs. One problem in infertility is that the ovarian follicles are not big enough and cannot respond to the hormone stimulation provided by in vitro fertilisation (IVF). In fact, IVF usually only results in conception for about 25 to 30 per cent of women. “Our approach has been to look inside the molecular network and, instead of hormones, apply chemicals or drugs downstream at the lower molecular factors and try to trace the growth of a normal egg,” he said. Upon activation from small primordial follicles (left) to primary follicles (right), the transcription factor FOXO3a shuttles from the nuclei of the oocytes (left, green signal) to the cytoplasm of the oocytes (right, green signal). About 10 to 15 per cent of couples have difficulty conceiving babies. Research at HKU on sperm and eggs is aiming to improve their chances of success. RAISING THE ODDS OF CONCEPTION Our approach has been to look inside the molecular network and, instead of hormones, apply chemicals or drugs downstream at the lower molecular factors and try to trace the growth of a normal egg. Professor Kui Liu quality and can become easily contaminated with the existing procedures. Professor Liu and Dr Chiu see growing demand for studies like theirs because couples are starting their families at older ages. In Hong Kong, for instance, the median age of women at first childbirth was 31.4 in 2015, according to the Census and Statistics Department – up from 29.4 in 2001 – meaning half of all women had children older than that age. Leaving pregnancies until later in life will only increase fertility problems. In addition, the change in Mainland China’s one-child policy in 2016 to allow couples to have two children has enticed older couples to try for another child. “Many older women are thinking of having other children and we hope to help them,” Dr Chiu said. █ 07 | 08 The University of Hong Kong Bulletin | May 2019 Cover Story
Infertility becomes a blockage to their life development. They don’t know how to move on because they are childless. Dr Celia Chan Hoi-yan “People have high expectations of ART and they experience psychological impacts during and after the process,” she said. Moreover, IVF is invasive because it involves extracting eggs and implanting embryos in women. Dr Chan’s previous studies have shown that women’s anxiety ahead of IVF treatment can be eased through mind-body relaxation techniques, and their worries after treatment – while they wait to find out if they are pregnant – can be mitigated through self-reflection and better knowledge about the process. She is now looking at grief, a common response for ART users given the low success rate. Some women undergo 10 or even 20 IVF cycles and pay millions of dollars for the service because couples are only entitled to three subsidised cycles in public hospitals. “It can be an emotional rollercoaster of hope and disappointment for couples,” she said. “Infertility becomes a blockage to their life development. They don’t know how to move on because they are childless.” Dr Chan has When the world’s first ‘test-tube’ baby, Louise Brown, was born in 1978, it was heralded as the dawn of a new era for infertile couples. By using donated eggs, sperm and/or surrogates, they could at last become parents. But the new era has not been such a simple matter for many couples, particularly in Hong Kong. For one thing, artificial reproduction technology (ART), such as the in vitro fertilisation (IVF) used to conceive Louise Brown, has a high fail rate of 70 to 75 per cent. For another, only married heterosexual couples in Hong Kong can access ART or surrogates. And if parents opt for a surrogate, they are not allowed to use donated eggs or sperm or pay for the service. All of this takes a heavy emotional toll on couples who are keen to have a baby, says Dr Celia Chan Hoi-yan of the Department of Social Work and Social Administration, who has been studying the impact and provides infertility counselling and psychological assessments. written a booklet on perinatal bereavement for these couples and anyone suffering a miscarriage. Surrogacy and ‘parenthood’ Surrogacy is also complicated for couples. Some women turn to this because they cannot carry babies in their uterus even if they can conceive. Hong Kong technically allows married heterosexual parents to arrange surrogacy for altruistic reasons, but they cannot pay for it even if it is conducted in another country, according to Ms Daisy Cheung of the Faculty of Law, who has written about surrogacy in Hong Kong. Parents who use a surrogate here or abroad must get a parental order within six months of the birth of the child. Until the court issues this, the surrogate mother is recognised as the legal mother and her husband as the legal father. “So even if the genetic material of the baby is yours and your husband’s and you give it to your sister to carry and she has a husband, they would be named as parents in the first place,” Ms Cheung said. Strangely, none of the centres licensed under the Council on Human Reproductive Technology are listed as providing surrogacy services, but there are anecdotal cases of parents using surrogates in Hong Kong. Others have looked abroad, such as Peter Lee Ka-kit, the son of Henderson Land Development Chairman Lee Shau-kee, who reportedly hired a California-based surrogate mother to give birth to his triplet sons. The case was referred to the police but no charges were made. “If commercial surrogacy is carried out abroad, it’s very difficult to enforce because you need clear evidence. There is also an argument that it’s not correct to apply extraterritorial criminality to situations that have a moral component to them – where the society may have different views on the morality of these actions,” she said. Better fertility awareness needed Ms Cheung also noted that there may be human rights implications regarding the denial of reproductive technology procedures, including both ART and surrogacy, to samesex and cohabiting couples. However, this has never been tested in the courts. Even if couples conceive through non-natural means, there is the question of what to tell the child. In Hong Kong, children have a right to know if they are conceived through nonnatural means but not to know the identity of the donors or surrogate. Dr Chan said men she has counselled tend to have more issues with donated sperm than women do for donated eggs. Dr Chan would like to see better fertility awareness among young people so they can make informed choices about when and whether to have a baby. “Young people are not very aware of the fertility clock and their own fertility ability. We want to raise their awareness because after 35, their fertility will drop. Media stories of women giving birth in their 40s are a distortion because those will still be high-risk pregnancies,” she said. █ Couples that cannot conceive naturally have other options in Hong Kong, but they can face restrictions in accessing them. HKU scholars have been looking at the psychological and legal issues involved. THE LIMITS OF ARTIFICIAL REPRODUCTION AND SURROGACY 09 | 10 The University of Hong Kong Bulletin | May 2019 Cover Story
Discovering your baby has an incurable inherited disorder can have a lifelong psychological, social and economic impact on families. But new insights into the molecular genetic bases of two such disorders – Hirschsprung disease and dwarfism – hold promise for developing therapies to lessen the impact. Moreover, the findings may have implications for understanding common disorders that affect millions of people globally. BRINGING HOPE FOR CONGENITAL DISORDERS Hirschsprung disease is a congenital affliction in which babies are born with a bowel that lacks nerve cells to control movement along the gut. The only option for treatment is to surgically remove the affected part of the bowel. But about one-third to one-half of these babies will then suffer lifelong residual problems such as enterocolitis (a potentially life-threatening infection of the bowel), chronic constipation, incontinence and, for a small number, the inability to absorb nutrients. Professor Paul Tam Kwong-hang, Li Shu-Pui Professor in Surgery and Chair Professor of Paediatric Surgery, is a world-leading expert on the disease and has received multiple honours for his work, most recently becoming the first Asian recipient of the Rehbein Medal from the European Paediatric Surgeons’ Association. He has studied treatments can be developed. Professor Tam and his colleagues have focussed on genetic studies and stem cell investigations to find answers. Alzheimer’s link Over the past decade, they conducted the first whole-genome genetic screening of Hirschsprung disease and identified a single gene that can cause the disease in 10 per cent of cases. They also unravelled some of the genetic complexities involved in the other 90 per cent of cases. “We have come to realise that it’s not just one gene but a constellation of changes in different genes that can cause this disease, and that the disease will be different in different patients,” said Dr Maria Mercedes Garcia-Barcelo, Associate the disease for more than three decades, motivated by the impact of the disease itself as well as by its prevalence in Asian populations, where it affects one in 3,000 births against the global average of one in 5,000 births. “The problem with Hirschsprung disease and its treatment is that it can affect patients’ future social behaviour, their educational accomplishments and other activities throughout their lives,” he said. “We overlooked these hidden disabilities in the past and the parents were usually just very grateful that we saved the life of their baby. But if you dig deeper, you can see they need more help. Their child’s long-term survival has come at some cost.” In order to improve that situation, better understanding of the disease is needed so better Team members for the research include (back row from left) Dr Li Peng, Dr Elly Ngan, Dr Clara Tang, (front row from left) Professor Paul Tam and Dr Maria Mercedes Garcia-Barcelo. We overlooked these hidden disabilities in the past and the parents were usually just very grateful that we saved the life of their baby. But if you dig deeper, you can see they need more help. Their child’s long-term survival has come at some cost. Professor Paul Tam Kwong-hang 11 | 12 The University of Hong Kong Bulletin | May 2019 Cover Story
sometimes the cells cannot fold properly and instead accumulate inside the cells. This causes a kind of ‘constipation’ that triggers the Integrated Stress Response (ISR), which ultimately ends up affecting the growth plates that control bone formation. This happens because the ISR causes a potent factor called SOX9, which controls the ways cartilage cells differentiate, to activate in the late stages of the bone development process when it should be shut off. As a result, bones do not form properly. Understanding the molecular development of MCDS meant that Professor Cheah and her team could start exploring whether the ISR could be inhibited. They treated pregnant mouse models that reproduced the same MCDS abnormality with a readily-available small molecule known to inhibit the ISR, and found it had a therapeutic effect: the dwarfism was prevented by inhibiting the ISR pathway without other side effects. “To our delight, when the babies were born, their dwarfism was about 95 per cent corrected and their bones were more normal,” she said. Professor of Surgery. “This means that a group of genes that lead to the disorder in patient A are going to be different from the group affecting patient B, and they will have different outcomes. Nonetheless, we know there is usually going to be more than one gene involved.” The team has also showed that mutations can affect the different pathways involved in bowel development. One pathway tells cells to migrate down the spinal cord to the gut, another tells the gut cells to differentiate into neurons, and a third tells these cells to divide and multiply. Last year, they also identified an additional pathway related to cell survival: even if cells reach their destinations and become neurons, they can still die due to an abnormal build-up of protein that suffocates the cell. The genetic basis of this action was discovered by Dr Clara Tang, Research Assistant Professor in the Department of Surgery, who also found it had wider implications beyond Hirschsprung disease. “This is a similar, overlapping mechanism to what we see in Alzheimer’s disease. Interestingly, Alzheimer’s patients can also have intestinal problems that cause constipation,” she said. Stem cell potential The team’s work has pointed to possible options for treatment, particularly with stem cells. If a patient’s own cells can be re-engineered through induced pluripotent stem cell treatment and placed back in the patient, this conceivably could address the genetic defects. However, further research will be needed first. fibrosis in other tissues that involve abnormal synthesis of matrix proteins, the impact of these findings extends beyond congenital dwarfism disorders. “Our work shows why it’s important to do fundamental research and understand the mechanisms of disease because this is how we find potential routes for treatment,” Professor Cheah said. “It’s like fixing a car – if we don’t know how things work, how can we fix them? And if we only did translational research, we could not acquire this basic knowledge and develop our own intellectual property. It can take many years to reach fruition, but basic research has the power to form a good foundation for future translation. The joy of seeing that the MCDS mouse pups were near normal was beyond description!” █ which may result in malformed bones or dwarfism. Current treatment options for dwarfism are extremely limited, but new research at HKU has highlighted a potential new path of therapy for some patients. Chair Professor of Biochemistry and Jimmy and Emily Tang Professor in Molecular Genetics, Kathryn Cheah, and her team have discovered the mechanism behind a genetic mutation that causes a certain kind of dwarfism, Metaphyseal chondrodysplasia, Schmid type (MCDS), which is characterised by short limbs and bowed legs, leading to a waddling gait and joint pain. Through this understanding, it may be possible in future to develop effective treatments for dwarfism caused by similar mechanisms. “Underlying all studies trying to develop drugs for diseases is the fact that you need to know the fundamental mechanism – why a genetic alteration results in that phenotype. Although just one gene is altered, it probably has a ripple effect, so that at the end of the day what you see in the patient is the sum total of all the changes that resulted from that first initiating event,” she said. With MCDS, the body produces an abnormal form of collagen X, which results in the dwarfism. Professor Cheah’s team showed how this happened. Integrated Stress Response Collagen X needs to fold so it can be transported to the matrix outside cartilage cells, where it normally would provide structural support. But This offers a potential new pathway for future drug development for human patients who would benefit significantly from even some amelioration of dwarfism. A patent has been filed for the treatment, although this will need more refinement and research before it can be applied in humans. Little people need help Nonetheless, after eight years of genetic investigations and deep mechanistic studies using mouse models, there may be hope of treating congenital dwarfism associated with the stress response such as that seen in MCDS. “For people who are dwarfs, being able to grow an extra inch or two will be incredibly important for them. Little people are teased by other children and in MCDS patients, because their bones are not formed properly, they also have pain from abnormal weight-bearing on their joints,” Professor Cheah said. Moreover, because activation of the ISR is the hallmark of many common diseases, such as osteoarthritis, spinal disc degeneration and The genetic studies of Hirschsprung disease are also uncovering other disease susceptibilities in patients with the disease, which could improve their outcomes from those diseases. For instance, the researchers found that a tiny percentage of Hirschsprung patients carry another genetic defect that makes them more susceptible to thyroid cancer. Already, they have identified an early-stage tumour in a patient who otherwise had no symptoms. More genetic information will enable more such links to be found and enable researchers to identify targets for treatment. The team already has whole genome sequences of hundreds of Hirschsprung patients, which have been developed through collaborations with overseas scholars and hospitals in Hong Kong, Mainland China and Vietnam, and they are continuing to add to that pool. “The lessons we learn from this rare disease can apply to the study of other diseases. Studying rare diseases can provide shortcuts for investigating other more common problems. It is a win-win situation,” Professor Tam said. A potential therapy for dwarfism Our skeletons provide the essential structural framework to support and protect our bodies from the repeated impact of walking, running and bearing weight. But skeletal disorders are the most frequent causes of severe long-term pain and physical disability. Apart from acquired disorders such as osteoporosis, there are more than 400 types of congenital disorders, many of Our work shows why it’s important to do fundamental research and understand the mechanisms of disease because this is how we find potential routes for treatment. Professor Kathryn Cheah An HKU-led international team of scientists – (from left) Professor Danny Chan, Dr Maggie Wang, Professor Kathryn Cheah and Dr Tommy Tan – has uncovered why cellular stress can cause dwarfism and provided a therapeutic lead that can be exploited to develop drugs to treat such bone disorders. 13 | 14 The University of Hong Kong Bulletin | May 2019 Cover Story
Ten years ago, it took a month to map the genome of a person using a huge computational server. Now this can be done in less than a day with a desktop computer, thanks to up-and-coming scientist Dr Luo Ruibang, who has also led the way in applying big data and artificial intelligence to genetic analysis. DATA WIZARD ADVANCES PRECISION MEDICINE algorithm are pathogenic. This requires comparing a patient’s mutations with multiple databases that do not completely agree with each other. Previously, doctors had to cut and paste their patient’s mutations into a search window for each database and write or type out the results manually for comparison, a process that took five hours per patient and was typically limited to about 10 databases. Dr Luo and his team vastly improved the process. After working with doctors for two years to understand how they used the databases, Dr Luo developed a platform that can search 31 databases within one hour – two hours in a worst-case scenario. Most importantly, it includes sophisticated rules for deciding when there is a conflict in the results from the search and how to present this to doctors. The platform was developed into a highlysuccessful start-up, L3 Bioinformatics Ltd, that was launched in 2014 with support from the Hong Kong Government, angel investor Beijing Already, he has applied machine learning to reduce the number of errors in reads, which is especially problematic for smaller DNA readers. “I’m the first to directly pull out the useful mutation signals from the noise in singlemolecule sequencing [also known as thirdgeneration sequencing],” he said. This opens the possibility of doctors being able to pipe a patient’s DNA sample into a USB-sized device and get results within a couple of hours. This discovery has also been found to be efficient at detecting pathogens, such as viruses, and he is working with Johns Hopkins University to develop that avenue further. Dr Luo is keen to do more technology transfer and stay at the frontier of science. He hopes more young people will join him. “I was not a typical top-student but after all these years, I find teaching students is fun, especially about cutting-edge technologies that they can’t find in textbooks. Hong Kong lacks experts in precision medicine and bioinformatics so one of my ambitions is to raise some good experts in this field for Hong Kong and globally.” █ Genomics Institute and HKU’s Technology Transfer Office, and has generated more than HK$60 million in revenue. The platform has been used to diagnose more than 5,000 cancers and rare diseases at the Hong Kong Sanatorium Hospital and Hong Kong’s Department of Health, as well as thousands more cases in Mainland China. Dr Luo worked with L3 Bioinformatics for two years but returned to academia in 2016 because there were still important research questions to tackle – particularly, how to improve the matching rate of DNA mutations to databases. No technology has achieved a better actionable rate than 30 per cent which means no diagnostic or therapeutic match can be found for genetic mutations in 70 per cent of cases. Pulling signals from the noise “There is still a lack of knowledge about human genomics – we are dealing with three billion characters. I hope to boost the matching rate to 40 or 50 per cent in future, leveraging artificial intelligence,” he said. Precision medicine is the new goal in medicine, as doctors seek to harness genetic information to provide patients with more effective diagnoses and treatments. But a key stumbling block has been the enormous quantity of this information. Each person’s chromosomes contain more than three billion characters. Until the work of Dr Luo Ruibang, sifting through that information was a laborious process. Dr Luo developed a new algorithm that greatly speeds up the process by quickly matching groups of characters called ‘reads’ to their chromosomes, so doctors and scientists can more readily detect mutations. Whereas previously it took one month to do this using a large powerful computer, at a cost of about HK$100,000, Dr Luo’s algorithm was able to reduce the time to less than a day using a laptop. The algorithm was developed with his former teacher and the current head of Computer Science at HKU, Professor Lam Tak-wah, in 2009 when Dr Luo was only 20 years old. It is now a global standard for genome alignment, having been downloaded more than 300,000 times. “It was not rocket science but there was a ‘eureka’ moment,” he said. “We were able to lower the complexity of the previous algorithm to reduce the time it takes to align the reads back to the chromosomes. That’s important for patients because they are awaiting their results.” The discovery was a first step in a career that, to date, has seen Dr Luo named by MIT Technology Review as one of the top 10 innovators in Asia Pacific in 2019, and by Forbes as one of the top ‘30 Under 30’ in Asia in 2017 in healthcare and science. Platform launches a start-up The next step was to apply big data analytics to provide better and faster interpretations of whether the genetic mutations detected by his There is still a lack of knowledge about human genomics – we are dealing with three billion characters. I hope to boost the matching rate to 40 or 50 per cent in future, leveraging artificial intelligence. Dr Luo Ruibang The miniaturised MinION® single molecule sequencing device used in the paper for reading out DNA. The deep neural network architecture published in the paper named ‘Clairvoyante’ for extracting weak variant signals from very noisy single molecule sequencing data. Dr Luo uses sequencing technologies to shorten the time required for cancer and rare disease diagnosis. Research 15 | 16 The University of Hong Kong Bulletin | May 2019
The maxim, you are what you eat, could very well apply to the history of soy sauce. Although soy sauce is ubiquitous across East Asia, it has taken hold in each region in different ways that are revealing about cultural and political currents. A SAUCY TAKE ON HISTORY empire – before then it was not a common item in the diet of southern Chinese. Even then, its popularity was concentrated in major urban centres. “Most peasants rarely had a taste of it,” Professor Leung said. Industrialisation was introduced to soy sauce making in the late 19th century, spearheaded by Japan. The country was keen to be seen as an equal to Western powers and brought in chemical fermentation and mass production methods. “Industrial meant modern, it meant it was better than handmade,” Dr Nakayama said. The Japanese also took their soy sauce to the places they colonised and invaded in the first half of the 20th century. In Taiwan, soybeans were under the control of the Japanese Government and commercial soy sauce was mostly made from yellow soybeans instead tradition? Do we really need to rely on chemical products? In Taiwan and Japan, we can see people not imagining modernity anymore, but imagining tradition,” Professor Leung said. Selling a new idea of tradition In Taiwan, soy sauce makers have returned to the traditional black beans and kept their business as smaller, family-run affairs – they are not very interested in reaching out to other markets. “We worry about their sustainability because their products are relatively expensive and they produce relatively few bottles. It’s quite different from Japan, where they are more enterprising,” Professor Leung said. In Japan, the scholars found producers who used traditional materials such as wooden barrels, albeit with modern hygiene standards (traditional fermentation is dirty and smelly), to produce luxury soy sauce. These entrepreneurs are selling a new idea of tradition that includes different varieties of soy sauce and even soy sauce sommeliers. Hong Kong and China, though, are still in the modernity loop. “The companies I interviewed don’t talk about preserving tradition, they talk about market share and the technological advances they’ve developed,” Professor Leung said. The scholars have also started looking at soy sauce in Vietnam and Korea and digging deeper into the story of soy sauce in China, to provide a fuller picture of the condiment’s place in East Asia. “Tradition is a moving target. What we think of as traditional in 2019 is very different from what traditional meant in 1905. Yet we have this constant process of re-imagining what soy sauce is supposed to be that’s a reflection of not just our times, but our social and cultural values,” Dr Nakayama said. █ of the black beans traditionally used by native Chinese. Conglomerates like Kikkoman followed the army or even led the way as they searched for new markets. China was not immune to this influence. Manufacturers started following the Japanese model and introduced chemical fermentation. However, the Chinese product could not compete with the Japanese industrial products in terms of price and quality. “Chinese manufacturers did not work together like the Japanese – China was very far behind,” Professor Leung said. In recent decades, the focus on modernisation and chemical processes has shifted. Consumers want products made without chemicals – organic, additive-free, handcrafted, gluten-free, low-sodium and so on. “It’s the beginning of the post-industrial story. People ask, what is Soy sauce is widely seen as a traditional part of East Asian cuisine. But research by Professor Angela Ki Che Leung, Joseph Needham – Philip Mao Professor in Chinese History, Science and Civilization and Chair Professor of History, and Dr Izumi Nakayama of the Hong Kong Institute for the Humanities and Social Sciences is finding that the condiment illustrates the region’s response to modernity. In the 19th and 20th centuries, soy sauce was transformed by industrialisation and colonisation into a dining table staple across the region and even globally. More recently, it has been caught up in the fashion for artisanal products, with handmade, luxury brands for sale. “Our research is part of a larger project looking at how technology is not autonomous but embedded in specific social, economic and political set-ups, and how it is used in East Asian societies to imagine and desire modernity. Soy sauce is a very good example,” Professor Leung said. The origins of soy sauce are murky but there is consensus that it originated in China, where it was considered to have medicinal properties, and was brought to Japan in about the 12th century. Japan was a trailblazer in expanding consumption, although this took a few hundred years. Conglomerates were organised in which families worked together to produce the ingredients and undertake different aspects of the manufacturing, such as fermenting soybeans to make the koji that is the base of the sause. Noda city north of Tokyo was one such centre, where the brand Kikkoman has roots going back to the 17th century. From modern to postmodern In China, soy sauce was more confined to the literati class who produced it at home. It did not become a popular condiment until the mid-18th century when Manchuria, the main source of soybeans, was fully integrated into the Chinese Soy sauce makers in Japan use traditional materials such as wooden barrels, albeit with modern hygiene, to produce luxury soy sauce. Our research is part of a larger project looking at how technology is not autonomous but embedded in specific social, economic and political set-ups, and how it is used in East Asian societies to imagine and desire modernity. Soy sauce is a very good example. Professor Angela Ki Che Leung Professor Leung’s visit to soy sauce makers in Taiwan. Research 17 | 18 The University of Hong Kong Bulletin | May 2019
A high-speed train was one of the inspirations behind the NJ Toothbrush, a new concept in brushing which targets all dental surfaces and niches, and enables users to brush more effectively. Fast track to healthy teeth “We may call gum disease a ‘silent disease’, and many patients wait too long,” he said. “Periodontitis has actually been associated with major life-threatening afflictions such as diabetes, heart disease and some forms of cancer, and most recently Porphyromonas gingivalis – the major pathogenic bacteria of periodontitis, has been found to be directly involved in Alzheimer’s disease/dementia.” Professor Jin and Dr Ng first met a couple of years ago, and started discussing the problem of low public awareness of oral health, oral hygiene challenges and potential ways to improve how people brush their teeth. “TC has a very inventive mind,” commented Professor Jin. “He did work with NASA and the European Space Agency some years ago, notably inventing the ‘cosmic’ drill that dug into the surface of Mars and collected the samples from the red planet in 2003 through the Beagle 2 lander.” The pair looked at the limitations of conventional toothbrushes, as well as at the physiognomy of the mouth and different sizes of front and back teeth. Targeting ’dead corners’ What they came up with is a novel product specifically designed to target all dental surfaces and niches, in particular the interdental, retromolar and sub-gumline niches, the so-called ‘dead corners’ where current toothbrushes may not reach effectively. They developed it using precise computermapping of six types of purpose-built bristlebundles that reach all dental-gingival surfaces and niches, with the aim of maximising control of plaque biofilms and thereby reducing the likelihood of oral inflammation. “Inspired by the high-speed train, the NJ Toothbrush literally stays on track,” said Professor Jin. “It follows the curving line of the teeth and couples precisely over the upper to lay people so we are very happy with this achievement. The patent was granted quickly as there is nothing similar on the global market. The TTO has already had meetings with potential developers, and we hope the NJ Toothbrush will be available on the market in 18 months or so.” In the future, it will also be possible to customise the NJ Toothbrush to individual needs. “You will be able to have a toothbrush tailor-made to fit your mouth precisely,” said Professor Jin, “thereby improving your teeth cleaning ability for better oral health and general health.” █ and lower dental arches. The tracking does the work for you – it guides the toothbrush and the hinged head means you don’t even have to turn the brush round to reach the other side of your mouth. “Another featured function is ‘automatic coupling’, whereby the head expands and contracts so that it always fits snugly round the tooth, whether a fat molar or thin incisor.” HKU’s Technology Transfer Office (TTO) gave the two inventors seed funding and encouragement, and has secured the patent for this new product. Professor Jin said: “HKU has many patents every year, but relatively few will go directly The Global Burden of Disease (GBD) study (1990–2010), the largest and most systemic worldwide health study which keeps track of 291 diseases across the globe, includes in its top 10 most prevalent afflictions the two most common oral diseases. “Number One on the GBD study is Untreated Decay in Adults; Number Six is Severe Gum Disease (severe periodontitis) and Number 10 is Untreated Decay in Children,” said Professor Jin Lijian, Modern Dental Laboratory Professor in Clinical Dental Science and Professor in Periodontology at the HKU Faculty of Dentistry. “Oral diseases cause a great deal of suffering, and have huge socioeconomic impacts worldwide in terms not only of money spent treating and researching them, but also in school and work hours lost,” he continued, citing too a survey of 27 European Union countries showing that 79 billion euros was spent on treating oral problems on annual average from 2008 to 2012, a figure predicted to reach 93 billion euros by next year. Further, the GBD study 2010 indicates that over half the world’s population (3.9 billion) has been affected by common oral diseases including decay, severe gum disease and tooth loss. There is much discomfort, suffering and money spent, and these were the factors which inspired Professor Jin, together with Dr TC Ng, a local dentist and pioneering designer of precision tools for space exploration, to invent the NJ Toothbrush, named using the initials of both their last names. Their toothbrush was awarded a Gold Medal at the 47th International Exhibition of Inventions of Geneva in April this year. “For oral health, proactive prevention is the key,” said Professor Jin. “One of the reasons these oral diseases are so prevalent is often lower awareness of oral health and lack of knowledge about basic oral health care. Other reasons may include fear of going to see the dentist and the common attitude problem that says, ‘I won’t seek help until I’m actually in pain.’ In Hong Kong, there is often a saying ‘mou tung, mou beng’, meaning ‘no pain, no disease’.” Hence, people frequently ignore decay, until it really hurts. Gum disease often creeps up unnoticed, as it can develop and progress without any warning pain. Inspired by the high-speed train, the NJ Toothbrush literally stays on track. It follows the curving line of the teeth and couples precisely over the upper and lower dental arches. Professor Jin Lijian Dr TC Ng (left) and Professor Jin Lijian (right) showcasing the NJ Toothbrush at the InnoCarnival 2018. HKU dental professionals have invented the ‘NJ Toothbrush’ – a revolutionary new concept in toothbrushing. Research 19 | 20 The University of Hong Kong Bulletin | May 2019
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